Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer
Identifieur interne : 002E41 ( Pmc/Corpus ); précédent : 002E40; suivant : 002E42Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer
Auteurs : Erica J. Childs ; Evelina Mocci ; Daniele Campa ; Paige M. Bracci ; Steven Gallinger ; Michael Goggins ; Donghui Li ; Rachel Neale ; Sara H. Olson ; Ghislaine Scelo ; Laufey T. Amundadottir ; William R. Bamlet ; Maarten F. Bijlsma ; Amanda Blackford ; Michael Borges ; Paul Brennan ; Hermann Brenner ; H Bas Bueno-De-Mesquita ; Federico Canzian ; Gabriele Capurso ; Giulia M. Cavestro ; Kari G. Chaffee ; Stephen J. Chanock ; Sean P. Cleary ; Michelle Cotterchio ; Lenka Foretova ; Charles Fuchs ; Niccola Funel ; Maria Gazouli ; Manal Hassan ; Joseph M. Herman ; Ivana Holcatova ; Elizabeth A. Holly ; Robert N. Hoover ; Rayjean J. Hung ; Vladimir Janout ; Timothy J. Key ; Juozas Kupcinskas ; Robert C. Kurtz ; Stefano Landi ; Lingeng Lu ; Ewa Malecka-Panas ; Andrea Mambrini ; Beatrice Mohelnikova-Duchonova ; John P. Neoptolemos ; Ann L. Oberg ; Irene Orlow ; Claudio Pasquali ; Raffaele Pezzilli ; Cosmeri Rizzato ; Amethyst Saldia ; Aldo Scarpa ; Rachael Z. Stolzenberg-Solomon ; Oliver Strobel ; Francesca Tavano ; Yogesh K. Vashist ; Pavel Vodicka ; Brian M. Wolpin ; Herbert Yu ; Gloria M. Petersen ; Harvey A. Risch ; Alison P. KleinSource :
- Nature genetics [ 1061-4036 ] ; 2015.
Url:
DOI: 10.1038/ng.3341
PubMed: 26098869
PubMed Central: 4520746
Links to Exploration step
PMC:4520746Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer</title>
<author><name sortKey="Childs, Erica J" sort="Childs, Erica J" uniqKey="Childs E" first="Erica J" last="Childs">Erica J. Childs</name>
<affiliation><nlm:aff id="A1">Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, MD</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mocci, Evelina" sort="Mocci, Evelina" uniqKey="Mocci E" first="Evelina" last="Mocci">Evelina Mocci</name>
<affiliation><nlm:aff id="A2">Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Campa, Daniele" sort="Campa, Daniele" uniqKey="Campa D" first="Daniele" last="Campa">Daniele Campa</name>
<affiliation><nlm:aff id="A3">Division of Cancer Epidemiology, DKFZ, Heidelberg, Germany</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A4">Department of Biology, University of Pisa, Pisa, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bracci, Paige M" sort="Bracci, Paige M" uniqKey="Bracci P" first="Paige M" last="Bracci">Paige M. Bracci</name>
<affiliation><nlm:aff id="A5">Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gallinger, Steven" sort="Gallinger, Steven" uniqKey="Gallinger S" first="Steven" last="Gallinger">Steven Gallinger</name>
<affiliation><nlm:aff id="A6">Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Goggins, Michael" sort="Goggins, Michael" uniqKey="Goggins M" first="Michael" last="Goggins">Michael Goggins</name>
<affiliation><nlm:aff id="A7">Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Li, Donghui" sort="Li, Donghui" uniqKey="Li D" first="Donghui" last="Li">Donghui Li</name>
<affiliation><nlm:aff id="A8">Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Neale, Rachel" sort="Neale, Rachel" uniqKey="Neale R" first="Rachel" last="Neale">Rachel Neale</name>
<affiliation><nlm:aff id="A9">Department of Population Health, QIMR Berghofer Medical Research Institute, Queensland, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Olson, Sara H" sort="Olson, Sara H" uniqKey="Olson S" first="Sara H" last="Olson">Sara H. Olson</name>
<affiliation><nlm:aff id="A10">Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Scelo, Ghislaine" sort="Scelo, Ghislaine" uniqKey="Scelo G" first="Ghislaine" last="Scelo">Ghislaine Scelo</name>
<affiliation><nlm:aff id="A11">International Agency for Research on Cancer (IARC), Lyon, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Amundadottir, Laufey T" sort="Amundadottir, Laufey T" uniqKey="Amundadottir L" first="Laufey T" last="Amundadottir">Laufey T. Amundadottir</name>
<affiliation><nlm:aff id="A12">Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bamlet, William R" sort="Bamlet, William R" uniqKey="Bamlet W" first="William R" last="Bamlet">William R. Bamlet</name>
<affiliation><nlm:aff id="A13">Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bijlsma, Maarten F" sort="Bijlsma, Maarten F" uniqKey="Bijlsma M" first="Maarten F" last="Bijlsma">Maarten F. Bijlsma</name>
<affiliation><nlm:aff id="A14">Laboratory for Experimental Oncology and Radiobiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Blackford, Amanda" sort="Blackford, Amanda" uniqKey="Blackford A" first="Amanda" last="Blackford">Amanda Blackford</name>
<affiliation><nlm:aff id="A2">Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Borges, Michael" sort="Borges, Michael" uniqKey="Borges M" first="Michael" last="Borges">Michael Borges</name>
<affiliation><nlm:aff id="A7">Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Brennan, Paul" sort="Brennan, Paul" uniqKey="Brennan P" first="Paul" last="Brennan">Paul Brennan</name>
<affiliation><nlm:aff id="A11">International Agency for Research on Cancer (IARC), Lyon, France</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="A15">Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bueno De Mesquita, H Bas" sort="Bueno De Mesquita, H Bas" uniqKey="Bueno De Mesquita H" first="H Bas" last="Bueno-De-Mesquita">H Bas Bueno-De-Mesquita</name>
<affiliation><nlm:aff id="A16">Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A17">Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A18">Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, United Kingdom</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A19">Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Canzian, Federico" sort="Canzian, Federico" uniqKey="Canzian F" first="Federico" last="Canzian">Federico Canzian</name>
<affiliation><nlm:aff id="A20">Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Capurso, Gabriele" sort="Capurso, Gabriele" uniqKey="Capurso G" first="Gabriele" last="Capurso">Gabriele Capurso</name>
<affiliation><nlm:aff id="A21">Digestive and Liver Disease Unit, “Sapienza” University of Rome, Rome, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Cavestro, Giulia M" sort="Cavestro, Giulia M" uniqKey="Cavestro G" first="Giulia M" last="Cavestro">Giulia M. Cavestro</name>
<affiliation><nlm:aff id="A22">Universitá Vita Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Chaffee, Kari G" sort="Chaffee, Kari G" uniqKey="Chaffee K" first="Kari G" last="Chaffee">Kari G. Chaffee</name>
<affiliation><nlm:aff id="A13">Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Chanock, Stephen J" sort="Chanock, Stephen J" uniqKey="Chanock S" first="Stephen J" last="Chanock">Stephen J. Chanock</name>
<affiliation><nlm:aff id="A12">Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Cleary, Sean P" sort="Cleary, Sean P" uniqKey="Cleary S" first="Sean P" last="Cleary">Sean P. Cleary</name>
<affiliation><nlm:aff id="A23">Department of Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A24">Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Cotterchio, Michelle" sort="Cotterchio, Michelle" uniqKey="Cotterchio M" first="Michelle" last="Cotterchio">Michelle Cotterchio</name>
<affiliation><nlm:aff id="A25">Cancer Care Ontario, University of Toronto, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A26">Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Foretova, Lenka" sort="Foretova, Lenka" uniqKey="Foretova L" first="Lenka" last="Foretova">Lenka Foretova</name>
<affiliation><nlm:aff id="A27">Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Brno, Czech Republic</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Fuchs, Charles" sort="Fuchs, Charles" uniqKey="Fuchs C" first="Charles" last="Fuchs">Charles Fuchs</name>
<affiliation><nlm:aff id="A28">Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A29">Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Funel, Niccola" sort="Funel, Niccola" uniqKey="Funel N" first="Niccola" last="Funel">Niccola Funel</name>
<affiliation><nlm:aff id="A30">Department of Surgery, Unit of Experimental Surgical Pathology, University Hospital of Pisa, Pisa, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gazouli, Maria" sort="Gazouli, Maria" uniqKey="Gazouli M" first="Maria" last="Gazouli">Maria Gazouli</name>
<affiliation><nlm:aff id="A31">Department of Medical Sciences, Laboratory of Biology, School of Medicine, University of Athens, Athens, Greece</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hassan, Manal" sort="Hassan, Manal" uniqKey="Hassan M" first="Manal" last="Hassan">Manal Hassan</name>
<affiliation><nlm:aff id="A8">Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Herman, Joseph M" sort="Herman, Joseph M" uniqKey="Herman J" first="Joseph M" last="Herman">Joseph M. Herman</name>
<affiliation><nlm:aff id="A32">Department of Radiation Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Holcatova, Ivana" sort="Holcatova, Ivana" uniqKey="Holcatova I" first="Ivana" last="Holcatova">Ivana Holcatova</name>
<affiliation><nlm:aff id="A33">Institute of Hygiene and Epidemiology, 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Holly, Elizabeth A" sort="Holly, Elizabeth A" uniqKey="Holly E" first="Elizabeth A" last="Holly">Elizabeth A. Holly</name>
<affiliation><nlm:aff id="A5">Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hoover, Robert N" sort="Hoover, Robert N" uniqKey="Hoover R" first="Robert N" last="Hoover">Robert N. Hoover</name>
<affiliation><nlm:aff id="A12">Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hung, Rayjean J" sort="Hung, Rayjean J" uniqKey="Hung R" first="Rayjean J" last="Hung">Rayjean J. Hung</name>
<affiliation><nlm:aff id="A6">Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Janout, Vladimir" sort="Janout, Vladimir" uniqKey="Janout V" first="Vladimir" last="Janout">Vladimir Janout</name>
<affiliation><nlm:aff id="A34">Department of Preventive Medicine, Faculty of Medicine, Palacky University, Olomouc, Czech Republic</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Key, Timothy J" sort="Key, Timothy J" uniqKey="Key T" first="Timothy J" last="Key">Timothy J. Key</name>
