Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent
Identifieur interne : 002901 ( Pmc/Corpus ); précédent : 002900; suivant : 002902Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent
Auteurs : Yan Guo ; Shaneda Warren Andersen ; Xiao-Ou Shu ; Kyriaki Michailidou ; Manjeet K. Bolla ; Qin Wang ; Montserrat Garcia-Closas ; Roger L. Milne ; Marjanka K. Schmidt ; Jenny Chang-Claude ; Allison Dunning ; Stig E. Bojesen ; Habibul Ahsan ; Kristiina Aittom Ki ; Irene L. Andrulis ; Hoda Anton-Culver ; Volker Arndt ; Matthias W. Beckmann ; Alicia Beeghly-Fadiel ; Javier Benitez ; Natalia V. Bogdanova ; Bernardo Bonanni ; Anne-Lise B Rresen-Dale ; Judith Brand ; Hiltrud Brauch ; Hermann Brenner ; Thomas Brüning ; Barbara Burwinkel ; Graham Casey ; Georgia Chenevix-Trench ; Fergus J. Couch ; Angela Cox ; Simon S. Cross ; Kamila Czene ; Peter Devilee ; Thilo Dörk ; Martine Dumont ; Peter A. Fasching ; Jonine Figueroa ; Dieter Flesch-Janys ; Olivia Fletcher ; Henrik Flyger ; Florentia Fostira ; Marilie Gammon ; Graham G. Giles ; Pascal Guénel ; Christopher A. Haiman ; Ute Hamann ; Maartje J. Hooning ; John L. Hopper ; Anna Jakubowska ; Farzana Jasmine ; Mark Jenkins ; Esther M. John ; Nichola Johnson ; Michael E. Jones ; Maria Kabisch ; Muhammad Kibriya ; Julia A. Knight ; Linetta B. Koppert ; Veli-Matti Kosma ; Vessela Kristensen ; Loic Le Marchand ; Eunjung Lee ; Jingmei Li ; Annika Lindblom ; Robert Luben ; Jan Lubinski ; Kathi E. Malone ; Arto Mannermaa ; Sara Margolin ; Frederik Marme ; Catriona Mclean ; Hanne Meijers-Heijboer ; Alfons Meindl ; Susan L. Neuhausen ; Heli Nevanlinna ; Patrick Neven ; Janet E. Olson ; Jose I. A. Perez ; Barbara Perkins ; Paolo Peterlongo ; Kelly-Anne Phillips ; Katri Pylk S ; Anja Rudolph ; Regina Santella ; Elinor J. Sawyer ; Rita K. Schmutzler ; Caroline Seynaeve ; Mitul Shah ; Martha J. Shrubsole ; Melissa C. Southey ; Anthony J. Swerdlow ; Amanda E. Toland ; Ian Tomlinson ; Diana Torres ; Thérèse Truong ; Giske Ursin ; Rob B. Van Der Luijt ; Senno Verhoef ; Alice S. Whittemore ; Robert Winqvist ; Hui Zhao ; Shilin Zhao ; Per Hall ; Jacques Simard ; Peter Kraft ; Paul Pharoah ; David Hunter ; Douglas F. Easton ; Wei ZhengSource :
- PLoS Medicine [ 1549-1277 ] ; 2016.
Abstract
Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.
We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases = 46,325, controls = 42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively.
In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR] = 0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56–0.75,
BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.
Url:
DOI: 10.1371/journal.pmed.1002105
PubMed: 27551723
PubMed Central: 4995025
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PMC:4995025Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent</title><author><name sortKey="Guo, Yan" sort="Guo, Yan" uniqKey="Guo Y" first="Yan" last="Guo">Yan Guo</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Warren Andersen, Shaneda" sort="Warren Andersen, Shaneda" uniqKey="Warren Andersen S" first="Shaneda" last="Warren Andersen">Shaneda Warren Andersen</name><affiliation><nlm:aff id="aff002"><addr-line>Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Shu, Xiao Ou" sort="Shu, Xiao Ou" uniqKey="Shu X" first="Xiao-Ou" last="Shu">Xiao-Ou Shu</name><affiliation><nlm:aff id="aff002"><addr-line>Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Michailidou, Kyriaki" sort="Michailidou, Kyriaki" uniqKey="Michailidou K" first="Kyriaki" last="Michailidou">Kyriaki Michailidou</name><affiliation><nlm:aff id="aff003"><addr-line>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bolla, Manjeet K" sort="Bolla, Manjeet K" uniqKey="Bolla M" first="Manjeet K." last="Bolla">Manjeet K. Bolla</name><affiliation><nlm:aff id="aff003"><addr-line>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Wang, Qin" sort="Wang, Qin" uniqKey="Wang Q" first="Qin" last="Wang">Qin Wang</name><affiliation><nlm:aff id="aff003"><addr-line>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Garcia Closas, Montserrat" sort="Garcia Closas, Montserrat" uniqKey="Garcia Closas M" first="Montserrat" last="Garcia-Closas">Montserrat Garcia-Closas</name><affiliation><nlm:aff id="aff004"><addr-line>Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff005"><addr-line>Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Milne, Roger L" sort="Milne, Roger L" uniqKey="Milne R" first="Roger L." last="Milne">Roger L. Milne</name><affiliation><nlm:aff id="aff006"><addr-line>Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff007"><addr-line>Centre for Epidemiology and Biostatistics, School of Population and Global health, The University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Schmidt, Marjanka K" sort="Schmidt, Marjanka K" uniqKey="Schmidt M" first="Marjanka K." last="Schmidt">Marjanka K. Schmidt</name><affiliation><nlm:aff id="aff008"><addr-line>Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chang Claude, Jenny" sort="Chang Claude, Jenny" uniqKey="Chang Claude J" first="Jenny" last="Chang-Claude">Jenny Chang-Claude</name><affiliation><nlm:aff id="aff009"><addr-line>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff010"><addr-line>Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dunning, Allison" sort="Dunning, Allison" uniqKey="Dunning A" first="Allison" last="Dunning">Allison Dunning</name><affiliation><nlm:aff id="aff011"><addr-line>Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bojesen, Stig E" sort="Bojesen, Stig E" uniqKey="Bojesen S" first="Stig E." last="Bojesen">Stig E. Bojesen</name><affiliation><nlm:aff id="aff012"><addr-line>Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff013"><addr-line>Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff014"><addr-line>Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ahsan, Habibul" sort="Ahsan, Habibul" uniqKey="Ahsan H" first="Habibul" last="Ahsan">Habibul Ahsan</name><affiliation><nlm:aff id="aff015"><addr-line>Department of Health Studies, The University of Chicago, Chicago, Illinois, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Aittom Ki, Kristiina" sort="Aittom Ki, Kristiina" uniqKey="Aittom Ki K" first="Kristiina" last="Aittom Ki">Kristiina Aittom Ki</name><affiliation><nlm:aff id="aff016"><addr-line>Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Andrulis, Irene L" sort="Andrulis, Irene L" uniqKey="Andrulis I" first="Irene L." last="Andrulis">Irene L. Andrulis</name><affiliation><nlm:aff id="aff017"><addr-line>Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff018"><addr-line>Department of Molecular Genetics, University of Toronto, Toronto, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Anton Culver, Hoda" sort="Anton Culver, Hoda" uniqKey="Anton Culver H" first="Hoda" last="Anton-Culver">Hoda Anton-Culver</name><affiliation><nlm:aff id="aff019"><addr-line>Department of Epidemiology, University of California Irvine, Irvine, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Arndt, Volker" sort="Arndt, Volker" uniqKey="Arndt V" first="Volker" last="Arndt">Volker Arndt</name><affiliation><nlm:aff id="aff020"><addr-line>Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Beckmann, Matthias W" sort="Beckmann, Matthias W" uniqKey="Beckmann M" first="Matthias W." last="Beckmann">Matthias W. Beckmann</name><affiliation><nlm:aff id="aff015"><addr-line>Department of Health Studies, The University of Chicago, Chicago, Illinois, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Beeghly Fadiel, Alicia" sort="Beeghly Fadiel, Alicia" uniqKey="Beeghly Fadiel A" first="Alicia" last="Beeghly-Fadiel">Alicia Beeghly-Fadiel</name><affiliation><nlm:aff id="aff002"><addr-line>Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Benitez, Javier" sort="Benitez, Javier" uniqKey="Benitez J" first="Javier" last="Benitez">Javier Benitez</name><affiliation><nlm:aff id="aff021"><addr-line>Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff022"><addr-line>Centro de Investigación en Red de Enfermedades Raras, Valencia, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bogdanova, Natalia V" sort="Bogdanova, Natalia V" uniqKey="Bogdanova N" first="Natalia V." last="Bogdanova">Natalia V. Bogdanova</name><affiliation><nlm:aff id="aff023"><addr-line>Department of Radiation Oncology, Hannover Medical School, Hannover, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bonanni, Bernardo" sort="Bonanni, Bernardo" uniqKey="Bonanni B" first="Bernardo" last="Bonanni">Bernardo Bonanni</name><affiliation><nlm:aff id="aff024"><addr-line>Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="B Rresen Dale, Anne Lise" sort="B Rresen Dale, Anne Lise" uniqKey="B Rresen Dale A" first="Anne-Lise" last="B Rresen-Dale">Anne-Lise B Rresen-Dale</name><affiliation><nlm:aff id="aff025"><addr-line>Department of Genetics, Institute for Cancer Research, Radiumhospitalet, Oslo University Hospital, Oslo University Hospital, Oslo, Norway</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff026"><addr-line>Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway</addr-line></nlm:aff></affiliation></author><author><name sortKey="Brand, Judith" sort="Brand, Judith" uniqKey="Brand J" first="Judith" last="Brand">Judith Brand</name><affiliation><nlm:aff id="aff027"><addr-line>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Brauch, Hiltrud" sort="Brauch, Hiltrud" uniqKey="Brauch H" first="Hiltrud" last="Brauch">Hiltrud Brauch</name><affiliation><nlm:aff id="aff028"><addr-line>German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff029"><addr-line>Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff030"><addr-line>University of Tübingen, Tübingen, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Brenner, Hermann" sort="Brenner, Hermann" uniqKey="Brenner H" first="Hermann" last="Brenner">Hermann Brenner</name><affiliation><nlm:aff id="aff020"><addr-line>Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff028"><addr-line>German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff031"><addr-line>Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bruning, Thomas" sort="Bruning, Thomas" uniqKey="Bruning T" first="Thomas" last="Brüning">Thomas Brüning</name><affiliation><nlm:aff id="aff032"><addr-line>Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum, Bochum, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Burwinkel, Barbara" sort="Burwinkel, Barbara" uniqKey="Burwinkel B" first="Barbara" last="Burwinkel">Barbara Burwinkel</name><affiliation><nlm:aff id="aff033"><addr-line>Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff034"><addr-line>Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Casey, Graham" sort="Casey, Graham" uniqKey="Casey G" first="Graham" last="Casey">Graham Casey</name><affiliation><nlm:aff id="aff035"><addr-line>Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chenevix Trench, Georgia" sort="Chenevix Trench, Georgia" uniqKey="Chenevix Trench G" first="Georgia" last="Chenevix-Trench">Georgia Chenevix-Trench</name><affiliation><nlm:aff id="aff036"><addr-line>Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Couch, Fergus J" sort="Couch, Fergus J" uniqKey="Couch F" first="Fergus J." last="Couch">Fergus J. Couch</name><affiliation><nlm:aff id="aff037"><addr-line>Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cox, Angela" sort="Cox, Angela" uniqKey="Cox A" first="Angela" last="Cox">Angela Cox</name><affiliation><nlm:aff id="aff038"><addr-line>Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cross, Simon S" sort="Cross, Simon S" uniqKey="Cross S" first="Simon S." last="Cross">Simon S. Cross</name><affiliation><nlm:aff id="aff011"><addr-line>Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Czene, Kamila" sort="Czene, Kamila" uniqKey="Czene K" first="Kamila" last="Czene">Kamila Czene</name><affiliation><nlm:aff id="aff027"><addr-line>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Devilee, Peter" sort="Devilee, Peter" uniqKey="Devilee P" first="Peter" last="Devilee">Peter Devilee</name><affiliation><nlm:aff id="aff039"><addr-line>Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dork, Thilo" sort="Dork, Thilo" uniqKey="Dork T" first="Thilo" last="Dörk">Thilo Dörk</name><affiliation><nlm:aff id="aff040"><addr-line>Gynaecology Research Unit, Hannover Medical School, Hannover, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dumont, Martine" sort="Dumont, Martine" uniqKey="Dumont M" first="Martine" last="Dumont">Martine Dumont</name><affiliation><nlm:aff id="aff041"><addr-line>Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Fasching, Peter A" sort="Fasching, Peter A" uniqKey="Fasching P" first="Peter A." last="Fasching">Peter A. Fasching</name><affiliation><nlm:aff id="aff042"><addr-line>Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff043"><addr-line>David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Figueroa, Jonine" sort="Figueroa, Jonine" uniqKey="Figueroa J" first="Jonine" last="Figueroa">Jonine Figueroa</name><affiliation><nlm:aff id="aff044"><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Flesch Janys, Dieter" sort="Flesch Janys, Dieter" uniqKey="Flesch Janys D" first="Dieter" last="Flesch-Janys">Dieter Flesch-Janys</name><affiliation><nlm:aff id="aff045"><addr-line>Institute for Medical Biometrics and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff046"><addr-line>Department of Cancer Epidemiology, Clinical Cancer Registry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Fletcher, Olivia" sort="Fletcher, Olivia" uniqKey="Fletcher O" first="Olivia" last="Fletcher">Olivia Fletcher</name><affiliation><nlm:aff id="aff005"><addr-line>Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Flyger, Henrik" sort="Flyger, Henrik" uniqKey="Flyger H" first="Henrik" last="Flyger">Henrik Flyger</name><affiliation><nlm:aff id="aff047"><addr-line>Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Fostira, Florentia" sort="Fostira, Florentia" uniqKey="Fostira F" first="Florentia" last="Fostira">Florentia Fostira</name><affiliation><nlm:aff id="aff048"><addr-line>Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research "Demokritos", Athens, Greece</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gammon, Marilie" sort="Gammon, Marilie" uniqKey="Gammon M" first="Marilie" last="Gammon">Marilie Gammon</name><affiliation><nlm:aff id="aff049"><addr-line>Departments of Epidemiology, University of North Carolina Chapel-Hill, Chapel Hill, North Carolina, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Giles, Graham G" sort="Giles, Graham G" uniqKey="Giles G" first="Graham G." last="Giles">Graham G. Giles</name><affiliation><nlm:aff id="aff006"><addr-line>Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff007"><addr-line>Centre for Epidemiology and Biostatistics, School of Population and Global health, The University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Guenel, Pascal" sort="Guenel, Pascal" uniqKey="Guenel P" first="Pascal" last="Guénel">Pascal Guénel</name><affiliation><nlm:aff id="aff050"><addr-line>Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, Villejuif, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff051"><addr-line>University Paris-Sud, Villejuif, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Haiman, Christopher A" sort="Haiman, Christopher A" uniqKey="Haiman C" first="Christopher A." last="Haiman">Christopher A. Haiman</name><affiliation><nlm:aff id="aff035"><addr-line>Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hamann, Ute" sort="Hamann, Ute" uniqKey="Hamann U" first="Ute" last="Hamann">Ute Hamann</name><affiliation><nlm:aff id="aff052"><addr-line>Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hooning, Maartje J" sort="Hooning, Maartje J" uniqKey="Hooning M" first="Maartje J." last="Hooning">Maartje J. Hooning</name><affiliation><nlm:aff id="aff053"><addr-line>Department of Surgical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hopper, John L" sort="Hopper, John L" uniqKey="Hopper J" first="John L." last="Hopper">John L. Hopper</name><affiliation><nlm:aff id="aff007"><addr-line>Centre for Epidemiology and Biostatistics, School of Population and Global health, The University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Jakubowska, Anna" sort="Jakubowska, Anna" uniqKey="Jakubowska A" first="Anna" last="Jakubowska">Anna Jakubowska</name><affiliation><nlm:aff id="aff054"><addr-line>Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Jasmine, Farzana" sort="Jasmine, Farzana" uniqKey="Jasmine F" first="Farzana" last="Jasmine">Farzana Jasmine</name><affiliation><nlm:aff id="aff015"><addr-line>Department of Health Studies, The University of Chicago, Chicago, Illinois, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Jenkins, Mark" sort="Jenkins, Mark" uniqKey="Jenkins M" first="Mark" last="Jenkins">Mark Jenkins</name><affiliation><nlm:aff id="aff007"><addr-line>Centre for Epidemiology and Biostatistics, School of Population and Global health, The University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="John, Esther M" sort="John, Esther M" uniqKey="John E" first="Esther M." last="John">Esther M. John</name><affiliation><nlm:aff id="aff055"><addr-line>Department of Epidemiology, Cancer Prevention Institute of California, Fremont, California, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff056"><addr-line>Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Johnson, Nichola" sort="Johnson, Nichola" uniqKey="Johnson N" first="Nichola" last="Johnson">Nichola Johnson</name><affiliation><nlm:aff id="aff005"><addr-line>Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Jones, Michael E" sort="Jones, Michael E" uniqKey="Jones M" first="Michael E." last="Jones">Michael E. Jones</name><affiliation><nlm:aff id="aff004"><addr-line>Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kabisch, Maria" sort="Kabisch, Maria" uniqKey="Kabisch M" first="Maria" last="Kabisch">Maria Kabisch</name><affiliation><nlm:aff id="aff052"><addr-line>Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kibriya, Muhammad" sort="Kibriya, Muhammad" uniqKey="Kibriya M" first="Muhammad" last="Kibriya">Muhammad Kibriya</name><affiliation><nlm:aff id="aff015"><addr-line>Department of Health Studies, The University of Chicago, Chicago, Illinois, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Knight, Julia A" sort="Knight, Julia A" uniqKey="Knight J" first="Julia A." last="Knight">Julia A. Knight</name><affiliation><nlm:aff id="aff057"><addr-line>Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff058"><addr-line>Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Koppert, Linetta B" sort="Koppert, Linetta B" uniqKey="Koppert L" first="Linetta B." last="Koppert">Linetta B. Koppert</name><affiliation><nlm:aff id="aff053"><addr-line>Department of Surgical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kosma, Veli Matti" sort="Kosma, Veli Matti" uniqKey="Kosma V" first="Veli-Matti" last="Kosma">Veli-Matti Kosma</name><affiliation><nlm:aff id="aff059"><addr-line>Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff060"><addr-line>Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff061"><addr-line>Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kristensen, Vessela" sort="Kristensen, Vessela" uniqKey="Kristensen V" first="Vessela" last="Kristensen">Vessela Kristensen</name><affiliation><nlm:aff id="aff025"><addr-line>Department of Genetics, Institute for Cancer Research, Radiumhospitalet, Oslo University Hospital, Oslo University Hospital, Oslo, Norway</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff026"><addr-line>Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff062"><addr-line>Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway</addr-line></nlm:aff></affiliation></author><author><name sortKey="Le Marchand, Loic" sort="Le Marchand, Loic" uniqKey="Le Marchand L" first="Loic" last="Le Marchand">Loic Le Marchand</name><affiliation><nlm:aff id="aff063"><addr-line>University of Hawaii Cancer Center, Honolulu, Hawaii, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lee, Eunjung" sort="Lee, Eunjung" uniqKey="Lee E" first="Eunjung" last="Lee">Eunjung Lee</name><affiliation><nlm:aff id="aff035"><addr-line>Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Li, Jingmei" sort="Li, Jingmei" uniqKey="Li J" first="Jingmei" last="Li">Jingmei Li</name><affiliation><nlm:aff id="aff027"><addr-line>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lindblom, Annika" sort="Lindblom, Annika" uniqKey="Lindblom A" first="Annika" last="Lindblom">Annika Lindblom</name><affiliation><nlm:aff id="aff064"><addr-line>Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Luben, Robert" sort="Luben, Robert" uniqKey="Luben R" first="Robert" last="Luben">Robert Luben</name><affiliation><nlm:aff id="aff065"><addr-line>Clinical Gerontology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lubinski, Jan" sort="Lubinski, Jan" uniqKey="Lubinski J" first="Jan" last="Lubinski">Jan Lubinski</name><affiliation><nlm:aff id="aff054"><addr-line>Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Malone, Kathi E" sort="Malone, Kathi E" uniqKey="Malone K" first="Kathi E." last="Malone">Kathi E. Malone</name><affiliation><nlm:aff id="aff066"><addr-line>Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mannermaa, Arto" sort="Mannermaa, Arto" uniqKey="Mannermaa A" first="Arto" last="Mannermaa">Arto Mannermaa</name><affiliation><nlm:aff id="aff059"><addr-line>Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff060"><addr-line>Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff061"><addr-line>Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Margolin, Sara" sort="Margolin, Sara" uniqKey="Margolin S" first="Sara" last="Margolin">Sara Margolin</name><affiliation><nlm:aff id="aff067"><addr-line>Department of Oncology – Pathology, Karolinska Institutet, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Marme, Frederik" sort="Marme, Frederik" uniqKey="Marme F" first="Frederik" last="Marme">Frederik Marme</name><affiliation><nlm:aff id="aff068"><addr-line>National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff069"><addr-line>Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mclean, Catriona" sort="Mclean, Catriona" uniqKey="Mclean C" first="Catriona" last="Mclean">Catriona Mclean</name><affiliation><nlm:aff id="aff070"><addr-line>Anatomical Pathology, The Alfred Hospital, Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Meijers Heijboer, Hanne" sort="Meijers Heijboer, Hanne" uniqKey="Meijers Heijboer H" first="Hanne" last="Meijers-Heijboer">Hanne Meijers-Heijboer</name><affiliation><nlm:aff id="aff071"><addr-line>Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Meindl, Alfons" sort="Meindl, Alfons" uniqKey="Meindl A" first="Alfons" last="Meindl">Alfons Meindl</name><affiliation><nlm:aff id="aff072"><addr-line>Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Neuhausen, Susan L" sort="Neuhausen, Susan L" uniqKey="Neuhausen