<affiliation><nlm:aff id="A35">Cancer Epidemiology Unit, University of Oxford, Oxford, U.K</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kupcinskas, Juozas" sort="Kupcinskas, Juozas" uniqKey="Kupcinskas J" first="Juozas" last="Kupcinskas">Juozas Kupcinskas</name>
<affiliation><nlm:aff id="A36">Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kurtz, Robert C" sort="Kurtz, Robert C" uniqKey="Kurtz R" first="Robert C" last="Kurtz">Robert C. Kurtz</name>
<affiliation><nlm:aff id="A37">Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Landi, Stefano" sort="Landi, Stefano" uniqKey="Landi S" first="Stefano" last="Landi">Stefano Landi</name>
<affiliation><nlm:aff id="A38">Department of Biology, Section of Genetics, University of Pisa, Pisa, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lu, Lingeng" sort="Lu, Lingeng" uniqKey="Lu L" first="Lingeng" last="Lu">Lingeng Lu</name>
<affiliation><nlm:aff id="A39">Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Malecka Panas, Ewa" sort="Malecka Panas, Ewa" uniqKey="Malecka Panas E" first="Ewa" last="Malecka-Panas">Ewa Malecka-Panas</name>
<affiliation><nlm:aff id="A40">Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mambrini, Andrea" sort="Mambrini, Andrea" uniqKey="Mambrini A" first="Andrea" last="Mambrini">Andrea Mambrini</name>
<affiliation><nlm:aff id="A41">Department of Oncology, ASL1 Massa Carrara, Massa Carrara, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mohelnikova Duchonova, Beatrice" sort="Mohelnikova Duchonova, Beatrice" uniqKey="Mohelnikova Duchonova B" first="Beatrice" last="Mohelnikova-Duchonova">Beatrice Mohelnikova-Duchonova</name>
<affiliation><nlm:aff id="A42">Laboratory of Toxicogenomics, Institute of Public Health, Prague, Czech Republic</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Neoptolemos, John P" sort="Neoptolemos, John P" uniqKey="Neoptolemos J" first="John P" last="Neoptolemos">John P. Neoptolemos</name>
<affiliation><nlm:aff id="A43">NIHR Pancreas Biomedical Research Unit, Liverpool Clinical Trials Unit and Cancer Research UK CTU Director, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, U.K</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Oberg, Ann L" sort="Oberg, Ann L" uniqKey="Oberg A" first="Ann L" last="Oberg">Ann L. Oberg</name>
<affiliation><nlm:aff id="A13">Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Orlow, Irene" sort="Orlow, Irene" uniqKey="Orlow I" first="Irene" last="Orlow">Irene Orlow</name>
<affiliation><nlm:aff id="A10">Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pasquali, Claudio" sort="Pasquali, Claudio" uniqKey="Pasquali C" first="Claudio" last="Pasquali">Claudio Pasquali</name>
<affiliation><nlm:aff id="A44">Department of Surgery, Gastroenterology and Oncology, University of Padua, Padua, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pezzilli, Raffaele" sort="Pezzilli, Raffaele" uniqKey="Pezzilli R" first="Raffaele" last="Pezzilli">Raffaele Pezzilli</name>
<affiliation><nlm:aff id="A45">Pancreas Unit, Department of Digestive Diseases, Sant’Orsola-Malpighi Hospital, Bologna, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Rizzato, Cosmeri" sort="Rizzato, Cosmeri" uniqKey="Rizzato C" first="Cosmeri" last="Rizzato">Cosmeri Rizzato</name>
<affiliation><nlm:aff id="A20">Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Saldia, Amethyst" sort="Saldia, Amethyst" uniqKey="Saldia A" first="Amethyst" last="Saldia">Amethyst Saldia</name>
<affiliation><nlm:aff id="A10">Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Scarpa, Aldo" sort="Scarpa, Aldo" uniqKey="Scarpa A" first="Aldo" last="Scarpa">Aldo Scarpa</name>
<affiliation><nlm:aff id="A46">ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Stolzenberg Solomon, Rachael Z" sort="Stolzenberg Solomon, Rachael Z" uniqKey="Stolzenberg Solomon R" first="Rachael Z" last="Stolzenberg-Solomon">Rachael Z. Stolzenberg-Solomon</name>
<affiliation><nlm:aff id="A47">Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Strobel, Oliver" sort="Strobel, Oliver" uniqKey="Strobel O" first="Oliver" last="Strobel">Oliver Strobel</name>
<affiliation><nlm:aff id="A48">Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tavano, Francesca" sort="Tavano, Francesca" uniqKey="Tavano F" first="Francesca" last="Tavano">Francesca Tavano</name>
<affiliation><nlm:aff id="A49">Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, Italy</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Vashist, Yogesh K" sort="Vashist, Yogesh K" uniqKey="Vashist Y" first="Yogesh K" last="Vashist">Yogesh K. Vashist</name>
<affiliation><nlm:aff id="A50">Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Vodicka, Pavel" sort="Vodicka, Pavel" uniqKey="Vodicka P" first="Pavel" last="Vodicka">Pavel Vodicka</name>
<affiliation><nlm:aff id="A51">Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences, Prague, Czech Republic</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Wolpin, Brian M" sort="Wolpin, Brian M" uniqKey="Wolpin B" first="Brian M" last="Wolpin">Brian M. Wolpin</name>
<affiliation><nlm:aff id="A28">Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A52">Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Yu, Herbert" sort="Yu, Herbert" uniqKey="Yu H" first="Herbert" last="Yu">Herbert Yu</name>
<affiliation><nlm:aff id="A53">Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Petersen, Gloria M" sort="Petersen, Gloria M" uniqKey="Petersen G" first="Gloria M" last="Petersen">Gloria M. Petersen</name>
<affiliation><nlm:aff id="A13">Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Risch, Harvey A" sort="Risch, Harvey A" uniqKey="Risch H" first="Harvey A" last="Risch">Harvey A. Risch</name>
<affiliation><nlm:aff id="A39">Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Klein, Alison P" sort="Klein, Alison P" uniqKey="Klein A" first="Alison P" last="Klein">Alison P. Klein</name>
<affiliation><nlm:aff id="A2">Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A7">Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD</nlm:aff>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">26098869</idno>
<idno type="pmc">4520746</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520746</idno>
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<idno type="doi">10.1038/ng.3341</idno>
<date when="2015">2015</date>
<idno type="wicri:Area/Pmc/Corpus">002E41</idno>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer</title>
<author><name sortKey="Childs, Erica J" sort="Childs, Erica J" uniqKey="Childs E" first="Erica J" last="Childs">Erica J. Childs</name>
<affiliation><nlm:aff id="A1">Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, MD</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Mocci, Evelina" sort="Mocci, Evelina" uniqKey="Mocci E" first="Evelina" last="Mocci">Evelina Mocci</name>
<affiliation><nlm:aff id="A2">Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Campa, Daniele" sort="Campa, Daniele" uniqKey="Campa D" first="Daniele" last="Campa">Daniele Campa</name>
<affiliation><nlm:aff id="A3">Division of Cancer Epidemiology, DKFZ, Heidelberg, Germany</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="A4">Department of Biology, University of Pisa, Pisa, Italy</nlm:aff>
</affiliation>
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<journal-id journal-id-type="pubmed-jr-id">2419</journal-id>
<journal-id journal-id-type="nlm-ta">Nat Genet</journal-id>
<journal-id journal-id-type="iso-abbrev">Nat. Genet.</journal-id>
<journal-title-group><journal-title>Nature genetics</journal-title>
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<issn pub-type="ppub">1061-4036</issn>
<issn pub-type="epub">1546-1718</issn>
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<article-meta><article-id pub-id-type="pmid">26098869</article-id>
<article-id pub-id-type="pmc">4520746</article-id>
<article-id pub-id-type="doi">10.1038/ng.3341</article-id>
<article-id pub-id-type="manuscript">NIHMS695333</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
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<given-names>Alison P</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A7">7</xref>
</contrib>
</contrib-group>
<aff id="A1"><label>1</label>
Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, MD</aff>
<aff id="A2"><label>2</label>
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD</aff>
<aff id="A3"><label>3</label>
Division of Cancer Epidemiology, DKFZ, Heidelberg, Germany</aff>
<aff id="A4"><label>4</label>
Department of Biology, University of Pisa, Pisa, Italy</aff>
<aff id="A5"><label>5</label>
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA</aff>
<aff id="A6"><label>6</label>
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada</aff>
<aff id="A7"><label>7</label>
Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD</aff>
<aff id="A8"><label>8</label>
Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX</aff>
<aff id="A9"><label>9</label>
Department of Population Health, QIMR Berghofer Medical Research Institute, Queensland, Australia</aff>
<aff id="A10"><label>10</label>
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY</aff>
<aff id="A11"><label>11</label>
International Agency for Research on Cancer (IARC), Lyon, France</aff>
<aff id="A12"><label>12</label>
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD</aff>
<aff id="A13"><label>13</label>
Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN</aff>
<aff id="A14"><label>14</label>
Laboratory for Experimental Oncology and Radiobiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands</aff>
<aff id="A15"><label>15</label>
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany</aff>
<aff id="A16"><label>16</label>
Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands</aff>
<aff id="A17"><label>17</label>
Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands</aff>
<aff id="A18"><label>18</label>
Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, United Kingdom</aff>
<aff id="A19"><label>19</label>
Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia</aff>
<aff id="A20"><label>20</label>
Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany</aff>
<aff id="A21"><label>21</label>
Digestive and Liver Disease Unit, “Sapienza” University of Rome, Rome, Italy</aff>
<aff id="A22"><label>22</label>
Universitá Vita Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan, Italy</aff>
<aff id="A23"><label>23</label>
Department of Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada</aff>
<aff id="A24"><label>24</label>
Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada</aff>
<aff id="A25"><label>25</label>
Cancer Care Ontario, University of Toronto, Toronto, Ontario, Canada</aff>
<aff id="A26"><label>26</label>
Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada</aff>
<aff id="A27"><label>27</label>
Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Brno, Czech Republic</aff>
<aff id="A28"><label>28</label>
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA</aff>
<aff id="A29"><label>29</label>
Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA</aff>
<aff id="A30"><label>30</label>
Department of Surgery, Unit of Experimental Surgical Pathology, University Hospital of Pisa, Pisa, Italy</aff>
<aff id="A31"><label>31</label>
Department of Medical Sciences, Laboratory of Biology, School of Medicine, University of Athens, Athens, Greece</aff>
<aff id="A32"><label>32</label>
Department of Radiation Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD</aff>
<aff id="A33"><label>33</label>
Institute of Hygiene and Epidemiology, 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic</aff>
<aff id="A34"><label>34</label>
Department of Preventive Medicine, Faculty of Medicine, Palacky University, Olomouc, Czech Republic</aff>
<aff id="A35"><label>35</label>
Cancer Epidemiology Unit, University of Oxford, Oxford, U.K</aff>
<aff id="A36"><label>36</label>
Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania</aff>
<aff id="A37"><label>37</label>
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY</aff>
<aff id="A38"><label>38</label>
Department of Biology, Section of Genetics, University of Pisa, Pisa, Italy</aff>
<aff id="A39"><label>39</label>
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT</aff>
<aff id="A40"><label>40</label>
Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland</aff>
<aff id="A41"><label>41</label>
Department of Oncology, ASL1 Massa Carrara, Massa Carrara, Italy</aff>
<aff id="A42"><label>42</label>
Laboratory of Toxicogenomics, Institute of Public Health, Prague, Czech Republic</aff>
<aff id="A43"><label>43</label>
NIHR Pancreas Biomedical Research Unit, Liverpool Clinical Trials Unit and Cancer Research UK CTU Director, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, U.K</aff>
<aff id="A44"><label>44</label>
Department of Surgery, Gastroenterology and Oncology, University of Padua, Padua, Italy</aff>
<aff id="A45"><label>45</label>
Pancreas Unit, Department of Digestive Diseases, Sant’Orsola-Malpighi Hospital, Bologna, Italy</aff>
<aff id="A46"><label>46</label>
ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy</aff>
<aff id="A47"><label>47</label>
Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD</aff>
<aff id="A48"><label>48</label>
Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany</aff>
<aff id="A49"><label>49</label>
Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, Italy</aff>
<aff id="A50"><label>50</label>
Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany</aff>
<aff id="A51"><label>51</label>
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences, Prague, Czech Republic</aff>
<aff id="A52"><label>52</label>
Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA</aff>
<aff id="A53"><label>53</label>
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI</aff>
<author-notes><corresp id="FN1">Correspondence should be addressed to: A.P.K (<email>aklein1@jhmi.edu</email>
)</corresp>
<fn id="FN2" fn-type="equal"><label>54</label>
<p>These authors contributed equally to this work.</p>
</fn>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>9</day>
<month>6</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="epub"><day>22</day>
<month>6</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="ppub"><month>8</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>01</day>
<month>2</month>
<year>2016</year>
</pub-date>
<volume>47</volume>
<issue>8</issue>
<fpage>911</fpage>
<lpage>916</lpage>
<pmc-comment>elocation-id from pubmed: 10.1038/ng.3341</pmc-comment>
<permissions><license xlink:href="http://www.nature.com/authors/editorial_policies/license.html#terms"><license-p>Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:<ext-link ext-link-type="uri" xlink:href="http://www.nature.com/authors/editorial_policies/license.html#terms">http://www.nature.com/authors/editorial_policies/license.html#terms</ext-link>
</license-p>
</license>
</permissions>
</article-meta>
</front>
<body><sec id="S1"><title>Introductory Paragraph</title>
<p id="P1">Pancreatic cancer is the fourth leading cause of cancer death in the developed world<sup><xref rid="R1" ref-type="bibr">1</xref>
</sup>
. Both inherited high-penetrant mutations in <italic>BRCA2</italic>
<sup><xref rid="R2" ref-type="bibr">2</xref>
</sup>
, <italic>ATM</italic>
<sup><xref rid="R3" ref-type="bibr">3</xref>
</sup>
, <italic>PALB2</italic>
<sup><xref rid="R4" ref-type="bibr">4</xref>
</sup>
, <italic>BRCA1</italic>
<sup><xref rid="R5" ref-type="bibr">5</xref>
</sup>
, <italic>STK11</italic>
<sup><xref rid="R6" ref-type="bibr">6</xref>
</sup>
, <italic>CDKN2A</italic>
<sup><xref rid="R7" ref-type="bibr">7</xref>
</sup>
and mismatch repair genes<sup><xref rid="R8" ref-type="bibr">8</xref>
</sup>
as well as low-penetrant loci are associated with increased risk<sup><xref rid="R9" ref-type="bibr">9</xref>
–<xref rid="R12" ref-type="bibr">12</xref>
</sup>
. To identify novel loci, we performed a genome-wide association study on 9,925 pancreatic cancer cases and 11,569 controls, including 4,164 newly genotyped cases and 3,792 controls in 9 studies from North America, Central Europe and Australia. Three newly associated regions were identified: 17q25.1 (<italic>LINC00673</italic>
, rs11655237, OR=1.26, 95%CI:1.19–1.34, P=1.42×10<sup>−14</sup>
), 7p13 (<italic>SUGCT</italic>
, rs17688601, OR=0.88, 95%CI:0.84–0.92, <italic>P</italic>
=1.41×10<sup>−8</sup>
), and 3q29 (<italic>TP63</italic>
, rs9854771, OR=0.89, 95%CI:0.85–0.93, P=2.35×10<sup>−8</sup>
). Significant association was detected on 2p13.3 (<italic>ETAA1</italic>
, rs1486134, OR=1.14, 95%CI:1.09–1.19, <italic>P</italic>
=3.36×10<sup>−9</sup>
), a region with prior suggestive evidence in the Han Chinese<sup><xref rid="R12" ref-type="bibr">12</xref>
</sup>
. We replicate previously reported associations at 9q34.2(<italic>ABO</italic>
)<sup><xref rid="R9" ref-type="bibr">9</xref>
</sup>
, 13q22.1(<italic>KLF5</italic>
)<sup><xref rid="R10" ref-type="bibr">10</xref>
</sup>
, 5p15.33 (<italic>TERT, CLPTM1</italic>
)<sup><xref rid="R10" ref-type="bibr">10</xref>
,<xref rid="R11" ref-type="bibr">11</xref>
</sup>
, 13q12.2 (<italic>PDX1</italic>
)<sup><xref rid="R11" ref-type="bibr">11</xref>
</sup>
, 1q32.1(<italic>NR5A2</italic>
)<sup><xref rid="R10" ref-type="bibr">10</xref>
</sup>
, 7q32.3(<italic>LINC-PINT</italic>
)<sup><xref rid="R11" ref-type="bibr">11</xref>
</sup>
, 16q23.1(<italic>BCAR1</italic>
)<sup><xref rid="R11" ref-type="bibr">11</xref>
</sup>
and 22q12.1 (<italic>ZNRF3</italic>
)<sup><xref rid="R11" ref-type="bibr">11</xref>
</sup>
. Our study identifies novel loci associated with pancreatic cancer risk.</p>
</sec>
<sec id="S2"><title>Main Text</title>
<p id="P2">We conducted a two-stage genome-wide association study (GWAS) of pancreatic cancer (<xref rid="F1" ref-type="fig">Fig. 1</xref>
). First, genome-wide genotyping of 8052 subjects from nine studies within the Pancreatic Cancer Case-Control Consortium (PanC4) (<xref rid="SD1" ref-type="supplementary-material">Supplementary Table 1</xref>
) was conducted using the HumanOmniExpressExome-8v1 array. The overall study was approved by the Johns Hopkins Institutional Review Board (IRB). Each individual study obtained IRB approval from their parent institution. After quality control (Online Methods, <xref rid="F1" ref-type="fig">Fig. 1</xref>
, <xref rid="SD1" ref-type="supplementary-material">Supplementary Table 2</xref>
), 7,956 individuals (4,164 cases and 3,792 controls) and 654,470 SNPs with call rates greater than 98% were analyzed. Unconditional logistic regression analysis adjusted for age and the first seven principal component eigenvectors was conducted under the log-additive genetic model (<xref rid="F2" ref-type="fig">Fig. 2</xref>
, <xref rid="SD1" ref-type="supplementary-material">Supplementary Fig. 1</xref>
).</p>
<p id="P3">Analysis of 7,956 newly genotyped PanC4 individuals identified a novel locus at 17q25.1 (<italic>LINC00673,</italic>
rs7214041, OR=1.38, 95%CI:1.26–1.51, <italic>P</italic>
=1.95×10<sup>−10</sup>
) significantly associated with pancreatic cancer risk (<xref rid="T1" ref-type="table">Table 1</xref>
, column ‘PanC4’). In addition we replicate regions that had previously been reported to be associated with pancreatic cancer in the Caucasian population (<xref rid="SD1" ref-type="supplementary-material">Supplementary Table 3</xref>
). These include: 9q34.2<sup><xref rid="R9" ref-type="bibr">9</xref>
</sup>
(<italic>ABO,</italic>
rs505922, OR=1.27, 95%CI:1.19–1.35, <italic>P</italic>
=1.72×10<sup>−13</sup>
), 13q22.1<sup><xref rid="R10" ref-type="bibr">10</xref>
</sup>
(<italic>KLF5</italic>
, rs9543325, OR=1.24, 95%CI:1.16–1.32, <italic>P</italic>
=2.26×10<sup>−10</sup>
), 5p15.33<sup><xref rid="R10" ref-type="bibr">10</xref>
</sup>
(<italic>CLPTM1</italic>
, rs401681, OR=1.2, 95% CI:1.13–1.28, <italic>P</italic>
=2.7×10<sup>−8</sup>
), 13q12.2<sup><xref rid="R11" ref-type="bibr">11</xref>
</sup>
(<italic>PDX1</italic>
, rs9581943, OR=1.17, 95%CI:1.10–1.24, <italic>P</italic>
=1.94×10<sup>−7</sup>
), 1q32.1<sup><xref rid="R10" ref-type="bibr">10</xref>
</sup>
(<italic>NR5A2</italic>
, rs3790844, OR=0.83, 95%CI:0.77–0.90, <italic>P</italic>
=3.05×10<sup>−6</sup>
), 7q32.3<sup><xref rid="R11" ref-type="bibr">11</xref>