S" first="Susan L." last="Neuhausen">Susan L. Neuhausen</name><affiliation><nlm:aff id="aff073"><addr-line>Beckman Research Institute of City of Hope, Duarte, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Nevanlinna, Heli" sort="Nevanlinna, Heli" uniqKey="Nevanlinna H" first="Heli" last="Nevanlinna">Heli Nevanlinna</name><affiliation><nlm:aff id="aff074"><addr-line>Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Neven, Patrick" sort="Neven, Patrick" uniqKey="Neven P" first="Patrick" last="Neven">Patrick Neven</name><affiliation><nlm:aff id="aff075"><addr-line>Department of Oncology, University Hospital Gasthuisberg, Leuven, Belgium</addr-line></nlm:aff></affiliation></author><author><name sortKey="Olson, Janet E" sort="Olson, Janet E" uniqKey="Olson J" first="Janet E." last="Olson">Janet E. Olson</name><affiliation><nlm:aff id="aff076"><addr-line>Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Perez, Jose I A" sort="Perez, Jose I A" uniqKey="Perez J" first="Jose I. A." last="Perez">Jose I. A. Perez</name><affiliation><nlm:aff id="aff077"><addr-line>Servicio de Cirugía General y Especialidades, Hospital Monte Naranco, Oviedo, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Perkins, Barbara" sort="Perkins, Barbara" uniqKey="Perkins B" first="Barbara" last="Perkins">Barbara Perkins</name><affiliation><nlm:aff id="aff078"><addr-line>Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Peterlongo, Paolo" sort="Peterlongo, Paolo" uniqKey="Peterlongo P" first="Paolo" last="Peterlongo">Paolo Peterlongo</name><affiliation><nlm:aff id="aff079"><addr-line>IFOM, Fondazione Istituto FIRC (Italian Foundation of Cancer Research) di Oncologia Molecolare, Milan, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Phillips, Kelly Anne" sort="Phillips, Kelly Anne" uniqKey="Phillips K" first="Kelly-Anne" last="Phillips">Kelly-Anne Phillips</name><affiliation><nlm:aff id="aff080"><addr-line>Peter MacCallum Cancer Center, The University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff081"><addr-line>Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff082"><addr-line>Department of Medicine, St Vincent’s Hospital, The University of Melbourne, Fitzroy, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Pylk S, Katri" sort="Pylk S, Katri" uniqKey="Pylk S K" first="Katri" last="Pylk S">Katri Pylk S</name><affiliation><nlm:aff id="aff083"><addr-line>Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, Oulu, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Rudolph, Anja" sort="Rudolph, Anja" uniqKey="Rudolph A" first="Anja" last="Rudolph">Anja Rudolph</name><affiliation><nlm:aff id="aff009"><addr-line>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Santella, Regina" sort="Santella, Regina" uniqKey="Santella R" first="Regina" last="Santella">Regina Santella</name><affiliation><nlm:aff id="aff084"><addr-line>Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff085"><addr-line>Department of Environmental Health Sciences, Mailman School of Public Health of Columbia University, New York, New York, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sawyer, Elinor J" sort="Sawyer, Elinor J" uniqKey="Sawyer E" first="Elinor J." last="Sawyer">Elinor J. Sawyer</name><affiliation><nlm:aff id="aff086"><addr-line>Research Oncology, Guy’s Hospital, King's College London, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Schmutzler, Rita K" sort="Schmutzler, Rita K" uniqKey="Schmutzler R" first="Rita K." last="Schmutzler">Rita K. Schmutzler</name><affiliation><nlm:aff id="aff087"><addr-line>Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne, Cologne, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff088"><addr-line>Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff089"><addr-line>Center for Molecular Medicine, University Hospital of Cologne, Cologne, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff090"><addr-line>Center of Familial Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Seynaeve, Caroline" sort="Seynaeve, Caroline" uniqKey="Seynaeve C" first="Caroline" last="Seynaeve">Caroline Seynaeve</name><affiliation><nlm:aff id="aff053"><addr-line>Department of Surgical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Shah, Mitul" sort="Shah, Mitul" uniqKey="Shah M" first="Mitul" last="Shah">Mitul Shah</name><affiliation><nlm:aff id="aff078"><addr-line>Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Shrubsole, Martha J" sort="Shrubsole, Martha J" uniqKey="Shrubsole M" first="Martha J." last="Shrubsole">Martha J. Shrubsole</name><affiliation><nlm:aff id="aff002"><addr-line>Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Southey, Melissa C" sort="Southey, Melissa C" uniqKey="Southey M" first="Melissa C." last="Southey">Melissa C. Southey</name><affiliation><nlm:aff id="aff091"><addr-line>Department of Pathology, The University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Swerdlow, Anthony J" sort="Swerdlow, Anthony J" uniqKey="Swerdlow A" first="Anthony J." last="Swerdlow">Anthony J. Swerdlow</name><affiliation><nlm:aff id="aff004"><addr-line>Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff092"><addr-line>Division of Breast Cancer Research, The Institute of Cancer Research, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Toland, Amanda E" sort="Toland, Amanda E" uniqKey="Toland A" first="Amanda E." last="Toland">Amanda E. Toland</name><affiliation><nlm:aff id="aff093"><addr-line>Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tomlinson, Ian" sort="Tomlinson, Ian" uniqKey="Tomlinson I" first="Ian" last="Tomlinson">Ian Tomlinson</name><affiliation><nlm:aff id="aff094"><addr-line>Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Torres, Diana" sort="Torres, Diana" uniqKey="Torres D" first="Diana" last="Torres">Diana Torres</name><affiliation><nlm:aff id="aff052"><addr-line>Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Truong, Therese" sort="Truong, Therese" uniqKey="Truong T" first="Thérèse" last="Truong">Thérèse Truong</name><affiliation><nlm:aff id="aff050"><addr-line>Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, Villejuif, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff051"><addr-line>University Paris-Sud, Villejuif, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ursin, Giske" sort="Ursin, Giske" uniqKey="Ursin G" first="Giske" last="Ursin">Giske Ursin</name><affiliation><nlm:aff id="aff095"><addr-line>Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway</addr-line></nlm:aff></affiliation></author><author><name sortKey="Van Der Luijt, Rob B" sort="Van Der Luijt, Rob B" uniqKey="Van Der Luijt R" first="Rob B." last="Van Der Luijt">Rob B. Van Der Luijt</name><affiliation><nlm:aff id="aff096"><addr-line>Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Verhoef, Senno" sort="Verhoef, Senno" uniqKey="Verhoef S" first="Senno" last="Verhoef">Senno Verhoef</name><affiliation><nlm:aff id="aff008"><addr-line>Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Whittemore, Alice S" sort="Whittemore, Alice S" uniqKey="Whittemore A" first="Alice S." last="Whittemore">Alice S. Whittemore</name><affiliation><nlm:aff id="aff056"><addr-line>Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Winqvist, Robert" sort="Winqvist, Robert" uniqKey="Winqvist R" first="Robert" last="Winqvist">Robert Winqvist</name><affiliation><nlm:aff id="aff083"><addr-line>Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, Oulu, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff097"><addr-line>Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Zhao, Hui" sort="Zhao, Hui" uniqKey="Zhao H" first="Hui" last="Zhao">Hui Zhao</name><affiliation><nlm:aff id="aff098"><addr-line>Vesalius Research Center, Leuven, Belgium</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff099"><addr-line>Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium</addr-line></nlm:aff></affiliation></author><author><name sortKey="Zhao, Shilin" sort="Zhao, Shilin" uniqKey="Zhao S" first="Shilin" last="Zhao">Shilin Zhao</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hall, Per" sort="Hall, Per" uniqKey="Hall P" first="Per" last="Hall">Per Hall</name><affiliation><nlm:aff id="aff027"><addr-line>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Simard, Jacques" sort="Simard, Jacques" uniqKey="Simard J" first="Jacques" last="Simard">Jacques Simard</name><affiliation><nlm:aff id="aff041"><addr-line>Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kraft, Peter" sort="Kraft, Peter" uniqKey="Kraft P" first="Peter" last="Kraft">Peter Kraft</name><affiliation><nlm:aff id="aff100"><addr-line>Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff101"><addr-line>Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Pharoah, Paul" sort="Pharoah, Paul" uniqKey="Pharoah P" first="Paul" last="Pharoah">Paul Pharoah</name><affiliation><nlm:aff id="aff003"><addr-line>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff078"><addr-line>Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hunter, David" sort="Hunter, David" uniqKey="Hunter D" first="David" last="Hunter">David Hunter</name><affiliation><nlm:aff id="aff100"><addr-line>Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff101"><addr-line>Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Easton, Douglas F" sort="Easton, Douglas F" uniqKey="Easton D" first="Douglas F." last="Easton">Douglas F. Easton</name><affiliation><nlm:aff id="aff003"><addr-line>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff078"><addr-line>Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Zheng, Wei" sort="Zheng, Wei" uniqKey="Zheng W" first="Wei" last="Zheng">Wei Zheng</name><affiliation><nlm:aff id="aff002"><addr-line>Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27551723</idno><idno type="pmc">4995025</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995025</idno><idno type="RBID">PMC:4995025</idno><idno type="doi">10.1371/journal.pmed.1002105</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">002901</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002901</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent</title><author><name sortKey="Guo, Yan" sort="Guo, Yan" uniqKey="Guo Y" first="Yan" last="Guo">Yan Guo</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Warren Andersen, Shaneda" sort="Warren Andersen, Shaneda" uniqKey="Warren Andersen S" first="Shaneda" last="Warren Andersen">Shaneda Warren Andersen</name><affiliation><nlm:aff id="aff002"><addr-line>Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Shu, Xiao Ou" sort="Shu, Xiao Ou" uniqKey="Shu X" first="Xiao-Ou" last="Shu">Xiao-Ou Shu</name><affiliation><nlm:aff id="aff002"><addr-line>Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Michailidou, Kyriaki" sort="Michailidou, Kyriaki" uniqKey="Michailidou K" first="Kyriaki" last="Michailidou">Kyriaki Michailidou</name><affiliation><nlm:aff id="aff003"><addr-line>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bolla, Manjeet K" sort="Bolla, Manjeet K" uniqKey="Bolla M" first="Manjeet K." last="Bolla">Manjeet K. Bolla</name><affiliation><nlm:aff id="aff003"><addr-line>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Wang, Qin" sort="Wang, Qin" uniqKey="Wang Q" first="Qin" last="Wang">Qin Wang</name><affiliation><nlm:aff id="aff003"><addr-line>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Garcia Closas, Montserrat" sort="Garcia Closas, Montserrat" uniqKey="Garcia Closas M" first="Montserrat" last="Garcia-Closas">Montserrat Garcia-Closas</name><affiliation><nlm:aff id="aff004"><addr-line>Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff005"><addr-line>Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Milne, Roger L" sort="Milne, Roger L" uniqKey="Milne R" first="Roger L." last="Milne">Roger L. Milne</name><affiliation><nlm:aff id="aff006"><addr-line>Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff007"><addr-line>Centre for Epidemiology and Biostatistics, School of Population and Global health, The University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Schmidt, Marjanka K" sort="Schmidt, Marjanka K" uniqKey="Schmidt M" first="Marjanka K." last="Schmidt">Marjanka K. Schmidt</name><affiliation><nlm:aff id="aff008"><addr-line>Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chang Claude, Jenny" sort="Chang Claude, Jenny" uniqKey="Chang Claude J" first="Jenny" last="Chang-Claude">Jenny Chang-Claude</name><affiliation><nlm:aff id="aff009"><addr-line>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff010"><addr-line>Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dunning, Allison" sort="Dunning, Allison" uniqKey="Dunning A" first="Allison" last="Dunning">Allison Dunning</name><affiliation><nlm:aff id="aff011"><addr-line>Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bojesen, Stig E" sort="Bojesen, Stig E" uniqKey="Bojesen S" first="Stig E." last="Bojesen">Stig E. Bojesen</name><affiliation><nlm:aff id="aff012"><addr-line>Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff013"><addr-line>Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff014"><addr-line>Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ahsan, Habibul" sort="Ahsan, Habibul" uniqKey="Ahsan H" first="Habibul" last="Ahsan">Habibul Ahsan</name><affiliation><nlm:aff id="aff015"><addr-line>Department of Health Studies, The University of Chicago, Chicago, Illinois, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Aittom Ki, Kristiina" sort="Aittom Ki, Kristiina" uniqKey="Aittom Ki K" first="Kristiina" last="Aittom Ki">Kristiina Aittom Ki</name><affiliation><nlm:aff id="aff016"><addr-line>Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Andrulis, Irene L" sort="Andrulis, Irene L" uniqKey="Andrulis I" first="Irene L." last="Andrulis">Irene L. Andrulis</name><affiliation><nlm:aff id="aff017"><addr-line>Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff018"><addr-line>Department of Molecular Genetics, University of Toronto, Toronto, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Anton Culver, Hoda" sort="Anton Culver, Hoda" uniqKey="Anton Culver H" first="Hoda" last="Anton-Culver">Hoda Anton-Culver</name><affiliation><nlm:aff id="aff019"><addr-line>Department of Epidemiology, University of California Irvine, Irvine, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Arndt, Volker" sort="Arndt, Volker" uniqKey="Arndt V" first="Volker" last="Arndt">Volker Arndt</name><affiliation><nlm:aff id="aff020"><addr-line>Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Beckmann, Matthias W" sort="Beckmann, Matthias W" uniqKey="Beckmann M" first="Matthias W." last="Beckmann">Matthias W. Beckmann</name><affiliation><nlm:aff id="aff015"><addr-line>Department of Health Studies, The University of Chicago, Chicago, Illinois, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Beeghly Fadiel, Alicia" sort="Beeghly Fadiel, Alicia" uniqKey="Beeghly Fadiel A" first="Alicia" last="Beeghly-Fadiel">Alicia Beeghly-Fadiel</name><affiliation><nlm:aff id="aff002"><addr-line>Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Benitez, Javier" sort="Benitez, Javier" uniqKey="Benitez J" first="Javier" last="Benitez">Javier Benitez</name><affiliation><nlm:aff id="aff021"><addr-line>Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff022"><addr-line>Centro de Investigación en Red de Enfermedades Raras, Valencia, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bogdanova, Natalia V" sort="Bogdanova, Natalia V" uniqKey="Bogdanova N" first="Natalia V." last="Bogdanova">Natalia V. Bogdanova</name><affiliation><nlm:aff id="aff023"><addr-line>Department of Radiation Oncology, Hannover Medical School, Hannover, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bonanni, Bernardo" sort="Bonanni, Bernardo" uniqKey="Bonanni B" first="Bernardo" last="Bonanni">Bernardo Bonanni</name><affiliation><nlm:aff id="aff024"><addr-line>Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="B Rresen Dale, Anne Lise" sort="B Rresen Dale, Anne Lise" uniqKey="B Rresen Dale A" first="Anne-Lise" last="B Rresen-Dale">Anne-Lise B Rresen-Dale</name><affiliation><nlm:aff id="aff025"><addr-line>Department of Genetics, Institute for Cancer Research, Radiumhospitalet, Oslo University Hospital, Oslo University Hospital, Oslo, Norway</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff026"><addr-line>Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway</addr-line></nlm:aff></affiliation></author><author><name sortKey="Brand, Judith" sort="Brand, Judith" uniqKey="Brand J" first="Judith" last="Brand">Judith Brand</name><affiliation><nlm:aff id="aff027"><addr-line>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Brauch, Hiltrud" sort="Brauch, Hiltrud" uniqKey="Brauch H" first="Hiltrud" last="Brauch">Hiltrud Brauch</name><affiliation><nlm:aff id="aff028"><addr-line>German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff029"><addr-line>Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff030"><addr-line>University of Tübingen, Tübingen, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Brenner, Hermann" sort="Brenner, Hermann" uniqKey="Brenner H" first="Hermann" last="Brenner">Hermann Brenner</name><affiliation><nlm:aff id="aff020"><addr-line>Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff028"><addr-line>German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff031"><addr-line>Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bruning, Thomas" sort="Bruning, Thomas" uniqKey="Bruning T" first="Thomas" last="Brüning">Thomas Brüning</name><affiliation><nlm:aff id="aff032"><addr-line>Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum, Bochum, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Burwinkel, Barbara" sort="Burwinkel, Barbara" uniqKey="Burwinkel B" first="Barbara" last="Burwinkel">Barbara Burwinkel</name><affiliation><nlm:aff id="aff033"><addr-line>Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff034"><addr-line>Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Casey, Graham" sort="Casey, Graham" uniqKey="Casey G" first="Graham" last="Casey">Graham Casey</name><affiliation><nlm:aff id="aff035"><addr-line>Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chenevix Trench, Georgia" sort="Chenevix Trench, Georgia" uniqKey="Chenevix Trench G" first="Georgia" last="Chenevix-Trench">Georgia Chenevix-Trench</name><affiliation><nlm:aff id="aff036"><addr-line>Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Couch, Fergus J" sort="Couch, Fergus J" uniqKey="Couch F" first="Fergus J." last="Couch">Fergus J. Couch</name><affiliation><nlm:aff id="aff037"><addr-line>Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cox, Angela" sort="Cox, Angela" uniqKey="Cox A" first="Angela" last="Cox">Angela Cox</name><affiliation><nlm:aff id="aff038"><addr-line>Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cross, Simon S" sort="Cross, Simon S" uniqKey="Cross S" first="Simon S." last="Cross">Simon S. Cross</name><affiliation><nlm:aff id="aff011"><addr-line>Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Czene, Kamila" sort="Czene, Kamila" uniqKey="Czene K" first="Kamila" last="Czene">Kamila Czene</name><affiliation><nlm:aff id="aff027"><addr-line>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Devilee, Peter" sort="Devilee, Peter" uniqKey="Devilee P" first="Peter" last="Devilee">Peter Devilee</name><affiliation><nlm:aff id="aff039"><addr-line>Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dork, Thilo" sort="Dork, Thilo" uniqKey="Dork T" first="Thilo" last="Dörk">Thilo Dörk</name><affiliation><nlm:aff id="aff040"><addr-line>Gynaecology Research Unit, Hannover Medical School, Hannover, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dumont, Martine" sort="Dumont, Martine" uniqKey="Dumont M" first="Martine" last="Dumont">Martine Dumont</name><affiliation><nlm:aff id="aff041"><addr-line>Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Fasching, Peter A" sort="Fasching, Peter A" uniqKey="Fasching P" first="Peter A." last="Fasching">Peter A. Fasching</name><affiliation><nlm:aff id="aff042"><addr-line>Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff043"><addr-line>David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Figueroa, Jonine" sort="Figueroa, Jonine" uniqKey="Figueroa J" first="Jonine" last="Figueroa">Jonine Figueroa</name><affiliation><nlm:aff id="aff044"><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Flesch Janys, Dieter" sort="Flesch Janys, Dieter" uniqKey="Flesch Janys D" first="Dieter" last="Flesch-Janys">Dieter Flesch-Janys</name><affiliation><nlm:aff id="aff045"><addr-line>Institute for Medical Biometrics and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff046"><addr-line>Department of Cancer Epidemiology, Clinical Cancer Registry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Fletcher, Olivia" sort="Fletcher, Olivia" uniqKey="Fletcher O" first="Olivia" last="Fletcher">Olivia Fletcher</name><affiliation><nlm:aff id="aff005"><addr-line>Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Flyger, Henrik" sort="Flyger, Henrik" uniqKey="Flyger H" first="Henrik" last="Flyger">Henrik Flyger</name><affiliation><nlm:aff id="aff047"><addr-line>Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Fostira, Florentia" sort="Fostira, Florentia" uniqKey="Fostira F" first="Florentia" last="Fostira">Florentia Fostira</name><affiliation><nlm:aff id="aff048"><addr-line>Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research "Demokritos", Athens, Greece</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gammon, Marilie" sort="Gammon, Marilie" uniqKey="Gammon M" first="Marilie" last="Gammon">Marilie Gammon</name><affiliation><nlm:aff id="aff049"><addr-line>Departments of Epidemiology, University of North Carolina Chapel-Hill, Chapel Hill, North Carolina, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Giles, Graham G" sort="Giles, Graham G" uniqKey="Giles G" first="Graham G." last="Giles">Graham G. Giles</name><affiliation><nlm:aff id="aff006"><addr-line>Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff007"><addr-line>Centre for Epidemiology and Biostatistics, School of Population and Global health, The University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Guenel, Pascal" sort="Guenel, Pascal" uniqKey="Guenel P" first="Pascal" last="Guénel">Pascal Guénel</name><affiliation><nlm:aff id="aff050"><addr-line>Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, Villejuif, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff051"><addr-line>University Paris-Sud, Villejuif, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Haiman, Christopher A" sort="Haiman, Christopher A" uniqKey="Haiman C" first="Christopher A." last="Haiman">Christopher A. Haiman</name><affiliation><nlm:aff id="aff035"><addr-line>Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hamann, Ute" sort="Hamann, Ute" uniqKey="Hamann U" first="Ute" last="Hamann">Ute Hamann</name><affiliation><nlm:aff id="aff052"><addr-line>Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hooning, Maartje J" sort="Hooning, Maartje J" uniqKey="Hooning M" first="Maartje J." last="Hooning">Maartje J. Hooning</name><affiliation><nlm:aff id="aff053"><addr-line>Department of Surgical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hopper, John L" sort="Hopper, John L" uniqKey="Hopper J" first="John L." last="Hopper">John L. Hopper</name><affiliation><nlm:aff id="aff007"><addr-line>Centre for Epidemiology and Biostatistics, School of Population and Global health, The University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Jakubowska, Anna" sort="Jakubowska, Anna" uniqKey="Jakubowska A" first="Anna" last="Jakubowska">Anna Jakubowska</name><affiliation><nlm:aff id="aff054"><addr-line>Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Jasmine, Farzana" sort="Jasmine, Farzana" uniqKey="Jasmine F" first="Farzana" last="Jasmine">Farzana Jasmine</name><affiliation><nlm:aff id="aff015"><addr-line>Department of Health Studies, The University of Chicago, Chicago, Illinois, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Jenkins, Mark" sort="Jenkins, Mark" uniqKey="Jenkins M" first="Mark" last="Jenkins">Mark Jenkins</name><affiliation><nlm:aff id="aff007"><addr-line>Centre for Epidemiology and Biostatistics, School of Population and Global health, The University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="John, Esther M" sort="John, Esther M" uniqKey="John E" first="Esther M." last="John">Esther M. John</name><affiliation><nlm:aff id="aff055"><addr-line>Department of Epidemiology, Cancer Prevention Institute of California, Fremont, California, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff056"><addr-line>Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Johnson, Nichola" sort="Johnson, Nichola" uniqKey="Johnson N" first="Nichola" last="Johnson">Nichola Johnson</name><affiliation><nlm:aff id="aff005"><addr-line>Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Jones, Michael E" sort="Jones, Michael E" uniqKey="Jones M" first="Michael E." last="Jones">Michael E. Jones</name><affiliation><nlm:aff id="aff004"><addr-line>Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kabisch, Maria" sort="Kabisch, Maria" uniqKey="Kabisch M" first="Maria" last="Kabisch">Maria Kabisch</name><affiliation><nlm:aff id="aff052"><addr-line>Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kibriya, Muhammad" sort="Kibriya, Muhammad" uniqKey="Kibriya M" first="Muhammad" last="Kibriya">Muhammad Kibriya</name><affiliation><nlm:aff id="aff015"><addr-line>Department of Health Studies, The University of Chicago, Chicago, Illinois, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Knight, Julia A" sort="Knight, Julia A" uniqKey="Knight J" first="Julia A." last="Knight">Julia A. Knight</name><affiliation><nlm:aff id="aff057"><addr-line>Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff058"><addr-line>Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Koppert, Linetta B" sort="Koppert, Linetta B" uniqKey="Koppert L" first="Linetta B." last="Koppert">Linetta B. Koppert</name><affiliation><nlm:aff id="aff053"><addr-line>Department of Surgical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kosma, Veli Matti" sort="Kosma, Veli Matti" uniqKey="Kosma V" first="Veli-Matti" last="Kosma">Veli-Matti Kosma</name><affiliation><nlm:aff id="aff059"><addr-line>Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff060"><addr-line>Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff061"><addr-line>Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kristensen, Vessela" sort="Kristensen, Vessela" uniqKey="Kristensen V" first="Vessela" last="Kristensen">Vessela Kristensen</name><affiliation><nlm:aff id="aff025"><addr-line>Department of Genetics, Institute for Cancer Research, Radiumhospitalet, Oslo University Hospital, Oslo University Hospital, Oslo, Norway</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff026"><addr-line>Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff062"><addr-line>Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway</addr-line></nlm:aff></affiliation></author><author><name sortKey="Le Marchand, Loic" sort="Le Marchand, Loic" uniqKey="Le Marchand L" first="Loic" last="Le Marchand">Loic Le Marchand</name><affiliation><nlm:aff id="aff063"><addr-line>University of Hawaii Cancer Center, Honolulu, Hawaii, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lee, Eunjung" sort="Lee, Eunjung" uniqKey="Lee E" first="Eunjung" last="Lee">Eunjung Lee</name><affiliation><nlm:aff id="aff035"><addr-line>Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Li, Jingmei" sort="Li, Jingmei" uniqKey="Li J" first="Jingmei" last="Li">Jingmei Li</name><affiliation><nlm:aff id="aff027"><addr-line>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lindblom, Annika" sort="Lindblom, Annika" uniqKey="Lindblom A" first="Annika" last="Lindblom">Annika Lindblom</name><affiliation><nlm:aff id="aff064"><addr-line>Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Luben, Robert" sort="Luben, Robert" uniqKey="Luben R" first="Robert" last="Luben">Robert Luben</name><affiliation><nlm:aff id="aff065"><addr-line>Clinical Gerontology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lubinski, Jan" sort="Lubinski, Jan" uniqKey="Lubinski J" first="Jan" last="Lubinski">Jan Lubinski</name><affiliation><nlm:aff id="aff054"><addr-line>Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Malone, Kathi E" sort="Malone, Kathi E" uniqKey="Malone K" first="Kathi E." last="Malone">Kathi E. Malone</name><affiliation><nlm:aff id="aff066"><addr-line>Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mannermaa, Arto" sort="Mannermaa, Arto" uniqKey="Mannermaa A" first="Arto" last="Mannermaa">Arto Mannermaa</name><affiliation><nlm:aff id="aff059"><addr-line>Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff060"><addr-line>Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff061"><addr-line>Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Margolin, Sara" sort="Margolin, Sara" uniqKey="Margolin S" first="Sara" last="Margolin">Sara Margolin</name><affiliation><nlm:aff id="aff067"><addr-line>Department of Oncology – Pathology, Karolinska Institutet, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Marme, Frederik" sort="Marme, Frederik" uniqKey="Marme F" first="Frederik" last="Marme">Frederik Marme</name><affiliation><nlm:aff id="aff068"><addr-line>National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff069"><addr-line>Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mclean, Catriona" sort="Mclean, Catriona" uniqKey="Mclean C" first="Catriona" last="Mclean">Catriona Mclean</name><affiliation><nlm:aff id="aff070"><addr-line>Anatomical Pathology, The Alfred Hospital, Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Meijers Heijboer, Hanne" sort="Meijers Heijboer, Hanne" uniqKey="Meijers Heijboer H" first="Hanne" last="Meijers-Heijboer">Hanne Meijers-Heijboer</name><affiliation><nlm:aff id="aff071"><addr-line>Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Meindl, Alfons" sort="Meindl, Alfons" uniqKey="Meindl A" first="Alfons" last="Meindl">Alfons Meindl</name><affiliation><nlm:aff id="aff072"><addr-line>Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Neuhausen, Susan L" sort="Neuhausen, Susan L" uniqKey="Neuhausen S" first="Susan L." last="Neuhausen">Susan L. Neuhausen</name><affiliation><nlm:aff id="aff073"><addr-line>Beckman Research Institute of City of Hope, Duarte, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Nevanlinna, Heli" sort="Nevanlinna, Heli" uniqKey="Nevanlinna H" first="Heli" last="Nevanlinna">Heli Nevanlinna</name><affiliation><nlm:aff id="aff074"><addr-line>Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Neven, Patrick" sort="Neven, Patrick" uniqKey="Neven P" first="Patrick" last="Neven">Patrick Neven</name><affiliation><nlm:aff id="aff075"><addr-line>Department of Oncology, University Hospital Gasthuisberg, Leuven, Belgium</addr-line></nlm:aff></affiliation></author><author><name sortKey="Olson, Janet E" sort="Olson, Janet E" uniqKey="Olson J" first="Janet E." last="Olson">Janet E. Olson</name><affiliation><nlm:aff id="aff076"><addr-line>Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Perez, Jose I A" sort="Perez, Jose I A" uniqKey="Perez J" first="Jose I. A." last="Perez">Jose I. A. Perez</name><affiliation><nlm:aff id="aff077"><addr-line>Servicio de Cirugía General y Especialidades, Hospital Monte Naranco, Oviedo, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Perkins, Barbara" sort="Perkins, Barbara" uniqKey="Perkins B" first="Barbara" last="Perkins">Barbara Perkins</name><affiliation><nlm:aff id="aff078"><addr-line>Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Peterlongo, Paolo" sort="Peterlongo, Paolo" uniqKey="Peterlongo P" first="Paolo" last="Peterlongo">Paolo Peterlongo</name><affiliation><nlm:aff id="aff079"><addr-line>IFOM, Fondazione Istituto FIRC (Italian Foundation of Cancer Research) di Oncologia Molecolare, Milan, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Phillips, Kelly Anne" sort="Phillips, Kelly Anne" uniqKey="Phillips K" first="Kelly-Anne" last="Phillips">Kelly-Anne Phillips</name><affiliation><nlm:aff id="aff080"><addr-line>Peter MacCallum Cancer Center, The University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff081"><addr-line>Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff082"><addr-line>Department of Medicine, St Vincent’s Hospital, The University of Melbourne, Fitzroy, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Pylk S, Katri" sort="Pylk S, Katri" uniqKey="Pylk S K" first="Katri" last="Pylk S">Katri Pylk S</name><affiliation><nlm:aff id="aff083"><addr-line>Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, Oulu, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Rudolph, Anja" sort="Rudolph, Anja" uniqKey="Rudolph A" first="Anja" last="Rudolph">Anja Rudolph</name><affiliation><nlm:aff id="aff009"><addr-line>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Santella, Regina" sort="Santella, Regina" uniqKey="Santella R" first="Regina" last="Santella">Regina Santella</name><affiliation><nlm:aff id="aff084"><addr-line>Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff085"><addr-line>Department of Environmental Health Sciences, Mailman School of Public Health of Columbia University, New York, New York, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sawyer, Elinor J" sort="Sawyer, Elinor J" uniqKey="Sawyer E" first="Elinor J." last="Sawyer">Elinor J. Sawyer</name><affiliation><nlm:aff id="aff086"><addr-line>Research Oncology, Guy’s Hospital, King's College London, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Schmutzler, Rita K" sort="Schmutzler, Rita K" uniqKey="Schmutzler R" first="Rita K." last="Schmutzler">Rita K. Schmutzler</name><affiliation><nlm:aff id="aff087"><addr-line>Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne, Cologne, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff088"><addr-line>Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff089"><addr-line>Center for Molecular Medicine, University Hospital of Cologne, Cologne, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff090"><addr-line>Center of Familial Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Seynaeve, Caroline" sort="Seynaeve, Caroline" uniqKey="Seynaeve C" first="Caroline" last="Seynaeve">Caroline Seynaeve</name><affiliation><nlm:aff id="aff053"><addr-line>Department of Surgical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Shah, Mitul" sort="Shah, Mitul" uniqKey="Shah M" first="Mitul" last="Shah">Mitul Shah</name><affiliation><nlm:aff id="aff078"><addr-line>Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Shrubsole, Martha J" sort="Shrubsole, Martha J" uniqKey="Shrubsole M" first="Martha J." last="Shrubsole">Martha J. Shrubsole</name><affiliation><nlm:aff id="aff002"><addr-line>Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Southey, Melissa C" sort="Southey, Melissa C" uniqKey="Southey M" first="Melissa C." last="Southey">Melissa C. Southey</name><affiliation><nlm:aff id="aff091"><addr-line>Department of Pathology, The University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Swerdlow, Anthony J" sort="Swerdlow, Anthony J" uniqKey="Swerdlow A" first="Anthony J." last="Swerdlow">Anthony J. Swerdlow</name><affiliation><nlm:aff id="aff004"><addr-line>Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff092"><addr-line>Division of Breast Cancer Research, The Institute of Cancer Research, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Toland, Amanda E" sort="Toland, Amanda E" uniqKey="Toland A" first="Amanda E." last="Toland">Amanda E. Toland</name><affiliation><nlm:aff id="aff093"><addr-line>Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tomlinson, Ian" sort="Tomlinson, Ian" uniqKey="Tomlinson I" first="Ian" last="Tomlinson">Ian Tomlinson</name><affiliation><nlm:aff id="aff094"><addr-line>Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Torres, Diana" sort="Torres, Diana" uniqKey="Torres D" first="Diana" last="Torres">Diana Torres</name><affiliation><nlm:aff id="aff052"><addr-line>Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Truong, Therese" sort="Truong, Therese" uniqKey="Truong T" first="Thérèse" last="Truong">Thérèse Truong</name><affiliation><nlm:aff id="aff050"><addr-line>Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, Villejuif, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff051"><addr-line>University Paris-Sud, Villejuif, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ursin, Giske" sort="Ursin, Giske" uniqKey="Ursin G" first="Giske" last="Ursin">Giske Ursin</name><affiliation><nlm:aff id="aff095"><addr-line>Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway</addr-line></nlm:aff></affiliation></author><author><name sortKey="Van Der Luijt, Rob B" sort="Van Der Luijt, Rob B" uniqKey="Van Der Luijt R" first="Rob B." last="Van Der Luijt">Rob B. Van Der Luijt</name><affiliation><nlm:aff id="aff096"><addr-line>Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Verhoef, Senno" sort="Verhoef, Senno" uniqKey="Verhoef S" first="Senno" last="Verhoef">Senno Verhoef</name><affiliation><nlm:aff id="aff008"><addr-line>Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Whittemore, Alice S" sort="Whittemore, Alice S" uniqKey="Whittemore A" first="Alice S." last="Whittemore">Alice S. Whittemore</name><affiliation><nlm:aff id="aff056"><addr-line>Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Winqvist, Robert" sort="Winqvist, Robert" uniqKey="Winqvist R" first="Robert" last="Winqvist">Robert Winqvist</name><affiliation><nlm:aff id="aff083"><addr-line>Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, Oulu, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff097"><addr-line>Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Zhao, Hui" sort="Zhao, Hui" uniqKey="Zhao H" first="Hui" last="Zhao">Hui Zhao</name><affiliation><nlm:aff id="aff098"><addr-line>Vesalius Research Center, Leuven, Belgium</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff099"><addr-line>Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium</addr-line></nlm:aff></affiliation></author><author><name sortKey="Zhao, Shilin" sort="Zhao, Shilin" uniqKey="Zhao S" first="Shilin" last="Zhao">Shilin Zhao</name><affiliation><nlm:aff id="aff001"><addr-line>Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hall, Per" sort="Hall, Per" uniqKey="Hall P" first="Per" last="Hall">Per Hall</name><affiliation><nlm:aff id="aff027"><addr-line>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Simard, Jacques" sort="Simard, Jacques" uniqKey="Simard J" first="Jacques" last="Simard">Jacques Simard</name><affiliation><nlm:aff id="aff041"><addr-line>Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kraft, Peter" sort="Kraft, Peter" uniqKey="Kraft P" first="Peter" last="Kraft">Peter Kraft</name><affiliation><nlm:aff id="aff100"><addr-line>Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff101"><addr-line>Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Pharoah, Paul" sort="Pharoah, Paul" uniqKey="Pharoah P" first="Paul" last="Pharoah">Paul Pharoah</name><affiliation><nlm:aff id="aff003"><addr-line>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff078"><addr-line>Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hunter, David" sort="Hunter, David" uniqKey="Hunter D" first="David" last="Hunter">David Hunter</name><affiliation><nlm:aff id="aff100"><addr-line>Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff101"><addr-line>Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Easton, Douglas F" sort="Easton, Douglas F" uniqKey="Easton D" first="Douglas F." last="Easton">Douglas F. Easton</name><affiliation><nlm:aff id="aff003"><addr-line>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff078"><addr-line>Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Zheng, Wei" sort="Zheng, Wei" uniqKey="Zheng W" first="Wei" last="Zheng">Wei Zheng</name><affiliation><nlm:aff id="aff002"><addr-line>Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">PLoS Medicine</title><idno type="ISSN">1549-1277</idno><idno type="eISSN">1549-1676</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="sec001"><title>Background</title><p>Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.</p></sec><sec id="sec002"><title>Methods</title><p>We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases = 46,325, controls = 42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively.</p></sec><sec id="sec003"><title>Results</title><p>In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR] = 0.65 per 5 kg/m<sup>2</sup> increase, 95% confidence interval [CI]: 0.56–0.75, <italic>p</italic> = 3.32 × 10<sup>−10</sup>). The associations were similar for both premenopausal (OR = 0.44, 95% CI:0.31–0.62, <italic>p</italic> = 9.91 × 10<sup>−8</sup>) and postmenopausal breast cancer (OR = 0.57, 95% CI: 0.46–0.71, <italic>p</italic> = 1.88 × 10<sup>−8</sup>). This association was replicated in the data from the DRIVE consortium (OR = 0.72, 95% CI: 0.60–0.84, <italic>p</italic> = 1.64 × 10<sup>−7</sup>). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at <italic>p</italic> < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk.</p></sec><sec id="sec004"><title>Conclusions</title><p>BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Renehan, Ag" uniqKey="Renehan A">AG Renehan</name></author><author><name sortKey="Tyson, M" uniqKey="Tyson M">M Tyson</name></author><author><name sortKey="Egger, M" uniqKey="Egger M">M Egger</name></author><author><name sortKey="Heller, Rf" uniqKey="Heller R">RF Heller</name></author><author><name sortKey="Zwahlen, M" uniqKey="Zwahlen M">M Zwahlen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Huang, Z" uniqKey="Huang Z">Z Huang</name></author><author><name sortKey="Hankinson, Se" uniqKey="Hankinson S">SE Hankinson</name></author><author><name sortKey="Colditz, Ga" uniqKey="Colditz G">GA Colditz</name></author><author><name sortKey="Stampfer, Mj" uniqKey="Stampfer M">MJ 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Med</journal-id><journal-id journal-id-type="iso-abbrev">PLoS Med</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosmed</journal-id><journal-title-group><journal-title>PLoS Medicine</journal-title></journal-title-group><issn pub-type="ppub">1549-1277</issn><issn pub-type="epub">1549-1676</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, CA USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">27551723</article-id><article-id pub-id-type="pmc">4995025</article-id><article-id pub-id-type="doi">10.1371/journal.pmed.1002105</article-id><article-id pub-id-type="publisher-id">PMEDICINE-D-15-03646</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Oncology</subject><subj-group><subject>Cancers and Neoplasms</subject><subj-group><subject>Breast Tumors</subject><subj-group><subject>Breast Cancer</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Genetics</subject><subj-group><subject>Human Genetics</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Physiology</subject><subj-group><subject>Physiological Parameters</subject><subj-group><subject>Body Weight</subject><subj-group><subject>Body Mass Index</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Physiology</subject><subj-group><subject>Physiological Parameters</subject><subj-group><subject>Body Weight</subject><subj-group><subject>Body Mass Index</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Oncology</subject><subj-group><subject>Cancer Risk Factors</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Social Sciences</subject><subj-group><subject>Sociology</subject><subj-group><subject>Consortia</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Computational Biology</subject><subj-group><subject>Genome Analysis</subject><subj-group><subject>Genome-Wide Association Studies</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Genetics</subject><subj-group><subject>Genomics</subject><subj-group><subject>Genome Analysis</subject><subj-group><subject>Genome-Wide Association Studies</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Genetics</subject><subj-group><subject>Human Genetics</subject><subj-group><subject>Genome-Wide Association Studies</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Epidemiology</subject><subj-group><subject>Genetic Epidemiology</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Endocrinology</subject><subj-group><subject>Endocrine Physiology</subject><subj-group><subject>Menstrual Cycle</subject><subj-group><subject>Menarche</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Physiology</subject><subj-group><subject>Endocrine Physiology</subject><subj-group><subject>Menstrual Cycle</subject><subj-group><subject>Menarche</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Physiology</subject><subj-group><subject>Endocrine Physiology</subject><subj-group><subject>Menstrual Cycle</subject><subj-group><subject>Menarche</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Physiology</subject><subj-group><subject>Reproductive Physiology</subject><subj-group><subject>Menstrual Cycle</subject><subj-group><subject>Menarche</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Physiology</subject><subj-group><subject>Reproductive Physiology</subject><subj-group><subject>Menstrual Cycle</subject><subj-group><subject>Menarche</subject></subj-group></subj-group></subj-group></subj-group></subj-group></article-categories><title-group><article-title>Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent</article-title><alt-title alt-title-type="running-head">BMI and Breast Cancer Risk: Mendelian Randomization Analyses of Data from Women of European Descent</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Guo</surname><given-names>Yan</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Warren Andersen</surname><given-names>Shaneda</given-names></name><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Shu</surname><given-names>Xiao-Ou</given-names></name><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Michailidou</surname><given-names>Kyriaki</given-names></name><xref ref-type="aff" rid="aff003"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bolla</surname><given-names>Manjeet K.