</sup>
(<italic>LINC-PINT</italic>
, rs6971499, OR=0.81, 95%CI:0.74–0.88, P=7.1×10<sup>−6</sup>
), 5p15.33<sup><xref rid="R11" ref-type="bibr">11</xref>
</sup>
(<italic>TERT</italic>
, rs2736098, OR=0.85, 95%CI: 0.78–0.93, P=2.31×10<sup>−5</sup>
), 16q23.1<sup><xref rid="R11" ref-type="bibr">11</xref>
</sup>
(<italic>BCAR1</italic>
, rs7190458, OR=1.4, 95%CI=1.22–1.60, P=1.01×10<sup>−4</sup>
), and 22q12.1<sup><xref rid="R11" ref-type="bibr">11</xref>
</sup>
(<italic>ZNRF3</italic>
, rs16986825, OR=1.14, 95% CI= 1.04–1.24, P= 2.72×10<sup>−3</sup>
). In contrast, other than 2p13.3 (<italic>ETAA1</italic>
, rs2035565, OR=1.15, 95%CI=1.07–1.25, P=2.69×10<sup>−4</sup>
) (<xref rid="SD1" ref-type="supplementary-material">Supplementary Table 3</xref>
) we observed no evidence of association (P>0.05) for SNPs previously reported to be associated (P<1×10<sup>−6</sup>
) with pancreatic cancer in Asian populations<sup><xref rid="R12" ref-type="bibr">12</xref>
,<xref rid="R13" ref-type="bibr">13</xref>
</sup>
. While all ethnic groups were included in our analyses, over 92% of our study population reported Caucasian ancestry. We obtained similar results when analysis was limited to individuals reporting European ancestry. Because of limited sample sizes we did not conduct independent analysis of other ethnic groups(results not shown).</p>
<p id="P4">We then conducted a genome-wide meta-analysis of the PanC4 data with data from PanScan 1<sup><xref rid="R9" ref-type="bibr">9</xref>
</sup>
and PanScan 2<sup><xref rid="R10" ref-type="bibr">10</xref>
</sup>
(Combined Stage 1, <xref rid="F1" ref-type="fig">Fig. 1</xref>
). After quality control (Online Methods and <xref rid="SD1" ref-type="supplementary-material">Supplementary Table 4</xref>
), we analyzed 528,179 SNPs and 3,746 individuals (1,856 cases and 1,890 controls) from PanScan 1 and 557,555 SNPs and 3,300 individuals (1,618 cases and 1,682 controls) from PanScan 2. Since the genotyping platforms differed across studies, missing genotypes were imputed using IMPUTE v2<sup><xref rid="R14" ref-type="bibr">14</xref>
</sup>
, with 1000 Genomes<sup><xref rid="R15" ref-type="bibr">15</xref>
</sup>
(release Dec 2013) and HapMap3<sup><xref rid="R16" ref-type="bibr">16</xref>
</sup>
(release #2,2009) as reference panels. For PanScan 1 and PanScan 2, we conducted association analysis using unconditional logistic regression including age and the first four principal components eigenvectors as covariates. Data from PanC4, PanScan 1, and PanScan 2 were combined (7,638 cases and 7,364 controls and 866,891 SNPs) and analyzed using a fixed-effects model implemented in METAL<sup><xref rid="R17" ref-type="bibr">17</xref>
</sup>
(<xref rid="F3" ref-type="fig">Fig. 3</xref>
). A QQ plot (<xref rid="SD1" ref-type="supplementary-material">Supplementary Fig. 2</xref>
) indicated appropriate control of type-1 errors, with λ values of 1.025 for PanC4, 0.998 for PanScan 1, and 1.017 for PanScan 2.</p>
<p id="P5">The Combined Stage 1 Analysis (<xref rid="T1" ref-type="table">Table 1</xref>
, column ‘Combined Stage 1’) yielded a second novel region of association at 3q29 (<italic>TP63</italic>
, rs9854771, OR=0.87, 95%CI:0.83–0.92, P=4.08×10<sup>−8</sup>
). A second SNP on 17q25.1 (rs11655237, OR=1.27, 95%CI:1.19–1.36, P=6.74×10<sup>−12</sup>
), which is in high LD (r<sup>2</sup>
=0.95) with rs7214041, also gave significant evidence of association in these combined data.</p>
<p id="P6">We next conducted a Stage 2 analysis in an independent set of 2,497 cases and 4,611 controls from the PANDoRA consortium<sup><xref rid="R18" ref-type="bibr">18</xref>
</sup>
. We selected twenty-five SNPs from 23 independent regions (<xref rid="SD1" ref-type="supplementary-material">Supplementary Table 5</xref>
) with p-values below 10<sup>−5</sup>
in either PanC4 or the Combined Stage 1 analyses. When multiple SNPs per region were associated, the most significant SNP was selected; SNPs on 17q25.1 and 2p13.3 were exceptions. After quality control (Online Methods, <xref rid="SD1" ref-type="supplementary-material">Supplementary Table 6</xref>
), 2,287 cases and 4,205 controls from the PANDoRA study were analyzed. Age-adjusted association analyses by country were carried out, and results were combined using a fixed-effect model. We observed independent evidence of association at 17q25.1 in the PANDoRA study (<xref rid="T1" ref-type="table">Table 1</xref>
, column ‘PANDoRA’: rs7214041, OR=1.25, 95%CI:1.11–1.41, <italic>P</italic>
=3.37×10<sup>−4</sup>
).</p>
<p id="P7">Combined analysis of the Stage 1 and 2 data for the 25 SNPs (<xref rid="T1" ref-type="table">Table 1</xref>
and <xref rid="SD1" ref-type="supplementary-material">Supplementary Table 5</xref>
, column ‘Combined Stage 1&2’) revealed two additional significantly associated loci: 2p13.3(<italic>ETAA1</italic>
, rs1486134, OR=1.14, 95%CI:1.09–1.19, P=3.36×10<sup>−9</sup>
) and 7p13(<italic>SUGCT</italic>
, rs17688601, OR=0.88, 95%CI:0.84–0.92, P=1.41×10<sup>−8</sup>
). Promising signals (<xref rid="SD1" ref-type="supplementary-material">Supplementary Table 7</xref>
) arose at 18q21.2(<italic>GRP</italic>
, rs1517037, OR=0.87, 95%CI:0.83–0.92, P=3.17×10<sup>−7</sup>
), 12q24.31(<italic>HNF1A,</italic>
rs7310409, OR= 1.11, 95%CI:1.06–1.15, P=6.34×10<sup>−7</sup>
), 1p13.1(<italic>WNT2B</italic>
, rs351365, OR=0.89, 95%CI:0.85–0.93, P=7.39×10<sup>−7</sup>
), and 20q13.11 (rs6073450, OR=1.11, 95%CI:1.06–1.15, P=9.21×10<sup>−7</sup>
).</p>
<p id="P8">We identified and replicated a novel region for association on 17q25.1 (<xref rid="F4" ref-type="fig">Fig. 4a</xref>
). Two highly correlated variants (rs11655237 and rs7214041, r<sup>2</sup>
=0.95) were associated with pancreatic cancer risk. Variant rs7214041 is to <italic>LINC00673</italic>
(long inter-genic non-protein coding RNA 673). rs11655237, a non-coding transcript variant, shows significant DNase hypersensitivity in multiple cancer cell lines and binds transcription factors including <italic>P300, FOXA1, FOXA2,</italic>
and the DNA repair protein <italic>RAD21</italic>
according to HaploReg v2<sup><xref rid="R19" ref-type="bibr">19</xref>
</sup>
. HaploRegV2 also indicated rs7214041 alters regulatory motifs for HNF1<sup><xref rid="R19" ref-type="bibr">19</xref>
</sup>
. Interestingly, we also found suggestive evidence of an association with rs7310409 located at the <italic>HNF1A</italic>
locus (12q24.31, <xref rid="SD1" ref-type="supplementary-material">Supplementary Fig. 3a</xref>
and <xref rid="SD1" ref-type="supplementary-material">Supplementary Table 7</xref>
). A recent study of the pancreatic cancer transcriptome suggests HNF1A may act as a tumor suppressor in pancreatic cancers<sup><xref rid="R20" ref-type="bibr">20</xref>
</sup>
. Variation in <italic>HNF1A</italic>
has been associated with risk of Type 2 diabetes<sup><xref rid="R21" ref-type="bibr">21</xref>
,<xref rid="R22" ref-type="bibr">22</xref>
</sup>
, a well-established risk factor for pancreatic cancer<sup><xref rid="R23" ref-type="bibr">23</xref>
–<xref rid="R25" ref-type="bibr">25</xref>
</sup>
, and maturity onset diabetes of the young (MODY)<sup><xref rid="R26" ref-type="bibr">26</xref>
</sup>
. Furthermore, variants in <italic>HNF1A</italic>
(in particular rs7310409) and <italic>HNF4A</italic>
were identified as risk factors for pancreatic cancer in pathway-based and candidate-SNP-based analyses of the PanScan data<sup><xref rid="R27" ref-type="bibr">27</xref>
,<xref rid="R28" ref-type="bibr">28</xref>
</sup>
.</p>
<p id="P9">We also identified significant association for two variants in high LD (rs9854771 and rs1515496, r<sup>2</sup>
=0.99) located in an intron of <italic>TP63</italic>
on 3q29 (<xref rid="F4" ref-type="fig">Fig. 4b</xref>
). p63 is a p53 homologue implicated in tumorigenesis and metastasis<sup><xref rid="R29" ref-type="bibr">29</xref>
</sup>
by playing a role in cell-cycle arrest and apoptosis. Overexpression of p63 can mimic p53 activation in certain experimental models<sup><xref rid="R30" ref-type="bibr">30</xref>
</sup>
. Interestingly, different isoforms of p63 have opposing effects; TAp63 has tumor suppressive effects while DNp63 has oncogenic effects<sup><xref rid="R31" ref-type="bibr">31</xref>
</sup>
. Danilov and colleagues suggested DNp63α was the predominant isoform in pancreatic cancer cell lines and promoted pancreatic cancer growth, motility and invasion<sup><xref rid="R32" ref-type="bibr">32</xref>
</sup>
. Previous GWAS studies of lung cancer and bladder cancer have demonstrated significant evidence of association for SNPs in <italic>TP63</italic>
<sup><xref rid="R33" ref-type="bibr">33</xref>
–<xref rid="R37" ref-type="bibr">37</xref>
</sup>
. HaploReg query of this region showed that both are predicted to be conserved elements via GERP, suggesting functional roles.</p>
<p id="P10">Our analysis revealed genome-wide significance in a region on 2p13.3 (rs1486134). A pancreatic cancer GWAS in Han Chinese subjects<sup><xref rid="R12" ref-type="bibr">12</xref>
</sup>
found suggestive evidence for another SNP on 2p13.3 (rs2035565) (<xref rid="SD1" ref-type="supplementary-material">Supplementary Table 3</xref>
). High LD is present throughout this region (<xref rid="F4" ref-type="fig">Fig. 4c</xref>
), including strong LD between rs1486134 and rs2035565 in European and Asian populations based on 1000 Genomes<sup><xref rid="R15" ref-type="bibr">15</xref>
</sup>
samples (r<sup>2</sup>
=0.91 and r<sup>2</sup>
=0.90 respectively). This region includes the gene <italic>ETAA1 (</italic>
Ewing tumor-associated antigen 1), alias <italic>ETAA16,</italic>
that may function as a tumor-specific cell surface antigen in the Ewing’s family of tumors<sup><xref rid="R38" ref-type="bibr">38</xref>
</sup>
.</p>
<p id="P11">We observed significant association on 7p13 for rs17688601, located in an intron of the <italic>SUGCT</italic>
(succinyl-CoA:glutarate-CoA transferase) gene (alias <italic>c7orf10</italic>
) (<xref rid="F4" ref-type="fig">Fig. 4d</xref>
). This variant is predicted in HaploREGV2 to alter binding of HNF1-4 and other DNA binding proteins<sup><xref rid="R19" ref-type="bibr">19</xref>