</given-names></name><xref ref-type="aff" rid="aff003"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Qin</given-names></name><xref ref-type="aff" rid="aff003"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Garcia-Closas</surname><given-names>Montserrat</given-names></name><xref ref-type="aff" rid="aff004"><sup>4</sup></xref><xref ref-type="aff" rid="aff005"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Milne</surname><given-names>Roger L.</given-names></name><xref ref-type="aff" rid="aff006"><sup>6</sup></xref><xref ref-type="aff" rid="aff007"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Schmidt</surname><given-names>Marjanka K.</given-names></name><xref ref-type="aff" rid="aff008"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Chang-Claude</surname><given-names>Jenny</given-names></name><xref ref-type="aff" rid="aff009"><sup>9</sup></xref><xref ref-type="aff" rid="aff010"><sup>10</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dunning</surname><given-names>Allison</given-names></name><xref ref-type="aff" rid="aff011"><sup>11</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bojesen</surname><given-names>Stig 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contrib-id-type="orcid">http://orcid.org/0000-0001-9320-8684</contrib-id><name><surname>Arndt</surname><given-names>Volker</given-names></name><xref ref-type="aff" rid="aff020"><sup>20</sup></xref></contrib><contrib contrib-type="author"><name><surname>Beckmann</surname><given-names>Matthias W.</given-names></name><xref ref-type="aff" rid="aff015"><sup>15</sup></xref></contrib><contrib contrib-type="author"><name><surname>Beeghly-Fadiel</surname><given-names>Alicia</given-names></name><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Benitez</surname><given-names>Javier</given-names></name><xref ref-type="aff" rid="aff021"><sup>21</sup></xref><xref ref-type="aff" rid="aff022"><sup>22</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bogdanova</surname><given-names>Natalia V.</given-names></name><xref ref-type="aff" rid="aff023"><sup>23</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bonanni</surname><given-names>Bernardo</given-names></name><xref ref-type="aff" rid="aff024"><sup>24</sup></xref></contrib><contrib contrib-type="author"><name><surname>Børresen-Dale</surname><given-names>Anne-Lise</given-names></name><xref ref-type="aff" rid="aff025"><sup>25</sup></xref><xref ref-type="aff" rid="aff026"><sup>26</sup></xref></contrib><contrib contrib-type="author"><name><surname>Brand</surname><given-names>Judith</given-names></name><xref ref-type="aff" rid="aff027"><sup>27</sup></xref></contrib><contrib contrib-type="author"><name><surname>Brauch</surname><given-names>Hiltrud</given-names></name><xref ref-type="aff" rid="aff028"><sup>28</sup></xref><xref ref-type="aff" rid="aff029"><sup>29</sup></xref><xref ref-type="aff" rid="aff030"><sup>30</sup></xref></contrib><contrib contrib-type="author"><name><surname>Brenner</surname><given-names>Hermann</given-names></name><xref ref-type="aff" rid="aff020"><sup>20</sup></xref><xref ref-type="aff" rid="aff028"><sup>28</sup></xref><xref ref-type="aff" rid="aff031"><sup>31</sup></xref></contrib><contrib contrib-type="author"><name><surname>Brüning</surname><given-names>Thomas</given-names></name><xref ref-type="aff" rid="aff032"><sup>32</sup></xref></contrib><contrib contrib-type="author"><name><surname>Burwinkel</surname><given-names>Barbara</given-names></name><xref ref-type="aff" rid="aff033"><sup>33</sup></xref><xref ref-type="aff" rid="aff034"><sup>34</sup></xref></contrib><contrib contrib-type="author"><name><surname>Casey</surname><given-names>Graham</given-names></name><xref ref-type="aff" rid="aff035"><sup>35</sup></xref></contrib><contrib contrib-type="author"><name><surname>Chenevix-Trench</surname><given-names>Georgia</given-names></name><xref ref-type="aff" rid="aff036"><sup>36</sup></xref></contrib><contrib contrib-type="author"><name><surname>Couch</surname><given-names>Fergus J.</given-names></name><xref ref-type="aff" rid="aff037"><sup>37</sup></xref></contrib><contrib contrib-type="author"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0002-5138-1099</contrib-id><name><surname>Cox</surname><given-names>Angela</given-names></name><xref ref-type="aff" rid="aff038"><sup>38</sup></xref></contrib><contrib contrib-type="author"><name><surname>Cross</surname><given-names>Simon S.</given-names></name><xref ref-type="aff" rid="aff011"><sup>11</sup></xref></contrib><contrib contrib-type="author"><name><surname>Czene</surname><given-names>Kamila</given-names></name><xref ref-type="aff" rid="aff027"><sup>27</sup></xref></contrib><contrib contrib-type="author"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0002-8023-2009</contrib-id><name><surname>Devilee</surname><given-names>Peter</given-names></name><xref ref-type="aff" rid="aff039"><sup>39</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dörk</surname><given-names>Thilo</given-names></name><xref ref-type="aff" rid="aff040"><sup>40</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dumont</surname><given-names>Martine</given-names></name><xref ref-type="aff" rid="aff041"><sup>41</sup></xref></contrib><contrib contrib-type="author"><name><surname>Fasching</surname><given-names>Peter A.</given-names></name><xref ref-type="aff" rid="aff042"><sup>42</sup></xref><xref ref-type="aff" rid="aff043"><sup>43</sup></xref></contrib><contrib contrib-type="author"><name><surname>Figueroa</surname><given-names>Jonine</given-names></name><xref ref-type="aff" rid="aff044"><sup>44</sup></xref></contrib><contrib contrib-type="author"><name><surname>Flesch-Janys</surname><given-names>Dieter</given-names></name><xref ref-type="aff" rid="aff045"><sup>45</sup></xref><xref ref-type="aff" rid="aff046"><sup>46</sup></xref></contrib><contrib contrib-type="author"><name><surname>Fletcher</surname><given-names>Olivia</given-names></name><xref ref-type="aff" rid="aff005"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Flyger</surname><given-names>Henrik</given-names></name><xref ref-type="aff" rid="aff047"><sup>47</sup></xref></contrib><contrib contrib-type="author"><name><surname>Fostira</surname><given-names>Florentia</given-names></name><xref ref-type="aff" rid="aff048"><sup>48</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gammon</surname><given-names>Marilie</given-names></name><xref ref-type="aff" rid="aff049"><sup>49</sup></xref></contrib><contrib contrib-type="author"><name><surname>Giles</surname><given-names>Graham G.</given-names></name><xref ref-type="aff" rid="aff006"><sup>6</sup></xref><xref ref-type="aff" rid="aff007"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Guénel</surname><given-names>Pascal</given-names></name><xref ref-type="aff" rid="aff050"><sup>50</sup></xref><xref ref-type="aff" rid="aff051"><sup>51</sup></xref></contrib><contrib contrib-type="author"><name><surname>Haiman</surname><given-names>Christopher A.</given-names></name><xref ref-type="aff" rid="aff035"><sup>35</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hamann</surname><given-names>Ute</given-names></name><xref ref-type="aff" rid="aff052"><sup>52</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hooning</surname><given-names>Maartje J.</given-names></name><xref ref-type="aff" rid="aff053"><sup>53</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hopper</surname><given-names>John L.</given-names></name><xref ref-type="aff" rid="aff007"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Jakubowska</surname><given-names>Anna</given-names></name><xref ref-type="aff" rid="aff054"><sup>54</sup></xref></contrib><contrib contrib-type="author"><name><surname>Jasmine</surname><given-names>Farzana</given-names></name><xref ref-type="aff" rid="aff015"><sup>15</sup></xref></contrib><contrib contrib-type="author"><name><surname>Jenkins</surname><given-names>Mark</given-names></name><xref ref-type="aff" rid="aff007"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>John</surname><given-names>Esther M.</given-names></name><xref ref-type="aff" rid="aff055"><sup>55</sup></xref><xref ref-type="aff" rid="aff056"><sup>56</sup></xref></contrib><contrib contrib-type="author"><name><surname>Johnson</surname><given-names>Nichola</given-names></name><xref ref-type="aff" rid="aff005"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Jones</surname><given-names>Michael E.</given-names></name><xref ref-type="aff" rid="aff004"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kabisch</surname><given-names>Maria</given-names></name><xref ref-type="aff" rid="aff052"><sup>52</sup></xref></contrib><contrib contrib-type="author"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0001-9784-6958</contrib-id><name><surname>Kibriya</surname><given-names>Muhammad</given-names></name><xref ref-type="aff" rid="aff015"><sup>15</sup></xref></contrib><contrib contrib-type="author"><name><surname>Knight</surname><given-names>Julia A.</given-names></name><xref ref-type="aff" rid="aff057"><sup>57</sup></xref><xref ref-type="aff" rid="aff058"><sup>58</sup></xref></contrib><contrib contrib-type="author"><name><surname>Koppert</surname><given-names>Linetta B.</given-names></name><xref ref-type="aff" rid="aff053"><sup>53</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kosma</surname><given-names>Veli-Matti</given-names></name><xref ref-type="aff" rid="aff059"><sup>59</sup></xref><xref ref-type="aff" rid="aff060"><sup>60</sup></xref><xref ref-type="aff" rid="aff061"><sup>61</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kristensen</surname><given-names>Vessela</given-names></name><xref ref-type="aff" rid="aff025"><sup>25</sup></xref><xref ref-type="aff" rid="aff026"><sup>26</sup></xref><xref ref-type="aff" rid="aff062"><sup>62</sup></xref></contrib><contrib contrib-type="author"><name><surname>Le Marchand</surname><given-names>Loic</given-names></name><xref ref-type="aff" rid="aff063"><sup>63</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lee</surname><given-names>Eunjung</given-names></name><xref ref-type="aff" rid="aff035"><sup>35</sup></xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Jingmei</given-names></name><xref ref-type="aff" rid="aff027"><sup>27</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lindblom</surname><given-names>Annika</given-names></name><xref ref-type="aff" rid="aff064"><sup>64</sup></xref></contrib><contrib contrib-type="author"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0002-5088-6343</contrib-id><name><surname>Luben</surname><given-names>Robert</given-names></name><xref ref-type="aff" rid="aff065"><sup>65</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lubinski</surname><given-names>Jan</given-names></name><xref ref-type="aff" rid="aff054"><sup>54</sup></xref></contrib><contrib contrib-type="author"><name><surname>Malone</surname><given-names>Kathi E.</given-names></name><xref ref-type="aff" rid="aff066"><sup>66</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mannermaa</surname><given-names>Arto</given-names></name><xref ref-type="aff" rid="aff059"><sup>59</sup></xref><xref ref-type="aff" rid="aff060"><sup>60</sup></xref><xref ref-type="aff" rid="aff061"><sup>61</sup></xref></contrib><contrib contrib-type="author"><name><surname>Margolin</surname><given-names>Sara</given-names></name><xref ref-type="aff" rid="aff067"><sup>67</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">http://orcid.org/0000-0002-6591-3367</contrib-id><name><surname>Marme</surname><given-names>Frederik</given-names></name><xref ref-type="aff" rid="aff068"><sup>68</sup></xref><xref ref-type="aff" rid="aff069"><sup>69</sup></xref></contrib><contrib contrib-type="author"><name><surname>McLean</surname><given-names>Catriona</given-names></name><xref ref-type="aff" rid="aff070"><sup>70</sup></xref></contrib><contrib contrib-type="author"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0003-1169-3853</contrib-id><name><surname>Meijers-Heijboer</surname><given-names>Hanne</given-names></name><xref ref-type="aff" rid="aff071"><sup>71</sup></xref></contrib><contrib contrib-type="author"><name><surname>Meindl</surname><given-names>Alfons</given-names></name><xref ref-type="aff" rid="aff072"><sup>72</sup></xref></contrib><contrib contrib-type="author"><name><surname>Neuhausen</surname><given-names>Susan L.</given-names></name><xref ref-type="aff" rid="aff073"><sup>73</sup></xref></contrib><contrib contrib-type="author"><name><surname>Nevanlinna</surname><given-names>Heli</given-names></name><xref ref-type="aff" rid="aff074"><sup>74</sup></xref></contrib><contrib contrib-type="author"><name><surname>Neven</surname><given-names>Patrick</given-names></name><xref ref-type="aff" rid="aff075"><sup>75</sup></xref></contrib><contrib contrib-type="author"><name><surname>Olson</surname><given-names>Janet E.</given-names></name><xref ref-type="aff" rid="aff076"><sup>76</sup></xref></contrib><contrib contrib-type="author"><name><surname>Perez</surname><given-names>Jose I. A.</given-names></name><xref ref-type="aff" rid="aff077"><sup>77</sup></xref></contrib><contrib contrib-type="author"><name><surname>Perkins</surname><given-names>Barbara</given-names></name><xref ref-type="aff" rid="aff078"><sup>78</sup></xref></contrib><contrib contrib-type="author"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0001-6951-6855</contrib-id><name><surname>Peterlongo</surname><given-names>Paolo</given-names></name><xref ref-type="aff" rid="aff079"><sup>79</sup></xref></contrib><contrib contrib-type="author"><name><surname>Phillips</surname><given-names>Kelly-Anne</given-names></name><xref ref-type="aff" rid="aff080"><sup>80</sup></xref><xref ref-type="aff" rid="aff081"><sup>81</sup></xref><xref ref-type="aff" rid="aff082"><sup>82</sup></xref></contrib><contrib contrib-type="author"><name><surname>Pylkäs</surname><given-names>Katri</given-names></name><xref ref-type="aff" rid="aff083"><sup>83</sup></xref></contrib><contrib contrib-type="author"><name><surname>Rudolph</surname><given-names>Anja</given-names></name><xref ref-type="aff" rid="aff009"><sup>9</sup></xref></contrib><contrib contrib-type="author"><name><surname>Santella</surname><given-names>Regina</given-names></name><xref ref-type="aff" rid="aff084"><sup>84</sup></xref><xref ref-type="aff" rid="aff085"><sup>85</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sawyer</surname><given-names>Elinor J.</given-names></name><xref ref-type="aff" rid="aff086"><sup>86</sup></xref></contrib><contrib contrib-type="author"><name><surname>Schmutzler</surname><given-names>Rita K.</given-names></name><xref ref-type="aff" rid="aff087"><sup>87</sup></xref><xref ref-type="aff" rid="aff088"><sup>88</sup></xref><xref ref-type="aff" rid="aff089"><sup>89</sup></xref><xref ref-type="aff" rid="aff090"><sup>90</sup></xref></contrib><contrib contrib-type="author"><name><surname>Seynaeve</surname><given-names>Caroline</given-names></name><xref ref-type="aff" rid="aff053"><sup>53</sup></xref></contrib><contrib contrib-type="author"><name><surname>Shah</surname><given-names>Mitul</given-names></name><xref ref-type="aff" rid="aff078"><sup>78</sup></xref></contrib><contrib contrib-type="author"><name><surname>Shrubsole</surname><given-names>Martha J.</given-names></name><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Southey</surname><given-names>Melissa C.</given-names></name><xref ref-type="aff" rid="aff091"><sup>91</sup></xref></contrib><contrib contrib-type="author"><name><surname>Swerdlow</surname><given-names>Anthony J.</given-names></name><xref ref-type="aff" rid="aff004"><sup>4</sup></xref><xref ref-type="aff" rid="aff092"><sup>92</sup></xref></contrib><contrib contrib-type="author"><name><surname>Toland</surname><given-names>Amanda E.</given-names></name><xref ref-type="aff" rid="aff093"><sup>93</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tomlinson</surname><given-names>Ian</given-names></name><xref ref-type="aff" rid="aff094"><sup>94</sup></xref></contrib><contrib contrib-type="author"><name><surname>Torres</surname><given-names>Diana</given-names></name><xref ref-type="aff" rid="aff052"><sup>52</sup></xref></contrib><contrib contrib-type="author"><name><surname>Truong</surname><given-names>Thérèse</given-names></name><xref ref-type="aff" rid="aff050"><sup>50</sup></xref><xref ref-type="aff" rid="aff051"><sup>51</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ursin</surname><given-names>Giske</given-names></name><xref ref-type="aff" rid="aff095"><sup>95</sup></xref></contrib><contrib contrib-type="author"><name><surname>Van Der Luijt</surname><given-names>Rob B.</given-names></name><xref ref-type="aff" rid="aff096"><sup>96</sup></xref></contrib><contrib contrib-type="author"><name><surname>Verhoef</surname><given-names>Senno</given-names></name><xref ref-type="aff" rid="aff008"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Whittemore</surname><given-names>Alice S.</given-names></name><xref ref-type="aff" rid="aff056"><sup>56</sup></xref></contrib><contrib contrib-type="author"><name><surname>Winqvist</surname><given-names>Robert</given-names></name><xref ref-type="aff" rid="aff083"><sup>83</sup></xref><xref ref-type="aff" rid="aff097"><sup>97</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zhao</surname><given-names>Hui</given-names></name><xref ref-type="aff" rid="aff098"><sup>98</sup></xref><xref ref-type="aff" rid="aff099"><sup>99</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zhao</surname><given-names>Shilin</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hall</surname><given-names>Per</given-names></name><xref ref-type="aff" rid="aff027"><sup>27</sup></xref></contrib><contrib contrib-type="author"><name><surname>Simard</surname><given-names>Jacques</given-names></name><xref ref-type="aff" rid="aff041"><sup>41</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kraft</surname><given-names>Peter</given-names></name><xref ref-type="aff" rid="aff100"><sup>100</sup></xref><xref ref-type="aff" rid="aff101"><sup>101</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">http://orcid.org/0000-0001-8494-732X</contrib-id><name><surname>Pharoah</surname><given-names>Paul</given-names></name><xref ref-type="aff" rid="aff003"><sup>3</sup></xref><xref ref-type="aff" rid="aff078"><sup>78</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hunter</surname><given-names>David</given-names></name><xref ref-type="aff" rid="aff100"><sup>100</sup></xref><xref ref-type="aff" rid="aff101"><sup>101</sup></xref></contrib><contrib contrib-type="author"><name><surname>Easton</surname><given-names>Douglas F.</given-names></name><xref ref-type="aff" rid="aff003"><sup>3</sup></xref><xref ref-type="aff" rid="aff078"><sup>78</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zheng</surname><given-names>Wei</given-names></name><xref ref-type="aff" rid="aff002"><sup>2</sup></xref><xref ref-type="corresp" rid="cor001">*</xref></contrib></contrib-group><aff id="aff001"><label>1</label><addr-line>Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, United States of America</addr-line></aff><aff id="aff002"><label>2</label><addr-line>Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America</addr-line></aff><aff id="aff003"><label>3</label><addr-line>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom</addr-line></aff><aff id="aff004"><label>4</label><addr-line>Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom</addr-line></aff><aff id="aff005"><label>5</label><addr-line>Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom</addr-line></aff><aff id="aff006"><label>6</label><addr-line>Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia</addr-line></aff><aff id="aff007"><label>7</label><addr-line>Centre for Epidemiology and Biostatistics, School of Population and Global health, The University of Melbourne, Melbourne, Australia</addr-line></aff><aff id="aff008"><label>8</label><addr-line>Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands</addr-line></aff><aff id="aff009"><label>9</label><addr-line>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></aff><aff id="aff010"><label>10</label><addr-line>Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany</addr-line></aff><aff id="aff011"><label>11</label><addr-line>Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, United Kingdom</addr-line></aff><aff id="aff012"><label>12</label><addr-line>Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark</addr-line></aff><aff id="aff013"><label>13</label><addr-line>Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark</addr-line></aff><aff id="aff014"><label>14</label><addr-line>Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark</addr-line></aff><aff id="aff015"><label>15</label><addr-line>Department of Health Studies, The University of Chicago, Chicago, Illinois, United States of America</addr-line></aff><aff id="aff016"><label>16</label><addr-line>Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland</addr-line></aff><aff id="aff017"><label>17</label><addr-line>Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada</addr-line></aff><aff id="aff018"><label>18</label><addr-line>Department of Molecular Genetics, University of Toronto, Toronto, Canada</addr-line></aff><aff id="aff019"><label>19</label><addr-line>Department of Epidemiology, University of California Irvine, Irvine, California, United States of America</addr-line></aff><aff id="aff020"><label>20</label><addr-line>Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></aff><aff id="aff021"><label>21</label><addr-line>Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain</addr-line></aff><aff id="aff022"><label>22</label><addr-line>Centro de Investigación en Red de Enfermedades Raras, Valencia, Spain</addr-line></aff><aff id="aff023"><label>23</label><addr-line>Department of Radiation Oncology, Hannover Medical School, Hannover, Germany</addr-line></aff><aff id="aff024"><label>24</label><addr-line>Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy</addr-line></aff><aff id="aff025"><label>25</label><addr-line>Department of Genetics, Institute for Cancer Research, Radiumhospitalet, Oslo University Hospital, Oslo University Hospital, Oslo, Norway</addr-line></aff><aff id="aff026"><label>26</label><addr-line>Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway</addr-line></aff><aff id="aff027"><label>27</label><addr-line>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden</addr-line></aff><aff id="aff028"><label>28</label><addr-line>German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></aff><aff id="aff029"><label>29</label><addr-line>Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany</addr-line></aff><aff