</sup>
. The SUGCT protein is involved in glutarate metabolism and mutations in this gene are associated with glutaric aciduria<sup><xref rid="R39" ref-type="bibr">39</xref>
</sup>
. While there is evidence of altered tricarboxylic acid cycle metabolism in pancreatic cancer<sup><xref rid="R40" ref-type="bibr">40</xref>
</sup>
, the role of this gene in pancreatic cancer risk is unclear.</p>
<p id="P12">Combined Stage 1 and Stage 2 identified suggestive evidence of association (P<1×10<sup>−6</sup>
) in four regions: 12q24.31(<italic>HNF1A</italic>
) (<xref rid="SD1" ref-type="supplementary-material">Supplementary Fig. 3a</xref>
), 18q21.2(<italic>GRP</italic>
) (<xref rid="SD1" ref-type="supplementary-material">Supplementary Fig. 3b</xref>
), 1p13.1(5′ of <italic>WNT2B</italic>
) (<xref rid="SD1" ref-type="supplementary-material">Supplementary Fig. 3c</xref>
), and 20q13.11 (<xref rid="SD1" ref-type="supplementary-material">Supplementary Fig. 3d</xref>
). GRP (gastrin releasing peptide) production has been associated with pancreatic tumor growth in vitro<sup><xref rid="R41" ref-type="bibr">41</xref>
</sup>
. WNT signaling plays an important role in pancreas development. <italic>WNT2B</italic>
(Wingless-Type MMTV Integration Site Family, Member 2B) is overexpressed in pancreatic cancer and has been associated with decreased survival<sup><xref rid="R42" ref-type="bibr">42</xref>
</sup>
. The 20q13.11 variant is located ~20kb of the HNF4A (MODY) gene, mutations of which are associated with early-onset diabetes<sup><xref rid="R43" ref-type="bibr">43</xref>
</sup>
.</p>
<p id="P13">In the PanC4 study we observed 11 SNPs on chromosome 9q31.3 (<xref rid="SD1" ref-type="supplementary-material">Supplementary Fig. 3e</xref>
) in moderate to high LD (r<sup>2</sup>
values between 0.6 and 1) with p-values from 7.00×10<sup>−8</sup>
to 2.73×10<sup>−6</sup>
, including rs10991043 (OR=1.19, 95%CI:1.12–1.26, P=7.00×10<sup>−8</sup>
) nearby the <italic>SMC2</italic>
(structural maintenance of chromosome 2) gene. This gene plays an important role in DNA repair in humans. While there was no evidence of association in the other study populations examined, the strong signal across multiple SNPs in PanC4 suggest that this region merits further investigation.</p>
<p id="P14">Further functional characterization of these associated regions is needed, including examining if these SNPs are functional through eQTL. Performing eQTL analysis of pancreatic tissues is challenging. Normal pancreatic tissue is primarily comprised of acinar cells (>90%), but pancreatic ductal adenocarcinoma has a ductal phenotype, and the appropriate normal tissue to analyze is debatable because the cell of origin of pancreatic ductal adenocarcinomas is debated. eQTL analysis of pancreatic tumor tissue is also problematic because the tumor tissue of a pancreatic ductal adenocarcinomas contains a variable mixture of cell types including fibroblasts, multiple types of immune cells, non-neoplastic pancreatic cells and cancer cells, with cancer cells representing only a minority of the total cell population. Furthermore, gene expression analysis of normal pancreatic tissue is often limited by the RNA degradation associated with high level RNAase expression in pancreatic acinar cells. An ideal study of pancreatic eQTLs for pancreatic cells would take into account these challenges.</p>
<p id="P15">Smoking is a well-established risk factor for pancreatic cancer<sup><xref rid="R44" ref-type="bibr">44</xref>
–<xref rid="R47" ref-type="bibr">47</xref>
</sup>
. For all nine SNPs identified in <xref rid="T1" ref-type="table">Table 1</xref>
and <xref rid="SD1" ref-type="supplementary-material">Supplementary Table 7</xref>
, we conducted an analysis stratified by smoking status (ever smoker vs. never smoker) in PanC4 samples. No qualitative differences in effect size between current smokers and never smokers were observed (results not shown). Furthermore, when we included an interaction term in the model, this term was not significant at the 0.05 level.</p>
<p id="P16">We estimated the heritability of pancreatic cancer due to common GWAS SNPs using data from PanC4 samples of Caucasian ancestry using only directly genotyped SNPs(3,828 cases, 3,551 controls and 620,357 SNPs) as well as the combined dataset (7,032 cases 6,866 controls 268,681 SNPs). Using a disease prevalence of 0.0149, reflecting the lifetime risk of pancreatic cancer, we estimated that 16.4% (95%CI: 10.4%–22.4%) in PanC4 and 13.1% (95%CI 9.9%–16.3%) for the combined dataset of the total phenotypic variation was explained by genome-wide common SNPs. The established associated regions (loci in <xref rid="T1" ref-type="table">Table 1</xref>
and <xref rid="SD1" ref-type="supplementary-material">Supplemental Table 3</xref>
), accounted for 3.0% (95%CI: 2.0%-3.9%) and 2.1%(95%CI 1.7%-3.1%) of the total phenotypic variation in the Panc4 population and the combined dataset, respectively.</p>
<p id="P17">We identified several novel regions involved in pancreatic cancer susceptibility, and provided additional evidence to support many of the established associations. While it is of interest that many of these highly associated variants are located in the introns of genes, these associations could be due to more distant genomic effects. Follow-up studies, including functional studies, are needed to fully understand how these variants (either directly or indirectly) impact risk of pancreatic cancer. Our work highlights the importance of common variation in pancreatic cancer risk.</p>
</sec>
<sec id="S3" specific-use="web-only"><title>Online Methods</title>
<sec id="S4"><title>Stage 1 Methods</title>
<sec id="S5"><title>PanC4 Quality Control</title>
<p id="P18">In total, 8052 individuals were selected for genotyping from studies participating in the Pancreatic Cancer Case-Control Consortium (PanC4). Participating sites included: The Central Europe study coordinated by the International Agency for Research on Cancer (IARC/Central Europe)<sup><xref rid="R48" ref-type="bibr">48</xref>
</sup>
, Johns Hopkins Hospital<sup><xref rid="R49" ref-type="bibr">49</xref>
,<xref rid="R50" ref-type="bibr">50</xref>
</sup>
, Mayo Clinic<sup><xref rid="R51" ref-type="bibr">51</xref>
</sup>
, MD Anderson Cancer Center<sup><xref rid="R52" ref-type="bibr">52</xref>
</sup>
, Memorial Sloane-Kettering Cancer Center<sup><xref rid="R53" ref-type="bibr">53</xref>
</sup>
, University of Toronto<sup><xref rid="R54" ref-type="bibr">54</xref>
</sup>
, Queensland<sup><xref rid="R55" ref-type="bibr">55</xref>
</sup>
, University of California San Francisco (UCSF)<sup><xref rid="R56" ref-type="bibr">56</xref>
</sup>
, and Yale University<sup><xref rid="R57" ref-type="bibr">57</xref>
</sup>
(<xref rid="SD1" ref-type="supplementary-material">Supplementary Table 1</xref>
). Cases were defined as individuals with adenocarcinoma of the pancreas. DNA samples from these individuals from PanC4, 180 study duplicates, 176 HapMap control samples, and 26 replicates from the previous pancreatic cancer GWAS PanScan 2<sup><xref rid="R10" ref-type="bibr">10</xref>
</sup>
, were genotyped on the IlluminaHumanOmniExpressExome-8v1 array at the Johns Hopkins Center for Inherited Disease Research (CIDR). Genotypes were called using GenomeStudio version 2011.1, Genotyping Module 1.9.4 and GenTrain version 1.0.</p>
<p id="P19">Genotyping results were inspected for quality by assessing the missing call rate, allelic imbalance, heterozygosity, discordance in reported versus genotyped gender, relatedness, ancestry and chromosomal anomalies. Unexpected relatedness between pairs of samples was assessed using the method of moments<sup><xref rid="R58" ref-type="bibr">58</xref>
</sup>
implemented in <italic>SNPRelate</italic>
<sup><xref rid="R59" ref-type="bibr">59</xref>
</sup>
. The median genotype call rate was 99.9%, with all individuals having a call rate greater than 98%. After removing individuals with excessive allele sharing, duplicates and subjects with incomplete information on age, 7,956 subjects (4,164 cases and 3,792 controls) were available for statistical analyses (<xref rid="SD1" ref-type="supplementary-material">Supplementary Table 2</xref>
). SNPs with the following characteristics were excluded from statistical analyses: positional duplicates, more than two discordant calls in study duplicates, technical failures or missing call rate greater than 2%, more than one Mendelian error in HapMap control trios, Hardy-Weinberg equilibrium p-value<10<sup>−6</sup>
, sex difference in allele frequency greater than 0.2 for autosomes/XY in samples of European ancestry, and minor allele frequencies (MAF) less than 0.005. Overall 654,470 SNPs passed the quality control filters applied; the median missing call rate was 0.024% and 98% of SNPs had a missing call rate less than 1% (<xref rid="SD1" ref-type="supplementary-material">Supplementary Table 2</xref>
).</p>
</sec>
<sec id="S6"><title>PanScan 1 and PanScan 2 Quality Control</title>
<p id="P20">PanScan 1 and PanScan 2 data were obtained from dbGAP<sup><xref rid="R60" ref-type="bibr">60</xref>
,<xref rid="R61" ref-type="bibr">61</xref>
</sup>
(dbGaP study accession: phs000206.v4.p3). Data from all participating sites apart from Group Health (which required a separate data sharing agreement) were included in the analysis. Previously published PanScan 1<sup><xref rid="R9" ref-type="bibr">9</xref>
</sup>
and PanScan 2<sup><xref rid="R10" ref-type="bibr">10</xref>
</sup>
studies used the Illumina HumanHap550 and Illumina Human 610-Quad chips respectively. Quality control was performed as described above for PanC4. Forty-five unexpected duplicates between PanScan 1, PanScan 2, and PanC4 were identified and removed from analyses of the PanScan datasets. After data cleaning, 528,179 SNPs and 3,746 individuals (1,856 cases, 1,890 controls) remained in PanScan 1, and 557,555 SNPs and 3,300 individuals (1,618 cases and 1,682 controls) remained in PanScan 2 (See <xref rid="SD1" ref-type="supplementary-material">Supplementary Table 4</xref>
).</p>
</sec>
<sec id="S7"><title>Association Analysis</title>