id="aff030"><label>30</label><addr-line>University of Tübingen, Tübingen, Germany</addr-line></aff><aff id="aff031"><label>31</label><addr-line>Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></aff><aff id="aff032"><label>32</label><addr-line>Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum, Bochum, Germany</addr-line></aff><aff id="aff033"><label>33</label><addr-line>Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></aff><aff id="aff034"><label>34</label><addr-line>Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></aff><aff id="aff035"><label>35</label><addr-line>Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America</addr-line></aff><aff id="aff036"><label>36</label><addr-line>Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia</addr-line></aff><aff id="aff037"><label>37</label><addr-line>Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America</addr-line></aff><aff id="aff038"><label>38</label><addr-line>Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, United Kingdom</addr-line></aff><aff id="aff039"><label>39</label><addr-line>Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands</addr-line></aff><aff id="aff040"><label>40</label><addr-line>Gynaecology Research Unit, Hannover Medical School, Hannover, Germany</addr-line></aff><aff id="aff041"><label>41</label><addr-line>Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Canada</addr-line></aff><aff id="aff042"><label>42</label><addr-line>Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany</addr-line></aff><aff id="aff043"><label>43</label><addr-line>David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, California, United States of America</addr-line></aff><aff id="aff044"><label>44</label><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America</addr-line></aff><aff id="aff045"><label>45</label><addr-line>Institute for Medical Biometrics and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany</addr-line></aff><aff id="aff046"><label>46</label><addr-line>Department of Cancer Epidemiology, Clinical Cancer Registry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany</addr-line></aff><aff id="aff047"><label>47</label><addr-line>Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark</addr-line></aff><aff id="aff048"><label>48</label><addr-line>Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research "Demokritos", Athens, Greece</addr-line></aff><aff id="aff049"><label>49</label><addr-line>Departments of Epidemiology, University of North Carolina Chapel-Hill, Chapel Hill, North Carolina, United States of America</addr-line></aff><aff id="aff050"><label>50</label><addr-line>Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, Villejuif, France</addr-line></aff><aff id="aff051"><label>51</label><addr-line>University Paris-Sud, Villejuif, France</addr-line></aff><aff id="aff052"><label>52</label><addr-line>Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></aff><aff id="aff053"><label>53</label><addr-line>Department of Surgical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands</addr-line></aff><aff id="aff054"><label>54</label><addr-line>Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland</addr-line></aff><aff id="aff055"><label>55</label><addr-line>Department of Epidemiology, Cancer Prevention Institute of California, Fremont, California, United States of America</addr-line></aff><aff id="aff056"><label>56</label><addr-line>Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California, United States of America</addr-line></aff><aff id="aff057"><label>57</label><addr-line>Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada</addr-line></aff><aff id="aff058"><label>58</label><addr-line>Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada</addr-line></aff><aff id="aff059"><label>59</label><addr-line>Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland</addr-line></aff><aff id="aff060"><label>60</label><addr-line>Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</addr-line></aff><aff id="aff061"><label>61</label><addr-line>Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland</addr-line></aff><aff id="aff062"><label>62</label><addr-line>Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway</addr-line></aff><aff id="aff063"><label>63</label><addr-line>University of Hawaii Cancer Center, Honolulu, Hawaii, United States of America</addr-line></aff><aff id="aff064"><label>64</label><addr-line>Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden</addr-line></aff><aff id="aff065"><label>65</label><addr-line>Clinical Gerontology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom</addr-line></aff><aff id="aff066"><label>66</label><addr-line>Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America</addr-line></aff><aff id="aff067"><label>67</label><addr-line>Department of Oncology – Pathology, Karolinska Institutet, Stockholm, Sweden</addr-line></aff><aff id="aff068"><label>68</label><addr-line>National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany</addr-line></aff><aff id="aff069"><label>69</label><addr-line>Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany</addr-line></aff><aff id="aff070"><label>70</label><addr-line>Anatomical Pathology, The Alfred Hospital, Melbourne, Australia</addr-line></aff><aff id="aff071"><label>71</label><addr-line>Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands</addr-line></aff><aff id="aff072"><label>72</label><addr-line>Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany</addr-line></aff><aff id="aff073"><label>73</label><addr-line>Beckman Research Institute of City of Hope, Duarte, California, United States of America</addr-line></aff><aff id="aff074"><label>74</label><addr-line>Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland</addr-line></aff><aff id="aff075"><label>75</label><addr-line>Department of Oncology, University Hospital Gasthuisberg, Leuven, Belgium</addr-line></aff><aff id="aff076"><label>76</label><addr-line>Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America</addr-line></aff><aff id="aff077"><label>77</label><addr-line>Servicio de Cirugía General y Especialidades, Hospital Monte Naranco, Oviedo, Spain</addr-line></aff><aff id="aff078"><label>78</label><addr-line>Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></aff><aff id="aff079"><label>79</label><addr-line>IFOM, Fondazione Istituto FIRC (Italian Foundation of Cancer Research) di Oncologia Molecolare, Milan, Italy</addr-line></aff><aff id="aff080"><label>80</label><addr-line>Peter MacCallum Cancer Center, The University of Melbourne, Melbourne, Australia</addr-line></aff><aff id="aff081"><label>81</label><addr-line>Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia</addr-line></aff><aff id="aff082"><label>82</label><addr-line>Department of Medicine, St Vincent’s Hospital, The University of Melbourne, Fitzroy, Australia</addr-line></aff><aff id="aff083"><label>83</label><addr-line>Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, Oulu, Finland</addr-line></aff><aff id="aff084"><label>84</label><addr-line>Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, United States of America</addr-line></aff><aff id="aff085"><label>85</label><addr-line>Department of Environmental Health Sciences, Mailman School of Public Health of Columbia University, New York, New York, United States of America</addr-line></aff><aff id="aff086"><label>86</label><addr-line>Research Oncology, Guy’s Hospital, King's College London, London, United Kingdom</addr-line></aff><aff id="aff087"><label>87</label><addr-line>Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne, Cologne, Germany</addr-line></aff><aff id="aff088"><label>88</label><addr-line>Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany</addr-line></aff><aff id="aff089"><label>89</label><addr-line>Center for Molecular Medicine, University Hospital of Cologne, Cologne, Germany</addr-line></aff><aff id="aff090"><label>90</label><addr-line>Center of Familial Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany</addr-line></aff><aff id="aff091"><label>91</label><addr-line>Department of Pathology, The University of Melbourne, Melbourne, Australia</addr-line></aff><aff id="aff092"><label>92</label><addr-line>Division of Breast Cancer Research, The Institute of Cancer Research, London, United Kingdom</addr-line></aff><aff id="aff093"><label>93</label><addr-line>Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America</addr-line></aff><aff id="aff094"><label>94</label><addr-line>Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom</addr-line></aff><aff id="aff095"><label>95</label><addr-line>Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway</addr-line></aff><aff id="aff096"><label>96</label><addr-line>Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands</addr-line></aff><aff id="aff097"><label>97</label><addr-line>Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland</addr-line></aff><aff id="aff098"><label>98</label><addr-line>Vesalius Research Center, Leuven, Belgium</addr-line></aff><aff id="aff099"><label>99</label><addr-line>Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium</addr-line></aff><aff id="aff100"><label>100</label><addr-line>Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts, United States of America</addr-line></aff><aff id="aff101"><label>101</label><addr-line>Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Beck</surname><given-names>Andrew H.</given-names></name><role>Academic Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>Harvard Medical School, UNITED STATES</addr-line></aff><author-notes><fn fn-type="COI-statement" id="coi001"><p>The authors have declared that no competing interests exist.</p></fn><fn fn-type="con" id="contrib001"><p>Analyzed the data: YG SWA WZ. Wrote the first draft of the manuscript: YG SWA WZ. Contributed to the writing of the manuscript: YG SWA WZ XOS. Agree with the manuscript’s results and conclusions: YG SWA XOS KM MKB QW MGC RLM MKS JCC AD SEB HA KA ILA HAC VA MWB ABF JBe NVB BBo ALBD JBr HBra HBre TB BBu GC GCT FJC AC SSC KC PD TD MD PAF JF DFJ OF HF FF MG GGG PG CAH UH MJH JLH AJ FJ MJ EMJ NJ MEJ MKa MKi JAK LBK VMK VK LLM EL JLi AL RL JLu KEM AMa SM FM CM HMH AMe SLN HN PN JEO JIAP BP PPe KAP KP AR RS EJS RKS CS MS MJS MCS AJS AET IT DT TT GU RBVDL SV ASW RW HZ SZ PH JS PK PPh DH DFE WZ. Contributed to the collection of data in the original consortia: XOS KM MKB QW MGC RLM MKS JCC AD SEB HA KA ILA HAC VA MWB ABF JBe NVB BBo ALBD JBr HBra HBre TB BBu GC GCT FJC AC SSC KC PD TD MD PAF JF DFJ OF HF FF MG GGG PG CAH UH MJH JLH AJ FJ MJ EMJ NJ MEJ MKa MKi JAK LBK VMK VK LLM EL JLi AL RL JLu KEM AMa SM FM CM HMH AMe SLN HN PN JEO JIAP BP PPe KAP KP AR RS EJS RKS CS MS MJS MCS AJS AET IT DT TT GU RBVDL SV ASW RW HZ SZ PH JS PK PPh DH DFE WZ. All authors have read, and confirm that they meet, ICMJE criteria for authorship.</p></fn><corresp id="cor001">* E-mail: <email>wei.zheng@vanderbilt.edu</email></corresp></author-notes><pub-date pub-type="epub"><day>23</day><month>8</month><year>2016</year></pub-date><pub-date pub-type="collection"><month>8</month><year>2016</year></pub-date><volume>13</volume><issue>8</issue><elocation-id>e1002105</elocation-id><history><date date-type="received"><day>3</day><month>12</month><year>2015</year></date><date date-type="accepted"><day>24</day><month>6</month><year>2016</year></date></history><permissions><copyright-statement>© 2016 Guo et al</copyright-statement><copyright-year>2016</copyright-year><copyright-holder>Guo et al</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="pmed.1002105.pdf"></self-uri><abstract><sec id="sec001"><title>Background</title><p>Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.</p></sec><sec id="sec002"><title>Methods</title><p>We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases = 46,325, controls = 42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively.</p></sec><sec id="sec003"><title>Results</title><p>In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR] = 0.65 per 5 kg/m<sup>2</sup> increase, 95% confidence interval [CI]: 0.56–0.75, <italic>p</italic> = 3.32 × 10<sup>−10</sup>). The associations were similar for both premenopausal (OR = 0.44, 95% CI:0.31–0.62, <italic>p</italic> = 9.91 × 10<sup>−8</sup>) and postmenopausal breast cancer (OR = 0.57, 95% CI: 0.46–0.71, <italic>p</italic> = 1.88 × 10<sup>−8</sup>). This association was replicated in the data from the DRIVE consortium (OR = 0.72, 95% CI: 0.60–0.84, <italic>p</italic> = 1.64 × 10<sup>−7</sup>). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at <italic>p</italic> < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk.</p></sec><sec id="sec004"><title>Conclusions</title><p>BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.</p></sec></abstract><abstract abstract-type="toc"><p>Using Mendelian randomization analysis, Wei Zheng and colleagues probe potentially causal associations between BMI and breast cancer risk in both pre- and postmenopausal women.</p></abstract><abstract abstract-type="summary"><title>Author Summary</title><sec id="sec005"><title>Why Was This Study Done?</title><list list-type="bullet"><list-item><p>Body mass index (BMI) has been linked to breast cancer risk in conventional population studies.</p></list-item><list-item><p>In these studies, high BMI is associated with reduced risk of breast cancer in premenopausal women but with increased risk in postmenopausal women. These changed risks may be caused by BMI or caused by environmental factors that are associated with BMI.</p></list-item><list-item><p>We sought to use a research tool from the genetics field to understand BMI’s causal role in breast cancer.</p></list-item></list></sec><sec id="sec006"><title>What Did the Researchers Do and Find?</title><list list-type="bullet"><list-item><p>We took advantage of previously identified genetic sequence variations that are associated with BMI in European populations and used these variants to predict BMI. These variants are set at birth and are not affected by environmental factors; thus, outcomes associated with high BMI as predicted by genetic variants are more likely to be caused by high BMI itself rather than by environmental factors that are associated with high BMI.</p></list-item><list-item><p>Using databases containing individual genetic sequences and breast cancer diagnoses in a European population, we tested whether genetically predicted BMI was associated with diagnosis of breast cancer in either pre- or postmenopausal women.</p></list-item><list-item><p>We found that genetically predicted high BMI was associated with decreased breast cancer risk, in both cancer databases. Unexpectedly, this was true for both pre- and postmenopausal women.</p></list-item></list></sec><sec id="sec007"><title>What Do These Findings Mean?</title><list list-type="bullet"><list-item><p>Our results from postmenopausal women contradict prior findings from population studies, which used measured, rather than genetically predicted, BMI.</p></list-item><list-item><p>BMI predicted using genetic variants identified to date may be more closely related to body weight in early life or midlife, which is negatively associated with risk of breast cancer. Measured high BMI later in life may be influenced by environmental factors that are associated with increased risk of breast cancer.</p></list-item><list-item><p>More research is needed on the interrelationship of genetic factors, environment, and BMI in the risk of breast cancer.</p></list-item></list></sec></abstract><funding-group><award-group id="award001"><funding-source><institution-wrap><institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/100000054</institution-id><institution>National Cancer Institute</institution></institution-wrap></funding-source><award-id>R37CA070867</award-id><principal-award-recipient><name><surname>Zheng</surname><given-names>Wei</given-names></name></principal-award-recipient></award-group><award-group id="award002"><funding-source><institution-wrap><institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/100000054</institution-id><institution>National Cancer Institute</institution></institution-wrap></funding-source><award-id>R25CA160056</award-id><principal-award-recipient><name><surname>Shu</surname><given-names>Xiao-Ou</given-names></name></principal-award-recipient></award-group><funding-statement>The work conducted for this project at Vanderbilt University is supported primarily by National Cancer Institute research grants (R37CA070867 and R25CA160056) and endowment funds for the Ingram Professorship and Anne Potter Wilson Chair. JF is a volunteer for the NCI in the Epidemiology and Biostatistics Program and has no role in funding decisions. A complete funding statement is available in the Supporting Information. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement></funding-group><counts><fig-count count="2"></fig-count><table-count count="3"></table-count><page-count count="18"></page-count></counts><custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name><meta-value>The GAME-ON summary statistics are free to access (<ext-link ext-link-type="uri" xlink:href="http://epi.grants.cancer.gov/gameon/">http://epi.grants.cancer.gov/gameon/</ext-link>). To request the data from the Breast Cancer Association Consortium (BCAC), readers are instructed to submit a concept proposal, which will be reviewed by the BCAC Data Access Coordination Committee (DACC) (<ext-link ext-link-type="uri" xlink:href="http://ccge.medschl.cam.ac.uk/consortia/bcac/">http://ccge.medschl.cam.ac.uk/consortia/bcac/</ext-link>). Over the past seven years, more than 500 concept proposals have been approved, including many from non-BCAC investigators.</meta-value></custom-meta></custom-meta-group></article-meta><notes><title>Data Availability</title><p>The GAME-ON summary statistics are free to access (<ext-link ext-link-type="uri" xlink:href="http://epi.grants.cancer.gov/gameon/">http://epi.grants.cancer.gov/gameon/</ext-link>). To request the data from the Breast Cancer Association Consortium (BCAC), readers are instructed to submit a concept proposal, which will be reviewed by the BCAC Data Access Coordination Committee (DACC) (<ext-link ext-link-type="uri" xlink:href="http://ccge.medschl.cam.ac.uk/consortia/bcac/">http://ccge.medschl.cam.ac.uk/consortia/bcac/</ext-link>). Over the past seven years, more than 500 concept proposals have been approved, including many from non-BCAC investigators.</p></notes></front><body><sec sec-type="intro" id="sec008"><title>Introduction</title><p>The association between body mass index (BMI) and breast cancer risk has been extensively investigated in observational epidemiologic studies. Most prospective cohort studies reported an inverse association between BMI and premenopausal breast cancer risk [<xref rid="pmed.1002105.ref001" ref-type="bibr">1</xref>–<xref rid="pmed.1002105.ref007" ref-type="bibr">7</xref>]. A modest positive association has been reported between BMI and postmenopausal breast cancer risk [<xref rid="pmed.1002105.ref001" ref-type="bibr">1</xref>,<xref rid="pmed.1002105.ref003" ref-type="bibr">3</xref>,<xref rid="pmed.1002105.ref008" ref-type="bibr">8</xref>], and this association was primarily limited to women who did not use postmenopausal hormone therapy (HT) [<xref rid="pmed.1002105.ref002" ref-type="bibr">2</xref>,<xref rid="pmed.1002105.ref009" ref-type="bibr">9</xref>,<xref rid="pmed.1002105.ref010" ref-type="bibr">10</xref>] or women diagnosed with estrogen receptor (ER)-positive breast cancer [<xref rid="pmed.1002105.ref010" ref-type="bibr">10</xref>].</p><p>Several explanations have been proposed for the opposite direction of the association between BMI and breast cancer risk by menopausal status. For example, it is postulated that overweight and obese women are more likely to experience anovulatory menstrual cycles, potentially leading to lower exposure to ovarian hormones and thus reducing the risk of breast cancer in premenopausal women [<xref rid="pmed.1002105.ref011" ref-type="bibr">11</xref>,<xref rid="pmed.1002105.ref012" ref-type="bibr">12</xref>]. Among postmenopausal women, the primary source of estrogen is the conversion of androgens in adipose tissue. Overweight women have been found to have higher estrogen levels than normal weight women, providing a possible explanation for positive associations observed between BMI and breast cancer risk in postmenopausal women. Although these postulated explanations are biologically plausible for the different associations observed between measured BMI and breast cancer risk in pre-and postmenopausal women, it remains unclear whether BMI is causally associated with breast cancer risk or serves as a surrogate measure for other risk factors. These uncertainties should be clearly communicated in public health messages about breast cancer prevention.</p><p>Recent genome-wide association studies (GWAS) have identified multiple loci associated with BMI. A genetic score, comprising BMI-associated single nucleotide polymorphisms (SNPs) capturing the portion of BMI determined by genetic factors, can be used in Mendelian randomization (MR) as the instrumental variable to evaluate the association between BMI and breast cancer risk by eliminating concerns of reverse causation and reducing the likelihood of selection bias and confounding in conventional epidemiologic studies. This is because the alleles associated with BMI should be randomly assigned to offspring from parents during gamete formation. In this study, data from two large consortia were used to conduct a MR analysis to assess the association between BMI and breast cancer risk.</p></sec><sec sec-type="materials|methods" id="sec009"><title>Methods</title><sec id="sec010"><title>Study Population: BCAC and DRIVE Consortia</title><p>We obtained data from two large consortia, the Breast Cancer Association Consortium (BCAC) and the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. All participating studies obtained written, informed consent from all subjects and received study protocol approval from their respective Institutional Review Boards. Our first analysis included 39 studies contributing participants of European ancestry to the BCAC Collaborative Oncological Gene Environment Study (COGS) project (<xref ref-type="supplementary-material" rid="pmed.1002105.s002">S1 Table</xref>). This analysis included data from 46,235 breast cancer cases and 42,482 controls. Selected characteristics of BCAC participants by study are provided in <xref ref-type="supplementary-material" rid="pmed.1002105.s003">S2 Table</xref>. Details of the genotyping protocol in the BCAC are described elsewhere [<xref rid="pmed.1002105.ref013" ref-type="bibr">13</xref>] (<ext-link ext-link-type="uri" xlink:href="http://ccge.medschl.cam.ac.uk/research/consortia/icogs/">http://ccge.medschl.cam.ac.uk/research/consortia/icogs/</ext-link>). Genotype data were obtained either by direct genotyping using a custom Illumina iSelect genotyping array (iCOGS) that contains 211,155 SNPs [<xref rid="pmed.1002105.ref013" ref-type="bibr">13</xref>] or by imputation, using data from the iCOGS array and the 1000 Genomes Project Phase I integrated variant set (March 2012 release) as the reference using the program IMPUTE2 [<xref rid="pmed.1002105.ref014" ref-type="bibr">14</xref>]. Population-specific variations in allele frequencies of the SNPs were accounted for by eight principal components using a set of 37,000 uncorrelated SNPs, including those selected as ancestry-informative markers, as previously described [<xref rid="pmed.1002105.ref013" ref-type="bibr">13</xref>].