<p id="P21">To investigate population structure, principal components analysis (PCA) was conducted separately for PanC4, PanScan 1 and PanScan 2 using <italic>SNPRelate</italic>
<sup><xref rid="R59" ref-type="bibr">59</xref>
</sup>
(<xref rid="SD1" ref-type="supplementary-material">Supplementary Fig. 4</xref>
). Genotype imputation was performed separately for PanScan 1, PanScan 2 and PanC4 using IMPUTE v2<sup><xref rid="R14" ref-type="bibr">14</xref>
</sup>
. Since PanScan 1 and PanScan 2 SNPs were originally mapped using an older genome assembly (NCBI build 36), we converted their genome position to genome assembly NCBI build 37 by using LIFTOVER. Markers not identified in the build 37 assembly were removed. To decrease computational time, we pre-phased genotypes to produce best-guess haplotypes using SHAPEIT v2 software<sup><xref rid="R62" ref-type="bibr">62</xref>
</sup>
. Both 1000 Genomes<sup><xref rid="R15" ref-type="bibr">15</xref>
</sup>
Phase I-integrated haplotypes (release Dec 2013) and HapMap3<sup><xref rid="R16" ref-type="bibr">16</xref>
</sup>
(release #2,2009) were used as reference panels during imputation.</p>
<p id="P22">After imputation, SNPs with quality scores < 0.3 were excluded from all subsequent analysis. Only SNPs directly genotyped in either PanC4, PanScan 1, or PanScan 2 and passing quality control filters were retained for analysis. This resulted in 866,891 SNPs in the Combined Stage 1 analysis. The expected genotype counts were then analyzed using the frequentist test option of SNPTEST<sup><xref rid="R63" ref-type="bibr">63</xref>
</sup>
. Decade of age and eigenvectors from PCA were included as covariates. The number of eigenvectors to include was chosen based on inspection of the scree plot and p-values from association between eigenvectors and pancreatic cancer status. The results from each study were then combined using a fixed-effects inverse standard error approach implemented by METAL<sup><xref rid="R17" ref-type="bibr">17</xref>
</sup>
(see <xref rid="SD1" ref-type="supplementary-material">Supplementary Table 5</xref>
, column ‘Combined Stage 1’). Test statistic inflation (λ), was estimated to be 1.025 for PanC4, 0.998 for PanScan 1, and 1.017 for PanScan 2. Test statistics for PanC4 and PanScan 2 were adjusted to account for small amounts of population stratification using METAL’s genomic control option. Our sample size gives us over 80% power to detect an odds ratio of 1.2 for SNPs with a minor allele frequency greater than 0.20. Manhattan and QQ plots of PanC4 GWAS are shown in <xref rid="F2" ref-type="fig">Fig. 2</xref>
and <xref rid="SD1" ref-type="supplementary-material">Supplementary Fig. 1</xref>
, respectively. Manhattan and QQ plots showing association results from the Combined Stage 1 analysis are shown in <xref rid="F3" ref-type="fig">Fig. 3</xref>
<bold>and</bold>
<xref rid="SD1" ref-type="supplementary-material">Supplementary Fig. 2</xref>
. To examine whether our association results were confounded by population stratification, we conducted a secondary analysis, restricting our samples to those of European ancestry based on a PCA analysis performed with PanC4 and Hapmap3 samples. The loci identified through association testing did not change, and their odds ratios and p-values did not vary significantly (results not shown).</p>
</sec>
</sec>
<sec id="S8"><title>Stage 2 Methods</title>
<sec id="S9"><title>PANDoRA Replication Study</title>
<p id="P23">Twenty-five SNPs from 23 independent regions identified as showing evidence of association (P<1×10<sup>−5</sup>
) in either the PanC4 analysis or the Combined Stage 1 analysis, were genotyped in samples from the PANcreatic Disease ReseArch (PANDoRA)<sup><xref rid="R18" ref-type="bibr">18</xref>
</sup>
consortium with TaqMan technology. These samples were drawn from case-control studies in six European countries: Czech Republic, Germany, Greece, Italy, Lithuania, and Poland. In total, 2497 cases with pancreatic cancer and 4611 controls were genotyped. 8% of samples were duplicated and overall concordance was >99%. <xref rid="SD1" ref-type="supplementary-material">Supplementary Table 6</xref>
shows the features of the PANDoRA dataset. Samples missing more than 2 SNPs (~15%) or missing covariate information were excluded from analyses. In total, 2,287 cases and 4,205 controls from the PANDoRA study remained after quality control.</p>
<p id="P24">Because PANDoRA is a collection of samples from various centers, we analyzed each country separately. Logistic regression models with additive effects of each allele were fit, as implemented in PLINK<sup><xref rid="R64" ref-type="bibr">64</xref>
</sup>
(<xref rid="SD1" ref-type="supplementary-material">Supplementary Table 5</xref>
, column ‘PANDoRA’). Two SNPs, rs16867971 for Greece and rs10850078 for Lithuania, showed evidence of departure from HWE in controls (P<0.001). The SNP violating HWE was not analyzed for that country. A final fixed-effects meta-analysis of PanC4, PanScan 1, PanScan 2, and PANDoRA (Combined Stage 1 and 2 analysis) was then conducted using METAL<sup><xref rid="R17" ref-type="bibr">17</xref>
</sup>
on the 25 SNPs chosen for inclusion in Stage 2. Results are in <xref rid="SD1" ref-type="supplementary-material">Supplementary Table 5</xref>
, column ‘Combined Stage 1&2’. To further interrogate these regions we examined all 1000G imputed SNPs (as described above) in regions with significant or suggestive (P<1×10<sup>−6</sup>
) evidence of association (<xref rid="F4" ref-type="fig">Fig. 4</xref>
and <xref rid="SD1" ref-type="supplementary-material">Supplemental Fig. 3</xref>
).</p>
<p id="P25">In our Combined Stage 1 analysis (<xref rid="SD1" ref-type="supplementary-material">Supplementary Table 5</xref>
, column ‘Combined Stage 1’), two SNPs selected for replication were observed to have heterogeneity p-values below 0.001. When restricting our analysis to individuals of European ancestry, heterogeneity p-values from the meta-analysis remained virtually unchanged, implying that the heterogeneity was not due to population stratification. One SNP, rs16867971, was directly genotyped in PanC4 and imputed in PanScan 1 and PanScan 2. We found evidence of association for rs16867971 in PanC4, but not in PanScan 1 or PanScan 2 (P>0.05). The second SNP, rs6706539, was also directly genotyped in PanC4 and imputed in PanScan 1 and PanScan 2. For rs6706539, allele A was associated with increased risk in PanScan 1 and PanScan 2 (P=0.008 and P=0.04, respectively) but protective in PanC4 (P=3.4×10<sup>−6</sup>
). Upon examination of the imputed and non-imputed SNPs adjacent to rs6706539, we found that r<sup>2</sup>
values between this SNP and other SNPs within 10kb were low, ranging from 0.05 to 0.18 in 1000 Genomes CEU samples. It is possible that this low LD made imputation of this SNP rather difficult. Additionally, inspection of the alleles coded as reference and alternate alleles for this SNP in PanC4 and 1000 Genomes suggests that this oddity is not due to differences in strand alignment.</p>
<p id="P26">Forest plots of our top hits (<xref rid="SD1" ref-type="supplementary-material">Supplemental Fig. 5a–5i</xref>
) showing the magnitude of odds ratios for each study population show that in the majority of the “top” SNPs, those with p-value <1×10<sup>−6</sup>
, the direction of the effect was consistent across populations. Additionally, none of the top SNPs showed significant heterogeneity (at the 0.05 level) in the Combined Stage 1 and Stage 2 analysis. However, in many instances the effect size in the PanScan I population was smaller than the association observed in PanScan II, PanC4 and PANDoRA. We conducted a random effects meta-analysis as well and overall the results were consistent with the results observed from the fixed-effect meta-analysis (results not shown).</p>
</sec>
<sec id="S10"><title>Heritability Analysis</title>
<p id="P27">Heritability analysis was performed using GCTA<sup><xref rid="R65" ref-type="bibr">65</xref>
</sup>
software. This analysis estimates the percentage of phenotypic variance explicated by common SNPs. We assumed a prevalence of 0.0149 (risk to age 90 in the US Caucasian population; SEER data collected in 2009–2011). We excluded individuals not clustering with HapMap<sup><xref rid="R16" ref-type="bibr">16</xref>
</sup>
CEU (CEPH- Utah residents with ancestry from northern and western Europe) samples in PCA analysis as well as individuals with estimated relationships > 0.05 or missing genotype rate >0.01. SNPs with missing rate>0.05, MAF <0.01 and HWE p-value<5×10<sup>−4</sup>
were also excluded. We estimated the overall heritability in the PanC4 study using SNP data, as well as the heritability attributed to the 12 regions with significant evidence of association in the Caucasian population plus the 6 suggestive regions identified.</p>
</sec>
<sec id="S11"><title>HaploReg</title>
<p id="P28">HaploReg is a tool used for exploring functional annotations of non-coding variants. For each variant and region identified in this study, we used HaploReg to gain insight into functional annotations including chromatin state (promoters and enhancers), conserved regions, variant effect on regulatory motifs and protein binding sites. Regions were defined by SNPs with r<sup>2</sup>
>0.8 to the associated SNP.</p>
</sec>
</sec>
</sec>
<sec sec-type="supplementary-material" id="S12"><title>Supplementary Material</title>
<supplementary-material content-type="local-data" id="SD1"><label>1</label>
<media xlink:href="NIHMS695333-supplement-1.pdf" orientation="portrait" xlink:type="simple" id="d37e1786" position="anchor"></media>
</supplementary-material>
</sec>
</body>
<back><ack id="S13"><p>This work was supported by RO1 CA 154823. Genotyping Services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to the Johns Hopkins University, contract number HHSN268201100011I.</p>
<p>The IARC/Central Europe study was supported by a grant from the US National Cancer Institute at the National Institutes of Health (R03 CA123546-02) and grants from the Ministry of Health of the Czech Republic (NR 9029-4/2006, NR9422-3, NR9998-3, MH CZ-DRO-MMCI 00209805).</p>
<p>The work at Johns Hopkins University was supported by the NCI Grants P50CA62924 and R01CA97075. Additional support was provided by Susan Wojcicki and Dennis Troper.</p>
<p>The Mayo Clinic Molecular Epidemiology of Pancreatic Cancer study is supported by the Mayo Clinic SPORE in Pancreatic Cancer (P50 CA102701).</p>
<p>The Memorial Sloan Kettering Cancer Center Pancreatic Tumor Registry is supported by P30CA008748, the Geoffrey Beene Foundation, the Arnold and Arlene Goldstein Family Foundation, and the Society of MSKCC.</p>
<p>The Queensland Pancreatic Cancer Study was supported by a grant from the National Health and Medical Research Council of Australia (NHMRC) (Grant number 442302). RE Neale is supported by a NHMRC Senior Research Fellowship (#1060183).</p>
<p>The UCSF pancreas study was supported by NIH-NCI grants (R01CA1009767, R01CA109767-S1) and the Joan Rombauer Pancreatic Cancer Fund. Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program; the NCI’s SEER Program under contract HHSN261201000140C awarded to CPIC; and the CDC’s National Program of Cancer Registries, under agreement #U58DP003862-01 awarded to the California Department of Public Health.</p>
<p>The Yale (CT) pancreas study is supported by National Cancer Institute at the U.S. National Institutes of Health, grant 5R01CA098870. The cooperation of 30 Connecticut hospitals, including Stamford Hospital, in allowing patient access, is gratefully acknowledged. The Connecticut Pancreas Cancer Study was approved by the State of Connecticut Department of Public Health Human Investigation Committee. Certain data used in that study were obtained from the Connecticut Tumor Registry in the Connecticut Department of Public Health. The authors assume full responsibility for analyses and interpretation of these data.</p>
<p>Studies included in PANDoRA were partly funded by: the Czech Science Foundation (No. P301/12/1734), the Internal Grant Agency of the Czech Ministry of Health (IGA NT 13 263); the Baden-Württemberg State Ministry of Research, Science and Arts (Prof. H. Brenner), the Heidelberger EPZ-Pancobank (Prof. M.W. Büchler and team: Prof. T. Hackert, Dr. N. A. Giese, Dr. Ch. Tjaden, E. Soyka, M. Meinhardt; Heidelberger Stiftung Chirurgie and BMBF grant 01GS08114), the BMBH (Prof. P. Schirmacher; BMBF grant 01EY1101), the “5×1000” voluntary contribution of the Italian Government, the Italian Ministry of Health (RC1203GA57, RC1303GA53, RC1303GA54, RC1303GA50), the Italian Association for Research on Cancer (Prof. A. Scarpa; AIRC n. 12182), the Italian Ministry of Research (Prof. A. Scarpa; FIRB - RBAP10AHJB), the Italian FIMP-Ministry of Health (Prof. A. Scarpa; CUP_J33G13000210001), and by the National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, UK. We would like to acknowledge the contribution of Dr Frederike Dijk and Prof. Oliver Busch (Academic Medical Center, Amsterdam, the Netherlands).</p>
<p>Assistance with genotype data quality control was provided by Cecelia Laurie and Cathy Laurie at University of Washington Genetic Analysis Center.</p>
</ack>
<fn-group><fn id="FN3"><p><bold>URLs</bold>
</p>
<p>PanC4: <ext-link ext-link-type="uri" xlink:href="www.panc4.org">www.panc4.org</ext-link>
</p>
<p>GLOBOCAN: <ext-link ext-link-type="uri" xlink:href="globocan.iarc.fr/Default.aspx">globocan.iarc.fr/Default.aspx</ext-link>
</p>
<p>PLINK: <ext-link ext-link-type="uri" xlink:href="pngu.mgh.harvard.edu/~purcell/plink/">pngu.mgh.harvard.edu/~purcell/plink/</ext-link>
</p>
<p>LIFTOVER: <ext-link ext-link-type="uri" xlink:href="genome.ucsc.edu/cgi-bin/hgLiftOver">genome.ucsc.edu/cgi-bin/hgLiftOver</ext-link>
</p>
<p>SHAPEIT: <ext-link ext-link-type="uri" xlink:href="mathgen.stats.ox.ac.uk/genetics_software/shapeit/shapeit.html">mathgen.stats.ox.ac.uk/genetics_software/shapeit/shapeit.html</ext-link>
</p>
<p>IMPUTE2: <ext-link ext-link-type="uri" xlink:href="mathgen.stats.ox.ac.uk/impute/impute_v2.html">mathgen.stats.ox.ac.uk/impute/impute_v2.html</ext-link>
</p>
<p>SNPTEST: <ext-link ext-link-type="uri" xlink:href="mathgen.stats.ox.ac.uk/genetics_software/snptest/snptest.html">mathgen.stats.ox.ac.uk/genetics_software/snptest/snptest.html</ext-link>
</p>
<p>METAL: <ext-link ext-link-type="uri" xlink:href="csg.sph.umich.edu/abecasis/metal/">csg.sph.umich.edu/abecasis/metal/</ext-link>
</p>
<p>HAPLOREG: <ext-link ext-link-type="uri" xlink:href="www.broadinstitute.org/mammals/haploreg/haploreg.php">www.broadinstitute.org/mammals/haploreg/haploreg.php</ext-link>
</p>
</fn>
<fn id="FN4" fn-type="con"><p><bold>Author Contributions</bold>
</p>
<p>D.C, G.M.P, H.A.R, and A.P.K organized and designed the study. F.C and A.P.K organized and supervised the genotyping of samples. E.J.C, E.M, D.C, and A.P.K designed and conducted the statistical analysis. E.J.C, E.M, M.G.G, and A.P.K drafted the first version of the manuscript. P.M.B, S.G, M.G.G, D.L, R.N., S.H.O, G.S, L.T.A, W.R.B, M.F.B, A.B, M.B, P.B, H.B, H.B.B-d-M, F.C, G.C, G.M.C, K.G.C, S.J.C, S.P.C, M.C, L.F, C.F, N.F, M.G, M.H, J.M.H, I.H, E.A.H, R.N.H, R.J.H, V.J, T.J.K, J.K, R.C.K, S.L, L.L, E.M-P, A.M, B.M-D, J.P.N, A.L.O, I.O, C.P, R.P, C.R, A.S, A.S, R.Z.S-S, O.S, F.T, Y.K.V, P.V, B.M.W, H.Y, G.M.P, H.A.R, and A.P.K contributed samples for the GWAS and/or the replication analysis. All authors contributed to the final version of the manuscript.</p>
</fn>
<fn id="FN5" fn-type="conflict"><p><bold>Competing Financial Interests</bold>
</p>
<p>Under a licensing agreement between Myriad Genetics, Inc., and the Johns Hopkins University, M. Goggins and A.P. Klein are entitled to a share of royalty received by the University on sales of products related to PALB2. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict-of-interest policies.</p>
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<floats-group><fig id="F1" orientation="portrait" position="float"><label>Figure 1</label>
<caption><p>Overview of Stage 1 and Stage 2 analyses</p>
</caption>
<graphic xlink:href="nihms695333f1"></graphic>
</fig>
<fig id="F2" orientation="portrait" position="float"><label>Figure 2</label>
<caption><p>Manhattan plot of PanC4 association analysis. Loci previously associated with pancreatic cancer in Caucasians are shown in black, 2p13.3 in blue and novel loci in red.</p>
</caption>
<graphic xlink:href="nihms695333f2"></graphic>
</fig>
<fig id="F3" orientation="portrait" position="float"><label>Figure 3</label>
<caption><p>Manhattan plot of Combined Stage 1 association analysis. Loci previously associated with pancreatic cancer in Caucasians are shown in black, 2p13.3 in blue and novel loci in red.</p>
</caption>
<graphic xlink:href="nihms695333f3"></graphic>
</fig>
<fig id="F4" orientation="portrait" position="float"><label>Figure 4</label>
<caption><p>Regional association and linkage disequilibrium (LD) plots for four novel genome-wide significant loci: (a) 17q25.1, (b) 3q29, (c) 2p13.3, and (d) 7p13. Association p-values are shown for three analyses: PanC4 only (black circles), Combined Stage 1 (PanC4, PanScan 1, and PanScan 2) (grey circles), and Combined Stage 1 and 2 (PanC4, PanScan 1, PanScan 2, and PANDoRA) (red circles). LD plots are based on 1000 Genomes European samples.</p>
</caption>
<graphic xlink:href="nihms695333f4a"></graphic>
<graphic xlink:href="nihms695333f4b"></graphic>
<graphic xlink:href="nihms695333f4c"></graphic>
<graphic xlink:href="nihms695333f4d"></graphic>
</fig>
<table-wrap id="T1" position="float" orientation="landscape"><label>Table 1</label>
<caption><p>Significant (P<5×10<sup>−8</sup>
) association results for pancreatic cancer</p>
</caption>
<table frame="box" rules="all"><thead><tr><th valign="middle" align="center" rowspan="1" colspan="1"></th>
<th valign="middle" align="center" rowspan="1" colspan="1"></th>
<th valign="middle" align="center" rowspan="1" colspan="1"></th>
<th colspan="4" valign="middle" align="center" rowspan="1">Stage 1</th>
<th colspan="2" valign="middle" align="center" rowspan="1">Stage 2</th>
</tr>
<tr><th valign="middle" align="center" rowspan="1" colspan="1">Chr<xref rid="TFN1" ref-type="table-fn">a</xref>
<break></break>
SNP Position<xref rid="TFN2" ref-type="table-fn">b</xref>
<break></break>
Gene</th>
<th valign="middle" align="center" rowspan="1" colspan="1">Effect Allele (Minor)/Reference Allele</th>
<th valign="middle" align="center" rowspan="1" colspan="1">Statistic</th>
<th valign="middle" align="center" rowspan="1" colspan="1">PanC4<break></break>
4,164 cases<break></break>
3,792 controls</th>
<th valign="middle" align="center" rowspan="1" colspan="1">PanScan 1<break></break>
1,856 cases, 1,890 controls</th>
<th valign="middle" align="center" rowspan="1" colspan="1">PanScan 2<break></break>
1,618 cases and 1,682 controls</th>
<th valign="middle" align="center" rowspan="1" colspan="1">Combined Stage 1<xref rid="TFN3" ref-type="table-fn">c</xref>
<break></break>
7,638 cases<break></break>
7,364 controls</th>
<th valign="middle" align="center" rowspan="1" colspan="1">PANDoRA<break></break>
2,497 cases<break></break>
4,611 controls</th>
<th valign="middle" align="center" rowspan="1" colspan="1">Combined Stage 1&2<xref rid="TFN4" ref-type="table-fn">d</xref>
<break></break>
9,925 cases<break></break>
11,569 controls</th>
</tr>
</thead>
<tbody><tr><td align="center" valign="middle" rowspan="4" colspan="1">17q25.1<xref rid="TFN8" ref-type="table-fn">h</xref>
<break></break>
rs11655237<break></break>
70,400,166<break></break>
<italic>LINC00673</italic>
</td>
<td align="center" valign="middle" rowspan="4" colspan="1">T/C</td>
<td align="center" valign="middle" rowspan="1" colspan="1">maf<xref rid="TFN5" ref-type="table-fn">e</xref>
<break></break>
cases;controls</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.146; 0.110</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.139; 0.129</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.149; 0.116</td>
<td align="center" valign="middle" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.135; 0.114</td>
<td align="center" valign="middle" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">info<xref rid="TFN6" ref-type="table-fn">f</xref>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.963</td>