</p><p>To further assess the association between genetically predicted BMI and breast cancer risk, we analyzed data from the DRIVE project, for which summary-level statistics from 16,003 breast cancer cases and 41,335 controls of European ancestry from 11 participating studies were available (<xref ref-type="supplementary-material" rid="pmed.1002105.s004">S3 Table</xref>). DRIVE project genotyping data were generated by Illumina and Affymetrix SNP genotyping arrays or by genotype imputation with the HapMap phase 2 CEU panel as reference using MACH v1.0 [<xref rid="pmed.1002105.ref015" ref-type="bibr">15</xref>] or IMPUTE [<xref rid="pmed.1002105.ref014" ref-type="bibr">14</xref>].</p></sec><sec id="sec011"><title>Selection of BMI-Associated SNPs</title><p>SNPs associated with variation in BMI were identified from the NHGRI-EBI Catalog of Published Genome-Wide Association Studies in August 2015 [<xref rid="pmed.1002105.ref016" ref-type="bibr">16</xref>]. Furthermore, we included all BMI-associated SNPs from the latest finding of Genetic Investigation of Anthropometric Traits (GIANT) [<xref rid="pmed.1002105.ref017" ref-type="bibr">17</xref>]. SNPs associated with BMI at genome-wide significance levels (<italic>p</italic> < 5 × 10<sup>−8</sup>) in populations of European ancestry were selected for this study. We selected independent SNPs, defined as r<sup>2</sup> < 0.1 based on International HapMap Project phase 3 data. For any two SNPs with an r<sup>2</sup> ≥ 0.1, the SNP with the lower <italic>p</italic>-value for association with BMI was selected. In total, 84 SNPs were selected for analysis. In BCAC data, 50 of the 84 SNPs were successfully genotyped, and the remaining 34 SNPs were imputed with high quality (imputation <italic>r</italic><sup>2</sup> > 0.8).</p></sec><sec id="sec012"><title>Statistical Analysis</title><p>Genetic scores for BMI (BMI-GS) used for MR were computed using previously described methods [<xref rid="pmed.1002105.ref018" ref-type="bibr">18</xref>–<xref rid="pmed.1002105.ref022" ref-type="bibr">22</xref>]. The GS used in our primary analysis was constructed using external weights, and calculated using the following formula: <inline-formula id="pmed.1002105.e001"><alternatives><graphic xlink:href="pmed.1002105.e001.jpg" id="pmed.1002105.e001g" mimetype="image" position="anchor" orientation="portrait"></graphic><mml:math id="M1"><mml:mrow><mml:mi>G</mml:mi><mml:mi>S</mml:mi><mml:mo>=</mml:mo><mml:mstyle displaystyle="true"><mml:msubsup><mml:mo>∑</mml:mo><mml:mrow><mml:mi>i</mml:mi><mml:mo>=</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mrow><mml:mn>84</mml:mn></mml:mrow></mml:msubsup><mml:mrow><mml:msub><mml:mi>β</mml:mi><mml:mi>i</mml:mi></mml:msub><mml:mi>S</mml:mi><mml:mi>N</mml:mi><mml:msub><mml:mi>P</mml:mi><mml:mi>i</mml:mi></mml:msub></mml:mrow></mml:mstyle></mml:mrow></mml:math></alternatives></inline-formula>, where <italic>β</italic><sub><italic>i</italic></sub> is the effect of the <italic>i</italic>th SNP for BMI reported in previous studies [<xref rid="pmed.1002105.ref017" ref-type="bibr">17</xref>] and <italic>SNP</italic><sub><italic>i</italic></sub> is the dosage of the effect allele (range: 0 to 2) of the <italic>i</italic>th SNP. To scale the GS to the unit of BMI, we first performed a linear regression among controls, observed BMI ~ GS + error, where the expectation of error is zero. From this regression we obtained <italic>β</italic><sub><italic>0</italic></sub> (slope = 18.99) and <italic>β</italic><sub><italic>1</italic></sub> (effect = 0.451). Then, we used the values of <italic>β</italic><sub><italic>0</italic></sub> and <italic>β</italic><sub><italic>1</italic></sub> to compute BMI-GS using the formula, BMI-GS = <italic>β</italic><sub><italic>0</italic></sub><italic>+ β</italic><sub><italic>1</italic></sub><italic>* GS</italic>. The BMI-GS is a linear transformation of GS, and thus, these two variables were perfectly correlated (r = 1.0).</p><p>Pooled analyses and meta-analysis were conducted to evaluate the association of BMI-GS with breast cancer risk. In pooled analysis, subjects from all BCAC studies were analyzed with adjustment for the BCAC study sites. In meta-analysis, we estimated the risk of breast cancer associated with BMI-GS in each of the BCAC studies, and then combined the results using a fixed effects model. Sensitivity analyses were performed using an unweighted BMI-GS to evaluate the robustness of the association (<xref ref-type="supplementary-material" rid="pmed.1002105.s005">S4 Table</xref>). The percentage of BMI variation explained by BMI-GS was calculated using linear regression models. We performed Egger regression [<xref rid="pmed.1002105.ref023" ref-type="bibr">23</xref>] analysis to detect possible pleiotropic effects of the instrumental variable used in our analyses.</p><p>Logistic regression was used to calculate adjusted odds ratios for the association between BMI-GS (continuously and categorically: 25.5–25.9, 26.0–26.5, and ≥26.5 kg/m<sup>2</sup>), versus <25.5. Traditional World Health Organization BMI cutoffs were not used because of the narrow range of the BMI predicted by BMI-GSs (range: 24.14–28.53).</p><p>We performed stratified analyses by factors that could potentially modify the association, including age, menopausal status, and postmenopausal HT. We assessed heterogeneity by hormone receptor status. Potential confounders included in logistic regression models were BCAC study site, age, and the eight principal components as described previously [<xref rid="pmed.1002105.ref013" ref-type="bibr">13</xref>]. In some analyses, we also adjusted for known and suspected breast cancer risk factors, including age at menarche, HT use, and smoking. We used the two-sample method [<xref rid="pmed.1002105.ref024" ref-type="bibr">24</xref>] to analyze the association of BMI-GS and breast cancer risk using the summary statistics data obtained from the DRIVE project (available on the Genetic Associations and Mechanisms in Oncology [GAME-ON] website: <ext-link ext-link-type="uri" xlink:href="http://gameon.dfci.harvard.edu">http://gameon.dfci.harvard.edu</ext-link>). The potential causal association between BMI (<italic>X</italic>) and breast cancer risk (<italic>Y</italic>) was modeled using BMI-associated SNPs as the instrumental variable [<xref rid="pmed.1002105.ref025" ref-type="bibr">25</xref>]. Specifically, the causal effect (<italic>β</italic><sub><italic>YX</italic></sub>) was calculated by using the Wald estimator: <inline-formula id="pmed.1002105.e002"><alternatives><graphic xlink:href="pmed.1002105.e002.jpg" id="pmed.1002105.e002g" mimetype="image" position="anchor" orientation="portrait"></graphic><mml:math id="M2"><mml:mrow><mml:msub><mml:mi>β</mml:mi><mml:mrow><mml:mi>Y</mml:mi><mml:mi>X</mml:mi></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:mfrac><mml:mrow><mml:msub><mml:mi>β</mml:mi><mml:mrow><mml:mi>Y</mml:mi><mml:mi>G</mml:mi></mml:mrow></mml:msub></mml:mrow><mml:mrow><mml:msub><mml:mi>β</mml:mi><mml:mrow><mml:mi>X</mml:mi><mml:mi>G</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:mfrac></mml:mrow></mml:math></alternatives></inline-formula>, where <italic>β</italic><sub><italic>YG</italic></sub> is the natural log-scale odds ratio (OR) for breast cancer risk associated with the instrumental variable; <italic>β</italic><sub><italic>XG</italic></sub> is the regression coefficient of the instrumental variable for BMI obtained from previous GWAS [<xref rid="pmed.1002105.ref017" ref-type="bibr">17</xref>]. The standard error for the causal effect was computed using the delta method [<xref rid="pmed.1002105.ref026" ref-type="bibr">26</xref>]: <inline-formula id="pmed.1002105.e003"><alternatives><graphic xlink:href="pmed.1002105.e003.jpg" id="pmed.1002105.e003g" mimetype="image" position="anchor" orientation="portrait"></graphic><mml:math id="M3"><mml:mrow><mml:mi>S</mml:mi><mml:msub><mml:mi>E</mml:mi><mml:mrow><mml:mi>Y</mml:mi><mml:mi>X</mml:mi></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:msqrt><mml:mrow><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:msup><mml:mrow><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mfrac><mml:mrow><mml:msub><mml:mi>S</mml:mi><mml:mrow><mml:mi>Y</mml:mi><mml:mi>G</mml:mi></mml:mrow></mml:msub></mml:mrow><mml:mrow><mml:msub><mml:mi>β</mml:mi><mml:mrow><mml:mi>X</mml:mi><mml:mi>G</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:mfrac></mml:mrow><mml:mo>)</mml:mo></mml:mrow></mml:mrow><mml:mn>2</mml:mn></mml:msup><mml:mo>+</mml:mo><mml:mfrac><mml:mrow><mml:msup><mml:mrow><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:msub><mml:mi>S</mml:mi><mml:mrow><mml:mi>X</mml:mi><mml:mi>G</mml:mi></mml:mrow></mml:msub><mml:msub><mml:mi>β</mml:mi><mml:mrow><mml:mi>Y</mml:mi><mml:mi>G</mml:mi></mml:mrow></mml:msub></mml:mrow><mml:mo>)</mml:mo></mml:mrow></mml:mrow><mml:mn>2</mml:mn></mml:msup></mml:mrow><mml:mrow><mml:msub><mml:mi>β</mml:mi><mml:mrow><mml:mi>X</mml:mi><mml:mi>G</mml:mi></mml:mrow></mml:msub><mml:msup><mml:mrow></mml:mrow><mml:mn>4</mml:mn></mml:msup></mml:mrow></mml:mfrac></mml:mrow><mml:mo>)</mml:mo></mml:mrow></mml:mrow></mml:msqrt></mml:mrow></mml:math></alternatives></inline-formula>; <italic>S</italic><sub><italic>YG</italic></sub> and <italic>S</italic><sub><italic>XG</italic></sub> are the corresponding standard errors. We used an inverse-variance weighted method [<xref rid="pmed.1002105.ref027" ref-type="bibr">27</xref>] to evaluate the combined association of the 84 BMI-associated SNPs with breast cancer risk.</p><p>To evaluate the associations between individual SNPs and breast cancer risk, summary estimates from the BCAC and DRIVE datasets were combined using the inverse-variance weighted method [<xref rid="pmed.1002105.ref028" ref-type="bibr">28</xref>]. Analyses were performed using PLINK (v 1.07), R (v 3.02), and SAS (v 9.3). A two-sided <italic>p</italic>-value < 0.05 was considered statistically significant unless stated otherwise.</p></sec></sec><sec sec-type="results" id="sec013"><title>Results</title><p>In pooled analyses including BCAC controls, the point estimates for the associations between all 84 SNPs and BMI were in the same direction as reported in the literature. However, only 39 of the 84 SNPs showed associations with BMI at <italic>p ≤ </italic>0.05, likely because of small sample size (<xref ref-type="supplementary-material" rid="pmed.1002105.s006">S5 Table</xref>).</p><p>As expected, we observed a positive association between BMI-GS and observed BMI in pooled analyses using data from controls (<italic>p</italic> < 0.001 for premenopausal women, <italic>p</italic> < 0.001for postmenopausal women, and <italic>p</italic> < 0.001for all controls combined) (<xref ref-type="table" rid="pmed.1002105.t001">Table 1</xref>). Using data from cases and controls combined, we showed associations of BMI-GS with age at menarche (<italic>p</italic> < 0.001), postmenopausal HT use (<italic>p</italic> = 0.004), smoking (<italic>p </italic>< 0.001), and weight (<italic>p</italic> < 0.001). Results were unchanged after adjusting for observed BMI (<xref ref-type="supplementary-material" rid="pmed.1002105.s007">S6 Table</xref>).</p><table-wrap id="pmed.1002105.t001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pmed.1002105.t001</object-id><label>Table 1</label><caption><title>Associations of the weighted BMI-GSs with BMI and traditional breast cancer risk factors.</title></caption><alternatives><graphic id="pmed.1002105.t001g" xlink:href="pmed.1002105.t001"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Outcome</th><th align="left" rowspan="1" colspan="1">Number of Participants</th><th align="left" rowspan="1" colspan="1">Summary Effect<xref ref-type="table-fn" rid="t001fn002">*</xref></th><th align="left" rowspan="1" colspan="1">Standard Error</th><th align="left" rowspan="1" colspan="1"><italic>P</italic>-value</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1"><bold>BMI (kg/m</bold><sup><bold>2</bold></sup><bold>)</bold><xref ref-type="table-fn" rid="t001fn003">†</xref></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"> Controls</td><td align="left" rowspan="1" colspan="1">22,056</td><td align="char" char="." rowspan="1" colspan="1">0.451</td><td align="char" char="." rowspan="1" colspan="1">0.0286</td><td align="left" rowspan="1" colspan="1">1.55 × 10<sup>−55</sup></td></tr><tr><td align="left" rowspan="1" colspan="1"> Premenopausal controls</td><td align="left" rowspan="1" colspan="1">5,532</td><td align="char" char="." rowspan="1" colspan="1">0.456</td><td align="char" char="." rowspan="1" colspan="1">0.0565</td><td align="left" rowspan="1" colspan="1">9.38 × 10<sup>−16</sup></td></tr><tr><td align="left" rowspan="1" colspan="1"> Postmenopausal controls</td><td align="left" rowspan="1" colspan="1">15,025</td><td align="char" char="." rowspan="1" colspan="1">0.449</td><td align="char" char="." rowspan="1" colspan="1">0.0345</td><td align="left" rowspan="1" colspan="1">4.96 × 10<sup>−38</sup></td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>Traditional Risk Factors</bold><xref ref-type="table-fn" rid="t001fn004">**</xref></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"> Age (years)</td><td align="left" rowspan="1" colspan="1">88,807</td><td align="char" char="." rowspan="1" colspan="1">0.0012</td><td align="char" char="." rowspan="1" colspan="1">0.0034</td><td align="left" rowspan="1" colspan="1">0.71</td></tr><tr><td align="left" rowspan="1" colspan="1"> Age at menarche (years)</td><td align="left" rowspan="1" colspan="1">53,990</td><td align="char" char="." rowspan="1" colspan="1">−0.0719</td><td align="char" char="." rowspan="1" colspan="1">0.0061</td><td align="left" rowspan="1" colspan="1">4.06 × 10<sup>−32</sup></td></tr><tr><td align="left" rowspan="1" colspan="1"> Menopausal status (post versus pre)</td><td align="left" rowspan="1" colspan="1">61,686</td><td align="char" char="." rowspan="1" colspan="1">0.0044</td><td align="char" char="." rowspan="1" colspan="1">0.0082</td><td align="left" rowspan="1" colspan="1">0.59</td></tr><tr><td align="left" rowspan="1" colspan="1"> Age at menopause (years)</td><td align="left" rowspan="1" colspan="1">26,921</td><td align="char" char="." rowspan="1" colspan="1">0.0359</td><td align="char" char="." rowspan="1" colspan="1">0.0322</td><td align="left" rowspan="1" colspan="1">0.26</td></tr><tr><td align="left" rowspan="1" colspan="1"> Family history of breast cancer (yes versus no)</td><td align="left" rowspan="1" colspan="1">47,417</td><td align="char" char="." rowspan="1" colspan="1">−0.0102</td><td align="char" char="." rowspan="1" colspan="1">0.0111</td><td align="left" rowspan="1" colspan="1">0.36</td></tr><tr><td align="left" rowspan="1" colspan="1"> Parous (yes versus no)</td><td align="left" rowspan="1" colspan="1">62,683</td><td align="char" char="." rowspan="1" colspan="1">0.0118</td><td align="char" char="." rowspan="1" colspan="1">0.0103</td><td align="left" rowspan="1" colspan="1">0.25</td></tr><tr><td align="left" rowspan="1" colspan="1"> Parity (numbers)</td><td align="left" rowspan="1" colspan="1">61,837</td><td align="char" char="." rowspan="1" colspan="1">0.0049</td><td align="char" char="." rowspan="1" colspan="1">0.0049</td><td align="left" rowspan="1" colspan="1">0.32</td></tr><tr><td align="left" rowspan="1" colspan="1"> Age at first live birth (years)</td><td align="left" rowspan="1" colspan="1">44,735</td><td align="char" char="." rowspan="1" colspan="1">−0.0563</td><td align="char" char="." rowspan="1" colspan="1">0.0206</td><td align="left" rowspan="1" colspan="1">0.006</td></tr><tr><td align="left" rowspan="1" colspan="1"> Use of HRT (postmenopausal) (ever versus never)</td><td align="left" rowspan="1" colspan="1">22,400</td><td align="char" char="." rowspan="1" colspan="1">−0.0367</td><td align="char" char="." rowspan="1" colspan="1">0.0128</td><td align="left" rowspan="1" colspan="1">0.004</td></tr><tr><td align="left" rowspan="1" colspan="1"> Breastfeeding (ever versus never)</td><td align="left" rowspan="1" colspan="1">43,321</td><td align="char" char="." rowspan="1" colspan="1">0.0125</td><td align="char" char="." rowspan="1" colspan="1">0.0095</td><td align="left" rowspan="1" colspan="1">0.19</td></tr><tr><td align="left" rowspan="1" colspan="1"> Smoking (ever versus never)</td><td align="left" rowspan="1" colspan="1">39,562</td><td align="char" char="." rowspan="1" colspan="1">0.0305</td><td align="char" char="." rowspan="1" colspan="1">0.009</td><td align="left" rowspan="1" colspan="1">0.0007</td></tr><tr><td align="left" rowspan="1" colspan="1"> Weight (control) (kg)</td><td align="left" rowspan="1" colspan="1">15,410</td><td align="char" char="." rowspan="1" colspan="1">1.3769</td><td align="char" char="." rowspan="1" colspan="1">0.0971</td><td align="left" rowspan="1" colspan="1">2.35 × 10<sup>−45</sup></td></tr><tr><td align="left" rowspan="1" colspan="1"> Height (cm)</td><td align="left" rowspan="1" colspan="1">50,706</td><td align="char" char="." rowspan="1" colspan="1">0.0336</td><td align="char" char="." rowspan="1" colspan="1">0.0255</td><td align="left" rowspan="1" colspan="1">0.19</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t001fn001"><p>HRT, hormone replacement therapy. The results stratified by menopausal status for significant risk factors are as follows: formatted as (summary effect, standard error, and <italic>p</italic>-value); age at menarche: premenopausal (−0.0802, 0.0106, 6.63 × 10<sup>−14</sup>) and postmenopausal (−0.0099, 0.001, 5.75 × 10<sup>−23</sup>); age at first birth: premenopausal (−0.0634, 0.0392, 0.11) and postmenopausal (−0.0431, 0.0246, 0.08); smoking: premenopausal (0.0382, 0.0168, 0.02) and postmenopausal (0.0285, 0.0109, 0.009); and weight: premenopausal (1.4767, 0.2133, 5.31 × 10<sup>−12</sup>) and postmenopausal: (1.3893, 0.1175, 5.24 × 10<sup>−32</sup>).</p></fn><fn id="t001fn002"><p>* The regression coefficient is presented for continuous variables and natural log-scale OR for dichotomous variables, per unit increase of the weighted BMI-GS.</p></fn><fn id="t001fn003"><p><sup>†</sup> There was no heterogeneity in the association of the weighted BMI-GS with observed BMI among cases and controls.</p></fn><fn id="t001fn004"><p>** The linear regression models fitting weight included only controls; models of all other traditional breast cancer risk factors included all subjects. The total number of subjects is 88,807 (cases + controls) in our dataset. A total of 22,056 controls have observed BMI. The premenopausal controls and the postmenopausal controls do not add up to the total number of controls because of missing menopausal status.</p></fn></table-wrap-foot></table-wrap><p>In pooled analyses of BCAC data, an inverse association was observed between breast cancer risk and genetically predicted BMI (<xref ref-type="table" rid="pmed.1002105.t002">Table 2</xref>). The OR per 5 kg/m<sup>2</sup> increase in BMI using meta-analyses was 0.65 (95% CI: 0.56–0.75, <italic>p</italic> < 3.32×10<sup>−10</sup>), which was similar to that derived from the pooled analyses, OR = 0.68 (95% CI: 0.58–0.81, <italic>p</italic> < 2.50 × 10<sup>−5</sup>). There was no apparent evidence for heterogeneity in the OR among BCAC studies (heterogeneity <italic>p</italic> = 0.06) (<xref ref-type="fig" rid="pmed.1002105.g001">Fig 1</xref>). MR-Egger regression testing on funnel plot asymmetry yielded <italic>p</italic> = 0.44, suggesting no violation of the basic assumptions for MR (<xref ref-type="supplementary-material" rid="pmed.1002105.s001">S1 Fig</xref>). In pooled analysis, adjusting for observed BMI did not change the results (OR = 0.57, 95% CI: 0.45–0.70, <italic>p</italic> = 8.17×10<sup>−9</sup><italic>)</italic>. As a part of the sensitivity analysis, we also performed pooled analysis adjusting for breast cancer risk factors as covariables. As expected, adjustment of these variables slightly attenuated the association. However, the association remained highly statistically significant (<xref ref-type="fig" rid="pmed.1002105.g002">Fig 2</xref>). The OR for the association between genetically predicted BMI and breast cancer risk was similar for pre- and postmenopausal women (heterogeneity test, <italic>p</italic> = 0.45), and in postmenopausal women, it was similar for women with and without use of HT (heterogeneity test, <italic>p</italic> = 0.42). There was some evidence for a stronger association for ER-positive tumors than ER-negative tumors (heterogeneity test, ER <italic>p</italic> = 0.03). Associations were similar in population-based studies (OR = 0.52, 95% CI: 0.38–0.70, <italic>p</italic> = 1.84×10<sup>−6</sup>) and non-population-based studies (OR = 0.71, 95% CI: 0.54–0.92, <italic>p</italic> = 0.007). Analyses using categorical variables of genetically predicted BMI showed inverse results similar to analyses treating predicted BMI as a continuous variable. We also stratified subjects by age (<50 y, 50–55 y, 55–65 y, >65 y) and found an inverse association between genetically predicted BMI and breast cancer risk for all age groups ≤ 65 y (<xref ref-type="supplementary-material" rid="pmed.1002105.s008">S7 Table</xref>). No association between predicted BMI and breast cancer was observed in the age group > 65 (OR = 0.85, 95% CI: 0.62–1.15, <italic>p</italic> = 0.29). The BMI predicted using unweighted GS was also associated with reduced breast cancer risk (<xref ref-type="fig" rid="pmed.1002105.g002">Fig 2</xref>). The effect sizes were similar, but somewhat weaker for unweighted analyses. The BMI-GS explained 1.23% of variation in BMI in the BCAC control group. Analyses of summary statistics from the DRIVE project replicated the inverse association between genetically predicted BMI and breast cancer risk, OR = 0.72 (95% CI: 0.60–0.84, <italic>p</italic> = 1.64×10<sup>−7</sup>) (<xref ref-type="supplementary-material" rid="pmed.1002105.s009">S8 Table</xref>). The strength of the association observed was similar to that observed in the BCAC dataset.</p><table-wrap id="pmed.1002105.t002" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pmed.1002105.t002</object-id><label>Table 2</label><caption><title>Associations between genetically predicted BMI and breast cancer risk.</title></caption><alternatives><graphic id="pmed.1002105.t002g" xlink:href="pmed.1002105.t002"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1"></th><th align="center" colspan="4" rowspan="1">By BMI Group<xref ref-type="table-fn" rid="t002fn002">*</xref></th><th align="center" colspan="2" rowspan="2">Per 5 kg/m<sup>2</sup> Increase <xref ref-type="table-fn" rid="t002fn003">†</xref></th></tr><tr><th align="left" rowspan="1" colspan="1"></th><th align="center" rowspan="2" colspan="1">Subjects</th><th align="center" rowspan="1" colspan="1">25.5–25.9</th><th align="center" rowspan="1" colspan="1">26.0–26.5</th><th align="center" rowspan="1" colspan="1">≥26.5</th></tr><tr><th align="left" rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1">OR (95% CI)</th><th align="left" rowspan="1" colspan="1">OR (95% CI)</th><th align="left" rowspan="1" colspan="1">OR (95% CI)</th><th align="left" rowspan="1" colspan="1">OR (95% CI)</th><th align="left" rowspan="1" colspan="1"><italic>P</italic>-value</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1"><bold>All Women Combined</bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"> All subjects</td><td align="right" rowspan="1" colspan="1">88,807</td><td align="left" rowspan="1" colspan="1">0.95 (0.87–1.02)</td><td align="left" rowspan="1" colspan="1">0.90 (0.82–0.98)</td><td align="left" rowspan="1" colspan="1">0.84 (0.71–0.97)</td><td align="left" rowspan="1" colspan="1">0.65 (0.56–0.75)</td><td align="left" rowspan="1" colspan="1">3.32 × 10<sup>−10</sup></td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>By Menopausal Status</bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"> Premenopausal</td><td align="right" rowspan="1" colspan="1">19,262</td><td align="left" rowspan="1" colspan="1">0.96 (0.88–1.05)</td><td align="left" rowspan="1" colspan="1">0.91 (0.83–1.00)</td><td align="left" rowspan="1" colspan="1">0.78 (0.67–0.9.0)</td><td align="left" rowspan="1" colspan="1">0.44 (0.31–0.62)</td><td align="left" rowspan="1" colspan="1">9.91 × 10<sup>−8</sup></td></tr><tr><td align="left" rowspan="1" colspan="1"> Postmenopausal</td><td align="right" rowspan="1" colspan="1">42,424</td><td align="left" rowspan="1" colspan="1">0.96 (0.9–1.01)</td><td align="left" rowspan="1" colspan="1">0.91 (0.85–0.96)</td><td align="left" rowspan="1" colspan="1">0.88 (0.81–0.96)</td><td align="left" rowspan="1" colspan="1">0.57 (0.46–0.71)</td><td align="left" rowspan="1" colspan="1">1.88 × 10<sup>−8</sup></td></tr><tr><td align="left" rowspan="1" colspan="1"> Never HRT use</td><td align="right" rowspan="1" colspan="1">11,433</td><td align="left" rowspan="1" colspan="1">0.98 (0.87–1.09)</td><td align="left" rowspan="1" colspan="1">0.92 (0.80–1.03)</td><td align="left" rowspan="1" colspan="1">0.89 (0.75–1.04)</td><td align="left" rowspan="1" colspan="1">0.60 (0.38–0.90)</td><td align="left" rowspan="1" colspan="1">0.0097</td></tr><tr><td align="left" rowspan="1" colspan="1"> Ever HRT use</td><td align="right" rowspan="1" colspan="1">10,967</td><td align="left" rowspan="1" colspan="1">0.93 (0.82–1.04)</td><td align="left" rowspan="1" colspan="1">0.86 (0.74–0.97)</td><td align="left" rowspan="1" colspan="1">0.84 (0.69–0.99)</td><td align="left" rowspan="1" colspan="1">0.47 (0.29–0.73)</td><td align="left" rowspan="1" colspan="1">0.0002</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>By ER Status</bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"> ER-positive</td><td align="right" rowspan="1" colspan="1">69,556</td><td align="left" rowspan="1" colspan="1">0.98 (0.93–1.02)</td><td align="left" rowspan="1" colspan="1">0.93 (0.89–0.98)</td><td align="left" rowspan="1" colspan="1">0.90 (0.84–0.96)</td><td align="left" rowspan="1" colspan="1">0.68 (0.57–0.81)</td><td align="left" rowspan="1" colspan="1">2.74 × 10<sup>−6</sup></td></tr><tr><td align="left" rowspan="1" colspan="1"> ER-negative</td><td align="right" rowspan="1" colspan="1">49,770</td><td align="left" rowspan="1" colspan="1">1.01 (0.87–1.15)</td><td align="left" rowspan="1" colspan="1">0.95 (0.88–1.02)</td><td align="left" rowspan="1" colspan="1">0.91 (0.83–0.98)</td><td align="left" rowspan="1" colspan="1">0.45 (0.33–0.59)</td><td align="left" rowspan="1" colspan="1">3.41 × 10<sup>−10</sup></td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>By PR Status</bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"> PR-positive</td><td align="right" rowspan="1" colspan="1">62,231</td><td align="left" rowspan="1" colspan="1">0.98 (0.93–1.02)</td><td align="left" rowspan="1" colspan="1">0.93 (0.87–0.98)</td><td align="left" rowspan="1" colspan="1">0.89 (0.82–0.95)</td><td align="left" rowspan="1" colspan="1">0.65 (0.53–0.78)</td><td align="left" rowspan="1" colspan="1">9.52 × 10<sup>−7</sup></td></tr><tr><td align="left" rowspan="1" colspan="1"> PR-negative</td><td align="right" rowspan="1" colspan="1">52,208</td><td align="left" rowspan="1" colspan="1">1.13 (1.01–1.25)</td><td align="left" rowspan="1" colspan="1">0.92 (0.86–0.98)</td><td align="left" rowspan="1" colspan="1">0.90(0.84–0.97)</td><td align="left" rowspan="1" colspan="1">0.47 (0.36–0.60)</td><td align="left" rowspan="1" colspan="1">2.84 × 10<sup>−11</sup></td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>By ER/PR Status</bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"> ER/PR-positive</td><td align="right" rowspan="1" colspan="1">61,430</td><td align="left" rowspan="1" colspan="1">0.97 (0.92–1.02)</td><td align="left" rowspan="1" colspan="1">0.93 (0.87–0.98)</td><td align="left" rowspan="1" colspan="1">0.89 (0.82–0.95)</td><td align="left" rowspan="1" colspan="1">0.66 (0.55–0.8)</td><td align="left" rowspan="1" colspan="1">5.46 × 10<sup>−6</sup></td></tr><tr><td align="left" rowspan="1" colspan="1"> ER/PR-negative</td><td align="right" rowspan="1" colspan="1">28,855</td><td align="left" rowspan="1" colspan="1">0.93 (0.85–1.01)</td><td align="left" rowspan="1" colspan="1">0.90 (0.82–0.98)</td><td align="left" rowspan="1" colspan="1">0.80 (0.69–0.90)</td><td align="left" rowspan="1" colspan="1">0.42 (0.3–0.58)</td><td align="left" rowspan="1" colspan="1">7.19 × 10<sup>−10</sup></td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t002fn001"><p>ER, estrogen receptor; PR, progesterone receptor. Models were adjusted for age, first eight principal components, study sites, age at menarche, parity, use of contraceptive, use of hormone replacement therapy, breast feeding, and smoking status.</p></fn><fn id="t002fn002"><p>* BMI <25 is used as reference.</p></fn><fn id="t002fn003"><p><sup>†</sup> Results are presented for per 5 kg/m<sup>2</sup> increase.</p></fn></table-wrap-foot></table-wrap><fig id="pmed.1002105.g001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pmed.1002105.g001</object-id><label>Fig 1</label><caption><title>Meta-analysis of the association between genetically predicted BMI and breast cancer risk in the BCAC.</title><p>The summary OR was calculated by combining individual analysis results from each study in BCAC (<italic>p</italic> for heterogeneity = 0.06).</p></caption><graphic xlink:href="pmed.1002105.g001"></graphic></fig><fig id="pmed.1002105.g002" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pmed.1002105.g002</object-id><label>Fig 2</label><caption><title>Sensitivity analyses using pooled data for associations between genetically predicted BMI and breast cancer risk in the BCAC.</title><p>(A) Adjusted for age, study sites, and the first eight principal components. (b) Adjusted for age, study sites, the first eight principal components, and additional breast cancer risk factors: age at menarche, parity, use of contraceptive, use of hormone replacement therapy, breast feeding, and smoking status. Weighted: the BMI-GS was constructed using the additive model weighted by external beta reported from previous literatures. Unweighted: the BMI-GS was constructed using the additive model without any weight.</p></caption><graphic xlink:href="pmed.1002105.g002"></graphic></fig><p>In pooled analysis of the BCAC data, 15 of the 84 SNPs analyzed in the study showed an inverse association with breast cancer risk, and one showed positive association with breast cancer risk at <italic>p</italic> < 0.05 (<xref ref-type="supplementary-material" rid="pmed.1002105.s010">S9</xref> and <xref ref-type="supplementary-material" rid="pmed.1002105.s011">S10</xref> Tables). In the DRIVE dataset, 12 of the 84 SNP were significantly inversely associated with breast cancer risk, including 9 SNPs that were also significant in the BCAC data (<xref ref-type="supplementary-material" rid="pmed.1002105.s009">S8</xref> and <xref ref-type="supplementary-material" rid="pmed.1002105.s011">S10</xref> Tables). When the datasets were combined, 17 SNPs showed an association with breast cancer risk at <italic>p</italic> < 0.05, and 16 of them showed an inverse association (<xref ref-type="table" rid="pmed.1002105.t003">Table 3</xref> and <xref ref-type="supplementary-material" rid="pmed.1002105.s011">S10 Table</xref>). Five of the associations remained statistically significant after adjusting for multiple comparisons (<italic>p</italic> < 0.0006 for 84 comparisons).</p><table-wrap id="pmed.1002105.t003" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pmed.1002105.t003</object-id><label>Table 3</label><caption><title>Significant associations detected at <italic>p</italic> < 0.05 between breast cancer risk and BMI-related SNPs.</title></caption><alternatives><graphic id="pmed.1002105.t003g" xlink:href="pmed.1002105.t003"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1"></th><th align="center" rowspan="1" colspan="1"></th><th align="center" rowspan="1" colspan="1"></th><th align="center" rowspan="1" colspan="1"></th><th align="center" rowspan="1" colspan="1"></th><th align="center" colspan="3" rowspan="1">BCAC<xref ref-type="table-fn" rid="t003fn001">*</xref></th><th align="center" colspan="3" rowspan="1">GAME-ON DRIVE</th><th align="center" colspan="2" rowspan="1">Combined</th></tr><tr><th align="center" rowspan="1" colspan="1">SNP</th><th align="center" rowspan="1" colspan="1">Chr</th><th align="center" rowspan="1" colspan="1">Position</th><th align="center" rowspan="1" colspan="1">Gene</th><th align="center" rowspan="1" colspan="1">Alleles</th><th align="center" rowspan="1" colspan="1">EAF</th><th align="center" rowspan="1" colspan="1">OR (95% CI)</th><th align="center" rowspan="1" colspan="1"><italic>P</italic></th><th align="center" rowspan="1" colspan="1">EAF</th><th align="center" rowspan="1" colspan="1">OR (95% CI)</th><th align="center" rowspan="1" colspan="1"><italic>P</italic></th><th align="center" rowspan="1" colspan="1">OR (95% CI)<xref ref-type="table-fn" rid="t003fn001">*</xref></th><th align="center" rowspan="1" colspan="1"><italic>P</italic></th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">rs1558902</td><td align="left" rowspan="1" colspan="1">16</td><td align="left" rowspan="1" colspan="1">53803574</td><td align="left" rowspan="1" colspan="1">RABEP1(N)</td><td align="left" rowspan="1" colspan="1">A/T</td><td align="char" char="." rowspan="1" colspan="1">0.41</td><td align="left" rowspan="1" colspan="1">0.93 (0.91–0.95)</td><td align="left" rowspan="1" colspan="1">2.77 × 10<sup>−14</sup></td><td align="char" char="." rowspan="1" colspan="1">0.68</td><td align="left" rowspan="1" colspan="1">0.95 (0.91–0.99)</td><td align="char" char="." rowspan="1" colspan="1">0.008</td><td align="left" rowspan="1" colspan="1">0.93 (0.91–0.95)</td><td align="left" rowspan="1" colspan="1">3.63 × 10<sup>−16</sup></td></tr><tr><td align="left" rowspan="1" colspan="1">rs713586</td><td align="left" rowspan="1" colspan="1">2</td><td align="left" rowspan="1" colspan="1">25158008</td><td align="left" rowspan="1" colspan="1">STXBP6(N)</td><td align="left" rowspan="1" colspan="1">C/T</td><td align="char" char="." rowspan="1" colspan="1">0.47</td><td align="left" rowspan="1" colspan="1">0.94 (0.92–0.97)</td><td align="left" rowspan="1" colspan="1">1.82 × 10<sup>−6</sup></td><td align="char" char="." rowspan="1" colspan="1">0.48</td><td align="left" rowspan="1" colspan="1">0.96 (0.93–1.00)</td><td align="char" char="." rowspan="1" colspan="1">0.03</td><td align="left" rowspan="1" colspan="1">0.95 (0.93–0.97)</td><td align="left" rowspan="1" colspan="1">3.19 × 10<sup>−7</sup></td></tr><tr><td align="left" rowspan="1" colspan="1">rs7903146</td><td align="left" rowspan="1" colspan="1">10</td><td align="left" rowspan="1" colspan="1">114758349</td><td align="left" rowspan="1" colspan="1">NRXN3</td><td align="left" rowspan="1" colspan="1">C/T</td><td align="char" char="." rowspan="1" colspan="1">0.72</td><td align="left" rowspan="1" colspan="1">0.96 (0.94–0.98)</td><td align="left" rowspan="1" colspan="1">7.01 × 10<sup>−5</sup></td><td align="char" char="." rowspan="1" colspan="1">0.70</td><td align="left" rowspan="1" colspan="1">0.96(0.92–1.00)</td><td align="char" char="." rowspan="1" colspan="1">0.04</td><td align="left" rowspan="1" colspan="1">0.96 (0.94–0.98)</td><td align="left" rowspan="1" colspan="1">8.65 × 10<sup>−6</sup></td></tr><tr><td align="left" rowspan="1" colspan="1">rs7599312</td><td align="left" rowspan="1" colspan="1">2</td><td align="left" rowspan="1" colspan="1">213413231</td><td align="left" rowspan="1" colspan="1">LMX1B(B,N)</td><td align="left" rowspan="1" colspan="1">G/A</td><td align="char" char="." rowspan="1" colspan="1">0.72</td><td align="left" rowspan="1" colspan="1">0.96 (0.94–0.98)</td><td align="left" rowspan="1" colspan="1">0.0004</td><td align="char" char="." rowspan="1" colspan="1">0.96</td><td align="left" rowspan="1" colspan="1">0.94(0.84–1.03)</td><td align="char" char="." rowspan="1" colspan="1">0.17</td><td align="left" rowspan="1" colspan="1">0.96 (0.94–0.98)</td><td align="left" rowspan="1" colspan="1">0.0002</td></tr><tr><td align="left" rowspan="1" colspan="1">rs17024393</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">110154688</td><td align="left" rowspan="1" colspan="1">BDNF(B/M)</td><td align="left" rowspan="1" colspan="1">C/T</td><td align="char" char="." rowspan="1" colspan="1">0.03</td><td align="left" rowspan="1" colspan="1">0.93 (0.87–0.98)</td><td align="left" rowspan="1" colspan="1">0.007</td><td align="char" char="." rowspan="1" colspan="1">0.41</td><td align="left" rowspan="1" colspan="1">0.96 (0.92–0.99)</td><td align="char" char="." rowspan="1" colspan="1">0.009</td><td align="left" rowspan="1" colspan="1">0.94 (0.91–0.97)</td><td align="left" rowspan="1" colspan="1">0.0003</td></tr><tr><td align="left" rowspan="1" colspan="1">rs2867125</td><td align="left" rowspan="1" colspan="1">2</td><td align="left" rowspan="1" colspan="1">622827</td><td align="left" rowspan="1" colspan="1">GNPDA2(N)</td><td align="left" rowspan="1" colspan="1">C/T</td><td align="char" char="." rowspan="1" colspan="1">0.83</td><td align="left" rowspan="1" colspan="1">0.96 (0.94–0.99)</td><td align="left" rowspan="1" colspan="1">0.003</td><td align="char" char="." rowspan="1" colspan="1">0.64</td><td align="left" rowspan="1" colspan="1">0.97 (0.94–1.00)</td><td align="char" char="." rowspan="1" colspan="1">0.07</td><td align="left" rowspan="1" colspan="1">0.96 (0.94–0.99)</td><td align="left" rowspan="1" colspan="1">0.0008</td></tr><tr><td align="left" rowspan="1" colspan="1">rs2287019</td><td align="left" rowspan="1" colspan="1">19</td><td align="left" rowspan="1" colspan="1">46202172</td><td align="left" rowspan="1" colspan="1">LI NG02(D,N)</td><td align="left" rowspan="1" colspan="1">C/T</td><td align="char" char="." rowspan="1" colspan="1">0.79</td><td align="left" rowspan="1" colspan="1">0.96 (0.93–0.99)</td><td align="left" rowspan="1" colspan="1">0.009</td><td align="char" char="." rowspan="1" colspan="1">0.80</td><td align="left" rowspan="1" colspan="1">0.96 (0.92–1.00)</td><td align="char" char="." rowspan="1" colspan="1">0.06</td><td align="left" rowspan="1" colspan="1">0.96 (0.94–0.99)</td><td align="left" rowspan="1" colspan="1">0.0010</td></tr><tr><td align="left" rowspan="1" colspan="1">rs3810291</td><td align="left" rowspan="1" colspan="1">19</td><td align="left" rowspan="1" colspan="1">47569003</td><td align="left" rowspan="1" colspan="1">CLIP1(N)</td><td align="left" rowspan="1" colspan="1">A/G</td><td align="char" char="." rowspan="1" colspan="1">0.67</td><td align="left" rowspan="1" colspan="1">0.98 (0.95–1.00)</td><td align="left" rowspan="1" colspan="1">0.01</td><td align="char" char="." rowspan="1" colspan="1">0.43</td><td align="left" rowspan="1" colspan="1">0.96 (0.92–0.99)</td><td align="char" char="." rowspan="1" colspan="1">0.01</td><td align="left" rowspan="1" colspan="1">0.97 (0.95–0.99)</td><td align="left" rowspan="1" colspan="1">0.002</td></tr><tr><td align="left" rowspan="1" colspan="1">rs571312</td><td align="left" rowspan="1" colspan="1">18</td><td align="left" rowspan="1" colspan="1">57839769</td><td align="left" rowspan="1" colspan="1">NT5C2(N)</td><td align="left" rowspan="1" colspan="1">A/C</td><td align="char" char="." rowspan="1" colspan="1">0.24</td><td align="left" rowspan="1" colspan="1">0.97 (0.95–1.00)</td><td align="left" rowspan="1" colspan="1">0.02</td><td align="char" char="." rowspan="1" colspan="1">0.23</td><td align="left" rowspan="1" colspan="1">0.96 (0.92–1.00)</td><td align="char" char="." rowspan="1" colspan="1">0.04</td><td align="left" rowspan="1" colspan="1">0.97 (0.95–0.99)</td><td align="left" rowspan="1" colspan="1">0.002</td></tr><tr><td align="left" rowspan="1" colspan="1">rs543874</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">177889480</td><td align="left" rowspan="1" colspan="1">ELAVL4(B,D,N,Q)</td><td align="left" rowspan="1" colspan="1">G/A</td><td align="char" char="." rowspan="1" colspan="1">0.19</td><td align="left" rowspan="1" colspan="1">0.97 (0.95–1.00)</td><td align="left" rowspan="1" colspan="1">0.04</td><td align="char" char="." rowspan="1" colspan="1">0.20</td><td align="left" rowspan="1" colspan="1">0.96 (0.92–1.00)</td><td align="char" char="." rowspan="1" colspan="1">0.04</td><td align="left" rowspan="1" colspan="1">0.97 (0.95–0.99)</td><td align="left" rowspan="1" colspan="1">0.005</td></tr><tr><td align="left" rowspan="1" colspan="1">rs12401738</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">78446761</td><td align="left" rowspan="1" colspan="1">HIP1(B,N)</td><td align="left" rowspan="1" colspan="1">A/G</td><td align="char" char="." rowspan="1" colspan="1">0.38</td><td align="left" rowspan="1" colspan="1">0.98 (0.96–1.00)</td><td align="left" rowspan="1" colspan="1">0.05</td><td align="char" char="." rowspan="1" colspan="1">0.38</td><td align="left" rowspan="1" colspan="1">0.96 (0.93–1.00)</td><td align="char" char="." rowspan="1" colspan="1">0.05</td><td align="left" rowspan="1" colspan="1">0.97 (0.96–0.99)</td><td align="left" rowspan="1" colspan="1">0.008</td></tr><tr><td align="left" rowspan="1" colspan="1">rs1528435</td><td align="left" rowspan="1" colspan="1">2</td><td align="left" rowspan="1" colspan="1">181550962</td><td align="left" rowspan="1" colspan="1">EHBP1(B,N)</td><td align="left" rowspan="1" colspan="1">T/C</td><td align="char" char="." rowspan="1" colspan="1">0.62</td><td align="left" rowspan="1" colspan="1">0.97 (0.95–0.99)</td><td align="left" rowspan="1" colspan="1">0.01</td><td align="char" char="." rowspan="1" colspan="1">0.63</td><td align="left" rowspan="1" colspan="1">0.98 (0.94–1.01)</td><td align="char" char="." rowspan="1" colspan="1">0.22</td><td align="left" rowspan="1" colspan="1">0.97 (0.96–0.99)</td><td align="left" rowspan="1" colspan="1">0.008</td></tr><tr><td align="left" rowspan="1" colspan="1">rs2112347</td><td align="left" rowspan="1" colspan="1">5</td><td align="left" rowspan="1" colspan="1">75015242</td><td align="left" rowspan="1" colspan="1">PRKDI(N)</td><td align="left" rowspan="1" colspan="1">T/G</td><td align="char" char="." rowspan="1" colspan="1">0.63</td><td align="left" rowspan="1" colspan="1">0.98 (0.96–1.00)</td><td align="left" rowspan="1" colspan="1">0.03</td><td align="char" char="." rowspan="1" colspan="1">0.44</td><td align="left" rowspan="1" colspan="1">0.97 (0.94–1.00)</td><td align="char" char="." rowspan="1" colspan="1">0.08</td><td align="left" rowspan="1" colspan="1">0.98 (0.96–0.99)</td><td align="left" rowspan="1" colspan="1">0.008</td></tr><tr><td align="left" rowspan="1" colspan="1">rs10733682</td><td align="left" rowspan="1" colspan="1">9</td><td align="left" rowspan="1" colspan="1">129460914</td><td align="left" rowspan="1" colspan="1">FUBPI(N)</td><td align="left" rowspan="1" colspan="1">A/G</td><td align="char" char="." rowspan="1" colspan="1">0.49</td><td align="left" rowspan="1" colspan="1">0.97 (0.95–0.99)</td><td align="left" rowspan="1" colspan="1">0.009</td><td align="char" char="." rowspan="1" colspan="1">0.47</td><td align="left" rowspan="1" colspan="1">0.99 (0.95–1.02)</td><td align="char" char="." rowspan="1" colspan="1">0.41</td><td align="left" rowspan="1" colspan="1">0.98 (0.96–0.99)</td><td align="left" rowspan="1" colspan="1">0.01</td></tr><tr><td align="left" rowspan="1" colspan="1">rs13191362</td><td align="left" rowspan="1" colspan="1">6</td><td align="left" rowspan="1" colspan="1">163033350</td><td align="left" rowspan="1" colspan="1">GPRC5B(C/Q)</td><td align="left" rowspan="1" colspan="1">A/G</td><td align="char" char="." rowspan="1" colspan="1">0.88</td><td align="left" rowspan="1" colspan="1">1.03 (1.00–1.06)</td><td align="left" rowspan="1" colspan="1">0.047</td><td align="char" char="." rowspan="1" colspan="1">0.87</td><td align="left" rowspan="1" colspan="1">1.04 (0.98–1.09)</td><td align="char" char="." rowspan="1" colspan="1">0.18</td><td align="left" rowspan="1" colspan="1">1.03 (1.01–1.06)</td><td align="left" rowspan="1" colspan="1">0.02</td></tr><tr><td align="left" rowspan="1" colspan="1">rs17405819</td><td align="left" rowspan="1" colspan="1">8</td><td align="left" rowspan="1" colspan="1">76806584</td><td align="left" rowspan="1" colspan="1">PRKD1(N)</td><td align="left" rowspan="1" colspan="1">T/C</td><td align="char" char="." rowspan="1" colspan="1">0.69</td><td align="left" rowspan="1" colspan="1">0.97 (0.95–1.00)</td><td align="left" rowspan="1" colspan="1">0.02</td><td align="char" char="." rowspan="1" colspan="1">0.69</td><td align="left" rowspan="1" colspan="1">0.99 (0.95–1.02)</td><td align="char" char="." rowspan="1" colspan="1">0.5</td><td align="left" rowspan="1" colspan="1">0.98 (0.96–1.00)</td><td align="left" rowspan="1" colspan="1">0.02</td></tr><tr><td align="left" rowspan="1" colspan="1">rs3736485</td><td align="left" rowspan="1" colspan="1">15</td><td align="left" rowspan="1" colspan="1">51748610</td><td align="left" rowspan="1" colspan="1">CADM2</td><td align="left" rowspan="1" colspan="1">A/G</td><td align="char" char="." rowspan="1" colspan="1">0.47</td><td align="left" rowspan="1" colspan="1">0.98 (0.96–1.00)</td><td align="left" rowspan="1" colspan="1">0.12</td><td align="char" char="." rowspan="1" colspan="1">0.43</td><td align="left" rowspan="1" colspan="1">0.98 (0.94–1.01)</td><td align="char" char="." rowspan="1" colspan="1">0.15</td><td align="left" rowspan="1" colspan="1">0.98 (0.96–1.00)</td><td align="left" rowspan="1" colspan="1">0.04</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t003fn001"><p>* Results are presented for per allele increase of BMI-related SNP. Chr, chromosome; EAF, effective allele frequency. BCAC models were adjusted for age, study, and first eight principal components.