<td align="center" valign="middle" rowspan="1" colspan="1">g</td>
<td align="center" valign="middle" rowspan="1" colspan="1">g</td>
<td align="center" valign="middle" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">OR (CI)<xref rid="TFN7" ref-type="table-fn">g</xref>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.38 (1.26 – 1.52)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.09 (0.96 – 1.25)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.34 (1.16 – 1.55)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.27 (1.19 – 1.36)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.24 (1.10 – 1.40)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.26 (1.19 – 1.34)</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">p-value</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.38×10<sup>−10</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.95×10<sup>−1</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2.95×10<sup>−4</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">6.74×10<sup>−12</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">6.40×10<sup>−4</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.42×10<sup>−14</sup>
</td>
</tr>
<tr><td align="center" valign="middle" rowspan="4" colspan="1">17q25.1<xref rid="TFN8" ref-type="table-fn">h</xref>
<break></break>
rs7214041<break></break>
70,401,476<break></break>
<italic>LINC00673</italic>
</td>
<td align="center" valign="middle" rowspan="4" colspan="1">T/C</td>
<td align="center" valign="middle" rowspan="1" colspan="1">maf<break></break>
cases;controls</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.148; 0.112</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.140; 0.133</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.150; 0.117</td>
<td align="center" valign="middle" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.139; 0.117</td>
<td align="center" valign="middle" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">info</td>
<td align="center" valign="middle" rowspan="1" colspan="1">g</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.966</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.96</td>
<td align="center" valign="middle" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">OR (CI)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.38 (1.26 – 1.51)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.07 (0.93 – 1.22)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.33 (1.15 – 1.53)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.26 (1.18 – 1.35)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.25 (1.11 – 1.41)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.26 (1.19 – 1.34)</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">p-value</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.95×10<sup>−10</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3.36×10<sup>−1</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3.69×10<sup>−4</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2.67×10<sup>−11</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3.37×10<sup>−4</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2.88×10<sup>−14</sup>
</td>
</tr>
<tr><td align="center" valign="middle" rowspan="4" colspan="1">2p13.3<break></break>
rs1486134<break></break>
67,639,769<break></break>
<italic>ETAA1</italic>
(2236bp 3′)</td>
<td align="center" valign="middle" rowspan="4" colspan="1">G/T</td>
<td align="center" valign="middle" rowspan="1" colspan="1">maf<break></break>
cases;controls</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.302; 0.275</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.305; 0.292</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.305; 0.276</td>
<td align="center" valign="middle" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.292; 0.273</td>
<td align="center" valign="middle" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">info</td>
<td align="center" valign="middle" rowspan="1" colspan="1">g</td>
<td align="center" valign="middle" rowspan="1" colspan="1">g</td>
<td align="center" valign="middle" rowspan="1" colspan="1">g</td>
<td align="center" valign="middle" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">OR (CI)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.14 (1.06 – 1.22)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.06 (0.96 – 1.18)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.15 (1.03 – 1.28)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.13 (1.08 – 1.19)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.16 (1.06 – 1.27)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.14 (1.09 – 1.19)</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">p-value</td>
<td align="center" valign="middle" rowspan="1" colspan="1">5.96×10<sup>−5</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.57×10<sup>−1</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">5.18×10<sup>−3</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">8.35×10<sup>−7</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">9.42×10<sup>−4</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3.36×10<sup>−9</sup>
</td>
</tr>
<tr><td align="center" valign="middle" rowspan="4" colspan="1">7p13<break></break>
rs17688601<break></break>
40,866,663<break></break>
<italic>SUGCT</italic>
</td>
<td align="center" valign="middle" rowspan="4" colspan="1">A/C</td>
<td align="center" valign="middle" rowspan="1" colspan="1">maf<break></break>
cases;controls</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.241; 0.263</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.218; 0.254</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.237; 0.268</td>
<td align="center" valign="middle" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.254; 0.277</td>
<td align="center" valign="middle" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">info</td>
<td align="center" valign="middle" rowspan="1" colspan="1">g</td>
<td align="center" valign="middle" rowspan="1" colspan="1">g</td>
<td align="center" valign="middle" rowspan="1" colspan="1">g</td>
<td align="center" valign="middle" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">OR (CI)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.89 (0.83 – 0.96)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.82 (0.73 – 0.91)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.85 (0.76 – 0.94)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.87 (0.82 – 0.91)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.91 (0.83 – 1.00)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.88 (0.84 – 0.92)</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">p-value</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.98×10<sup>−3</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.66×10<sup>−4</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">8.72×10<sup>−3</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">9.77×10<sup>−8</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3.93×10<sup>−2</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.41×10<sup>−8</sup>
</td>
</tr>
<tr><td align="center" valign="middle" rowspan="4" colspan="1">3q29<break></break>
rs9854771<break></break>
189,508,471<break></break>
<italic>TP63</italic>
</td>
<td align="center" valign="middle" rowspan="4" colspan="1">A/G</td>
<td align="center" valign="middle" rowspan="1" colspan="1">maf<break></break>
cases;controls</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.328; 0.362</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.336; 0.366</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.325; 0.356</td>
<td align="center" valign="middle" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.341; 0.356</td>
<td align="center" valign="middle" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">info</td>
<td align="center" valign="middle" rowspan="1" colspan="1">g</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.998</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.998</td>
<td align="center" valign="middle" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">OR (CI)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.86 (0.81 – 0.92)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.88 (0.80 – 0.90)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.87 (0.79 – 0.97)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.87 (0.83 – 0.92)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.93 (0.86 – 1.01)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.89 (0.85 – 0.93)</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">p-value</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3.10×10<sup>−5</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">7.94×10<sup>−3</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.55×10<sup>−2</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">4.08×10<sup>−8</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.01×10<sup>−1</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2.35×10<sup>−8</sup>
</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn id="TFN1"><label>a</label>
<p>Cytogenetic regions according to NCBI Human Genome Build 37 and NCBI’s Map Viewer</p>
</fn>
<fn id="TFN2"><label>b</label>
<p>SNP position according to NCBI Human Genome Build 37</p>
</fn>
<fn id="TFN3"><label>c</label>
<p>Results from the Combined Stage 1 meta-analysis of PanC4, PanScan 1, and PanScan 2</p>
</fn>
<fn id="TFN4"><label>d</label>
<p>Results from the Combined Stage 1 and 2 meta-analysis of PanC4, PanScan 1, PanScan 2, and PANDoRA</p>
</fn>
<fn id="TFN5"><label>e</label>
<p>MAF- minor allele frequency</p>
</fn>
<fn id="TFN6"><label>f</label>
<p>Quality of imputation metric. See online methods for more detail. If snp is genotyped and not imputed, a ‘g’ is reported</p>
</fn>
<fn id="TFN7"><label>g</label>
<p>Allelic Odds Ratio and corresponding 95% Confidence Interval</p>
</fn>
<fn id="TFN8"><label>h</label>
<p>R<sup>2</sup>
>0.95</p>
</fn>
</table-wrap-foot>
</table-wrap>
</floats-group>
</pmc>
</record>
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