</p></fn></table-wrap-foot></table-wrap><p>Using data from BCAC, we conducted pooled analyses to evaluate the association of observed BMI with breast cancer risk by study design. Data from prospective cohort studies showed a positive association between observed BMI and breast cancer risk among postmenopausal women, while an inverse association was seen among premenopausal women (<xref ref-type="supplementary-material" rid="pmed.1002105.s012">S11 Table</xref>). Data from nonprospective studies, however, showed an inverse association for both pre- and postmenopausal women. Additional adjustment for BMI-GS did not alter the association between observed BMI and breast cancer risk.</p></sec><sec sec-type="conclusions" id="sec014"><title>Discussion</title><p>Utilizing data from two large consortia, we found in this large MR study a consistent inverse association between BMI predicted by GWAS-identified genetic variants and premenopausal breast cancer risk in all subgroups examined, which is qualitatively consistent with the majority of published epidemiologic studies using measured BMI, although our predicted association, a 46% reduction in risk per 5 kg/m<sup>2</sup> increase in BMI, is larger than that estimated in observational studies using measured BMI [<xref rid="pmed.1002105.ref001" ref-type="bibr">1</xref>,<xref rid="pmed.1002105.ref003" ref-type="bibr">3</xref>,<xref rid="pmed.1002105.ref005" ref-type="bibr">5</xref>,<xref rid="pmed.1002105.ref008" ref-type="bibr">8</xref>,<xref rid="pmed.1002105.ref029" ref-type="bibr">29</xref>]. Prominent hypotheses regarding the underlying cause of the association between higher BMI and decreased premenopausal breast cancer risk implicate more frequent anovulation, lower endogenous estrogen levels, and fewer breast cell divisions in obese women as compared to leaner women.</p><p>Our MR analyses demonstrate an inverse association between genetically predicted BMI and postmenopausal breast cancer risk, with a predicted effect similar to that seen in premenopausal women. In contrast, previous large observational studies indicate a 5%–15% increased risk for postmenopausal breast cancer per 5 kg/m<sup>2</sup> increase in BMI [<xref rid="pmed.1002105.ref001" ref-type="bibr">1</xref>,<xref rid="pmed.1002105.ref008" ref-type="bibr">8</xref>]. In our analysis of prospective cohort studies included in BCAC, we observed a similar increase in breast cancer risk associated with observed BMI among postmenopausal women. However, this positive association was not found in the analysis of data from case-control studies included in BCAC, perhaps due to reverse causation. Because disease diagnosis and progress could change body weight, BMI measured after cancer diagnosis, which is done in most case-control studies, does not reflect usual or long-term BMI, and case-control studies are biased in evaluating the association of BMI and cancer risk. Because no BMI data from cases were used in our MR analyses, we have effectively overcome the possible influence of reverse causation in our study results from MR analyses.</p><p>The finding for an inverse association between BMI predicted using GWAS-identified SNPs and postmenopausal breast cancer risk differs from findings reported previously in studies using measured BMI, revealing a complex relationship of genetic determinants of BMI, weight gain, and breast cancer risk. A recent study found that a BMI-GS composed of 31 GWAS-identified SNPs (the majority of which are included in our study) was positively associated with annual weight gain between age 20 y and the time of the study baseline interview when participants were middle-aged [<xref rid="pmed.1002105.ref030" ref-type="bibr">30</xref>]. On the other hand, this GS was related to a reduced weight in later adulthood. These results suggest that the genetic portion of BMI, as measured using the BMI-GS in our study, may reflect an early-life BMI.</p><p>Several studies found that early-life BMI was inversely associated with breast cancer risk, and this inverse association is consistent in premenopausal [<xref rid="pmed.1002105.ref031" ref-type="bibr">31</xref>,<xref rid="pmed.1002105.ref032" ref-type="bibr">32</xref>] and postmenopausal [<xref rid="pmed.1002105.ref031" ref-type="bibr">31</xref>,<xref rid="pmed.1002105.ref033" ref-type="bibr">33</xref>] women. It is possible that weight gain during later adulthood, not adult BMI per se, is related to increased postmenopausal breast cancer risk among overweight women as determined using measured BMI. However, we were unable to directly evaluate this hypothesis in our study because adult weight change was not consistently measured in the BCAC contributing studies. Furthermore, the SNPs used to construct the BMI-GS were identified from genetic association studies that included mostly middle-aged adults, and thus, they may not be able to measure weight gain in later adulthood adequately.</p><p>After menopause, the primary source of estrogen is formed in adipose tissue, [<xref rid="pmed.1002105.ref011" ref-type="bibr">11</xref>,<xref rid="pmed.1002105.ref034" ref-type="bibr">34</xref>] causing overweight and obese postmenopausal women to have higher circulating overall and free estradiol levels than their normal BMI counterparts. In premenopausal women, a high BMI is related to anovulatory menstrual cycles. Women with high BMI in both pre- and postmenopause may have lower lifetime estrogen exposure (and thus lower risk of breast cancer) than those who gain weight primarily after menopause. Additionally, measured BMI in postmenopausal women may be a surrogate breast cancer risk factor for adiposity-related changes occurring near or after menopause, such as age-associated slowing metabolism and inflammation associated with increased abdominal fat [<xref rid="pmed.1002105.ref035" ref-type="bibr">35</xref>]. Previous investigations support the theory that adult weight gain is positively associated with postmenopausal breast cancer risk, and some investigators have suggested that weight gain may be a more important risk factor for postmenopausal woman than postmenopausal BMI [<xref rid="pmed.1002105.ref036" ref-type="bibr">36</xref>,<xref rid="pmed.1002105.ref037" ref-type="bibr">37</xref>]. Future research will be necessary to determine the potentially complicated causal mechanisms underlying the association between BMI and breast cancer risk for postmenopausal women.</p><p>In our study, we observed associations of high BMI-GS with early age at menarche, low prevalence of postmenopausal HT use, and high prevalence of cigarette smoking. It is known that high body weight is associated with an early age at menarche [<xref rid="pmed.1002105.ref038" ref-type="bibr">38</xref>], and overweight women are more likely to smoke cigarettes regularly to reduce or maintain body weight [<xref rid="pmed.1002105.ref039" ref-type="bibr">39</xref>,<xref rid="pmed.1002105.ref040" ref-type="bibr">40</xref>]. Overweight women are less likely to use HT [<xref rid="pmed.1002105.ref041" ref-type="bibr">41</xref>] (likely because their endogenous estrogen levels are higher than normal/underweight women, and thus, they are less likely to experience postmenopausal symptoms—the major reason for HT use). Therefore, it is most likely that the association of these variables with the BMI-GS is mediated through BMI, indicating that the association of the BMI-GS with these breast cancer risk factors does not violate the assumption of MR analyses in our study. Indeed, analyses without adjusting for these variables revealed a stronger association of BMI-GS with breast cancer risk than those with adjustments of these variables. Some of the BMI-associated variants may be associated with certain functions in the central nervous system [<xref rid="pmed.1002105.ref017" ref-type="bibr">17</xref>], and these functions in turn are associated with BMI and perhaps other behaviors currently unknown to us. It is also possible that some of the BMI-associated SNPs may be related to other traits. However, we were unable to evaluate these hypotheses in our study. It would be interesting to further evaluate possible pleiotropic effects of BMI-GS in future large MR analyses with extensively measured environmental factors.</p><p>We evaluated whether postmenopausal HT use may modify the association between BMI-GS and breast cancer risk or whether the association may vary by tumor hormone receptor status. Unlike some conventional observational studies on observed BMI-postmenopausal breast cancer association [<xref rid="pmed.1002105.ref009" ref-type="bibr">9</xref>,<xref rid="pmed.1002105.ref042" ref-type="bibr">42</xref>], we did not find the association for BMI-GS to be modified by HT use. We found that the association between the BMI-GS and breast cancer risk was consistent across hormone receptor subtypes. Although ER-positive and ER-negative breast cancer are heterogeneous clinically, they do have a number of shared risk factors, such as age at menarche, benign breast disease, and family history [<xref rid="pmed.1002105.ref043" ref-type="bibr">43</xref>].</p><p>Our study has certain limitations. To date, GWAS-identified SNPs represent a small, but statistically significant, portion of the explained variance of observed BMI—approximately 2.7% [<xref rid="pmed.1002105.ref017" ref-type="bibr">17</xref>,<xref rid="pmed.1002105.ref044" ref-type="bibr">44</xref>,<xref rid="pmed.1002105.ref045" ref-type="bibr">45</xref>]. Nevertheless, the instrumental variable created in our study is sufficiently strong for conducting MR analyses [<xref rid="pmed.1002105.ref046" ref-type="bibr">46</xref>]. Only summary statistics data were available from the DRIVE project, and thus, we were unable to perform analyses stratified by menopausal status and hormone receptor status. However, most of the subjects included in the DRIVE project were postmenopausal women, and the strength of the association between BMI-GS and breast cancer observed in BCAC and DRIVE consortia was similar.</p><p>Using data from approximately 146,000 women involved in two large consortia, we provide strong evidence of an inverse association between genetically predicted BMI and breast cancer risk for both premenopausal and postmenopausal women. The present study adds to the body of knowledge on the influence of body mass on breast cancer risk and points to further work required to elucidate the mechanisms responsible for the complex relationship between BMI and breast cancer risk. Our study, along with recent findings of an association of BMI-GS with weight gain in early adult life but weight loss in late adult life, suggests that weight gain later in adulthood may explain, at least partially, the positive association reported from previous studies between measured adult BMI and postmenopausal breast cancer risk, providing further support for lifestyle modification to reduce obesity as the primary prevention of breast cancer.</p></sec><sec sec-type="supplementary-material" id="sec015"><title>Supporting Information</title><supplementary-material content-type="local-data" id="pmed.1002105.s001"><label>S1 Fig</label><caption><title>Egger regression funnel plot from the meta-analysis.</title><p>The presence of funnel plot asymmetry indicates bias.</p><p>(EPS)</p></caption><media xlink:href="pmed.1002105.s001.eps"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pmed.1002105.s002"><label>S1 Table</label><caption><title>Description of BCAC studies participating in this analysis.</title><p>(DOCX)</p></caption><media xlink:href="pmed.1002105.s002.docx"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pmed.1002105.s003"><label>S2 Table</label><caption><title>Characteristics of study participants included in the BCAC.</title><p>(DOCX)</p></caption><media xlink:href="pmed.1002105.s003.docx"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pmed.1002105.s004"><label>S3 Table</label><caption><title>Description of GAME-ON DRIVE Consortium studies participating in this analysis.</title><p>(DOCX)</p></caption><media xlink:href="pmed.1002105.s004.docx"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pmed.1002105.s005"><label>S4 Table</label><caption><title>GS computed for sensitivity analyses.</title><p>(DOCX)</p></caption><media xlink:href="pmed.1002105.s005.docx"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pmed.1002105.s006"><label>S5 Table</label><caption><title>Associations of the 84 SNPs with observed BMI in the BCAC.</title><p>(DOCX)</p></caption><media xlink:href="pmed.1002105.s006.docx"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pmed.1002105.s007"><label>S6 Table</label><caption><title>Associations of the weighted BMI-GS with traditional breast cancer risk factors adjusting for observed BMI.</title><p>(DOCX)</p></caption><media xlink:href="pmed.1002105.s007.docx"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pmed.1002105.s008"><label>S7 Table</label><caption><title>Association of genetically predicted BMI and breast cancer risk, stratified by age group.</title><p>(DOCX)</p></caption><media xlink:href="pmed.1002105.s008.docx"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pmed.1002105.s009"><label>S8 Table</label><caption><title>MR analysis of BMI and breast cancer risk in women using summary data from published BMI GWAS and DRIVE Breast Cancer GWAS.</title><p>(DOCX)</p></caption><media xlink:href="pmed.1002105.s009.docx"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pmed.1002105.s010"><label>S9 Table</label><caption><title>Associations of the 84 SNPs with breast cancer risk in the BCAC.</title><p>(DOCX)</p></caption><media xlink:href="pmed.1002105.s010.docx"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pmed.1002105.s011"><label>S10 Table</label><caption><title>Association of breast cancer risk with 84 BMI-related SNPs.</title><p>(DOCX)</p></caption><media xlink:href="pmed.1002105.s011.docx"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pmed.1002105.s012"><label>S11 Table</label><caption><title>The associations between observed BMI and breast cancer risk using BCAC data.</title><p>(DOCX)</p></caption><media xlink:href="pmed.1002105.s012.docx"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pmed.1002105.s013"><label>S1 Text</label><caption><title>Complete funding statement.</title><p>(DOCX)</p></caption><media xlink:href="pmed.1002105.s013.docx"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material></sec></body><back><ack><p>We thank Meir Stampfer for his helpful comments and all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. We also would like to thank the following: Andrew Berchuck (OCAC); Rosalind A. Eeles, Ali Amin Al Olama, Zsofia Kote-Jarai, and Sara Benlloch (PRACTICAL); Antonis Antoniou, Lesley McGuffog, and Ken Offit (CIMBA); Andrew Lee, Ed Dicks, Craig Luccarini, and the staff of the Centre for Genetic Epidemiology Laboratory; the staff of the CNIO genotyping unit; Sylvie LaBoissière, Frederic Robidoux, and the staff of the McGill University and Génome Québec Innovation Centre; the staff of the Copenhagen DNA laboratory; and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer, and the staff of Mayo Clinic Genotyping Core Facility. The authors also wish to thank the following: Maggie Angelakos, Judi Maskiell, and Gillian Dite (ABCFS); Annegien Broeks, Sten Cornelissen, Richard van Hien, Frans Hogervorst, Senno Verhoef, Laura van 't Veer, Emiel Rutgers, Ellen van der Schoot, and Femke Atsma (ABCS); Matthias Rübner, Silke Landrith, Alexander Hein, Michael Schneider, and Sonja Oeser (BBCC); Eileen Williams, Elaine Ryder-Mills, and Kara Sargus (BBCS); Niall McInerney, Gabrielle Colleran, Andrew Rowan, and Angela Jones (BIGGS); Peter Bugert, and Medical Faculty Mannheim (BSUCH); staff and participants of the Copenhagen General Population Study, Dorthe Uldall Andersen, Maria Birna Arnadottir, Anne Bank, and Dorthe Kjeldgård Hansen for the excellent technical assistance, and The Danish Breast Cancer Group (DBCG) for the tumor information (CGPS); Charo Alonso and Primitiva Menendez (CNIO-BCS); Leslie Bernstein, James Lacey, Sophia Wang, Huiyan Ma, Yani Lu, and Jessica Clague DeHart at the Beckman Research Institute of City of Hope, Dennis Deapen, Rich Pinder, Eunjung Lee, and Fred Schumacher at the University of Southern California, Pam Horn-Ross, Peggy Reynolds, Christina Clarke Dur and David Nelson at the Cancer Prevention Institute of California, and Argyrios Ziogas, and Hannah Park at the University of California Irvine (CTS); Hartwig Ziegler, Sonja Wolf, and Volker Hermann (ESTHER); Heide Hellebrand and Stefanie Engert (GC-HBOC); The GENICA Network (Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Germany [HB, Wing-Yee Lo, Christina Justenhoven], Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany [Yon-Dschun Ko, Christian Baisch], Institute of Pathology, University of Bonn, Germany [Hans-Peter Fischer], Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ) [Ute Hamann], Heidelberg, Germany and Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany [TB, Beate Pesch, Sylvia Rabstein, Anne Lotz], Institute of Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Germany [Volker Harth]); Kirsimari Aaltonen, Karl von Smitten, Sofia Khan, Tuomas Heikkinen, and Irja Erkkilä (HEBCS); Peter Hillemanns, Hans Christiansen, and Johann H. Karstens (HMBCS); Eija Myöhänen and Helena Kemiläinen (KBCP); Heather Thorne and Eveline Niedermayr (kConFab/AOCS); Gilian Peuteman, Dominiek Smeets, Thomas Van Brussel, and Kathleen Corthouts (LMBC); Petra Seibold, Judith Heinz, Nadia Obi, Alina Vrieling, Ursula Eilber, Sabine Behrens, Muhabbet Celik, and Til Olchers (MARIE); Paolo Peterlongo of IFOM, the FIRC Institute of Molecular Oncology, Siranoush Manoukian, Bernard Peissel, and Daniela Zaffaroni of the Fondazione IRCCS Istituto Nazionale dei Tumori [INT], Monica Barile, and Irene Feroce of the Istituto Europeo di Oncologia [IEO] and Loris Bernard and the personnel of the Cogentech Cancer Genetic Test Laboratory (MBCSG); Martine Tranchant at CHU de Québec Research Center, and Marie-France Valois, Annie Turgeon, and Lea Heguy at McGill University Health Center, Royal Victoria Hospital, McGill University (MTLGEBCS); NBCS study group (NBCS); Meeri Otsukka and Kari Mononen (OBCS); Teresa Selander, Gord Glendon, and Nayana Weerasooriya (OFBCR); Ellie Krol-Warmerdam, Jannet Blom, and Jan Molenaar (ORIGO); Louise Brinton, Mark Sherman, Stephen Chanock, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Pei Chao, and Michael Stagner (PBCS); The Swedish Medical Research Counsel (pKARMA and SASBAC); Ans van den Ouweland, Anja Nieuwlaat, Ellen Crepin, and Petra Bos (RBCS); Sue Higham, Helen Cramp, Dan Connley, Ian Brock, Malcolm Reed, and Sabapathy Balasubramanian (SBCS); the SEARCH and EPIC teams (SEARCH); and Robert Pilarski, Charles Shapiro, the OSU Breast Cancer Tissue Bank, and the Human Genetics Sample Bank (TNBCC). We thank Margreet Ausems, Christi van Asperen, Senno Verhoef, and Rogier van Oldenburg for providing samples from their Clinical Genetic centers; Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera, and Marjolein Peters for their help in creating the GWAS database; and Karol Estrada and Maksim V. Struchalin for their support in creation and analysis of imputed data.</p></ack><glossary><title>Abbreviations</title><def-list><def-item><term>BCAC</term><def><p>Breast Cancer Association Consortium</p></def></def-item><def-item><term>BMI</term><def><p>body mass index</p></def></def-item><def-item><term>COGS</term><def><p>Collaborative Oncological Gene Environment Study</p></def></def-item><def-item><term>DRIVE</term><def><p>Discovery, Biology, and Risk of Inherited Variants in Breast Cancer</p></def></def-item><def-item><term>ER</term><def><p>estrogen receptor</p></def></def-item><def-item><term>GAME-ON</term><def><p>Genetic Associations and Mechanisms in Oncology</p></def></def-item><def-item><term>GIANT</term><def><p>Genetic Investigation of Anthropometric Traits</p></def></def-item><def-item><term>GS</term><def><p>genetic score</p></def></def-item><def-item><term>GWAS</term><def><p>genome-wide association studies</p></def></def-item><def-item><term>HRT</term><def><p>hormone replacement therapy</p></def></def-item><def-item><term>HT</term><def><p>hormone therapy</p></def></def-item><def-item><term>MR</term><def><p>Mendelian randomization</p></def></def-item><def-item><term>OR</term><def><p>odds ratio</p></def></def-item><def-item><term>SNP</term><def><p>single nucleotide polymorphism</p></def></def-item></def-list></glossary><ref-list><title>References</title><ref id="pmed.1002105.ref001"><label>1</label><mixed-citation publication-type="journal"><name><surname>Renehan</surname><given-names>AG</given-names></name>, <name><surname>Tyson</surname><given-names>M</given-names></name>, <name><surname>Egger</surname><given-names>M</given-names></name>, <name><surname>Heller</surname><given-names>RF</given-names></name>, <name><surname>Zwahlen</surname><given-names>M</given-names></name>. <article-title>Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies</article-title>. <source>Lancet</source>. <year>2008</year>;<volume>371</volume>(<issue>9612</issue>):<fpage>569</fpage>–<lpage>78</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1016/S0140-6736(08)60269-X">10.1016/S0140-6736(08)60269-X</ext-link></comment>.<pub-id pub-id-type="pmid">18280327</pub-id></mixed-citation></ref><ref id="pmed.1002105.ref002"><label>2</label><mixed-citation publication-type="journal"><name><surname>Huang</surname><given-names>Z</given-names></name>, <name><surname>Hankinson</surname><given-names>SE</given-names></name>, <name><surname>Colditz</surname><given-names>GA</given-names></name>, <name><surname>Stampfer</surname><given-names>MJ</given-names></name>, <name><surname>Hunter</surname><given-names>DJ</given-names></name>, <name><surname>Manson</surname><given-names>JE</given-names></name>, <etal>et al</etal><article-title>Dual effects of weight and weight gain on breast cancer risk</article-title>. <source>JAMA</source>. <year>1997</year>;<volume>278</volume>(<issue>17</issue>):<fpage>1407</fpage>–<lpage>11</lpage>. 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