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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Pubertal development and prostate cancer risk: Mendelian randomization study in a population-based cohort</title><author><name sortKey="Bonilla, Carolina" sort="Bonilla, Carolina" uniqKey="Bonilla C" first="Carolina" last="Bonilla">Carolina Bonilla</name><affiliation><nlm:aff id="Aff1">School of Social and Community Medicine, University of Bristol, Bristol, UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff2">MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK</nlm:aff></affiliation></author><author><name sortKey="Lewis, Sarah J" sort="Lewis, Sarah J" uniqKey="Lewis S" first="Sarah J." last="Lewis">Sarah J. Lewis</name><affiliation><nlm:aff id="Aff1">School of Social and Community Medicine, University of Bristol, Bristol, UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff2">MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK</nlm:aff></affiliation></author><author><name sortKey="Martin, Richard M" sort="Martin, Richard M" uniqKey="Martin R" first="Richard M." last="Martin">Richard M. Martin</name><affiliation><nlm:aff id="Aff1">School of Social and Community Medicine, University of Bristol, Bristol, UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff2">MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff3">National Institute for Health Research, Bristol Biomedical Research Unit in Nutrition, Bristol, UK</nlm:aff></affiliation></author><author><name sortKey="Donovan, Jenny L" sort="Donovan, Jenny L" uniqKey="Donovan J" first="Jenny L." last="Donovan">Jenny L. Donovan</name><affiliation><nlm:aff id="Aff1">School of Social and Community Medicine, University of Bristol, Bristol, UK</nlm:aff></affiliation></author><author><name sortKey="Hamdy, Freddie C" sort="Hamdy, Freddie C" uniqKey="Hamdy F" first="Freddie C." last="Hamdy">Freddie C. Hamdy</name><affiliation><nlm:aff id="Aff4">Nuffield Department of Surgery, University of Oxford, Oxford, UK</nlm:aff></affiliation></author><author><name sortKey="Neal, David E" sort="Neal, David E" uniqKey="Neal D" first="David E." last="Neal">David E. Neal</name><affiliation><nlm:aff id="Aff4">Nuffield Department of Surgery, University of Oxford, Oxford, UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff5">Surgical Oncology (Uro-Oncology: S4), University of Cambridge, Box 279, Addenbrooke’s Hospital, Hills Road, Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Eeles, Rosalind" sort="Eeles, Rosalind" uniqKey="Eeles R" first="Rosalind" last="Eeles">Rosalind Eeles</name><affiliation><nlm:aff id="Aff6">The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG Surrey UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff7">The Royal Marsden NHS Foundation Trust, Fulham and Sutton London and Surrey, UK</nlm:aff></affiliation></author><author><name sortKey="Easton, Doug" sort="Easton, Doug" uniqKey="Easton D" first="Doug" last="Easton">Doug Easton</name><affiliation><nlm:aff id="Aff8">Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Kote Jarai, Zsofia" sort="Kote Jarai, Zsofia" uniqKey="Kote Jarai Z" first="Zsofia" last="Kote-Jarai">Zsofia Kote-Jarai</name><affiliation><nlm:aff id="Aff6">The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG Surrey UK</nlm:aff></affiliation></author><author><name sortKey="Al Olama, Ali Amin" sort="Al Olama, Ali Amin" uniqKey="Al Olama A" first="Ali Amin" last="Al Olama">Ali Amin Al Olama</name><affiliation><nlm:aff id="Aff8">Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Benlloch, Sara" sort="Benlloch, Sara" uniqKey="Benlloch S" first="Sara" last="Benlloch">Sara Benlloch</name><affiliation><nlm:aff id="Aff8">Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Muir, Kenneth" sort="Muir, Kenneth" uniqKey="Muir K" first="Kenneth" last="Muir">Kenneth Muir</name><affiliation><nlm:aff id="Aff9">University of Warwick, Coventry, UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff10">Institute of Population Health, The University of Manchester, Manchester, M13 9PL UK</nlm:aff></affiliation></author><author><name sortKey="Giles, Graham G" sort="Giles, Graham G" uniqKey="Giles G" first="Graham G." last="Giles">Graham G. Giles</name><affiliation><nlm:aff id="Aff11">The Cancer Council Victoria, 615 St. Kilda Road, Melbourne, Victoria 3004 Australia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff12">Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria 3010 Australia</nlm:aff></affiliation></author><author><name sortKey="Wiklund, Fredrik" sort="Wiklund, Fredrik" uniqKey="Wiklund F" first="Fredrik" last="Wiklund">Fredrik Wiklund</name><affiliation><nlm:aff id="Aff13">Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden</nlm:aff></affiliation></author><author><name sortKey="Gronberg, Henrik" sort="Gronberg, Henrik" uniqKey="Gronberg H" first="Henrik" last="Gronberg">Henrik Gronberg</name><affiliation><nlm:aff id="Aff13">Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden</nlm:aff></affiliation></author><author><name sortKey="Haiman, Christopher A" sort="Haiman, Christopher A" uniqKey="Haiman C" first="Christopher A." last="Haiman">Christopher A. Haiman</name><affiliation><nlm:aff id="Aff14">Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA USA</nlm:aff></affiliation></author><author><name sortKey="Schleutker, Johanna" sort="Schleutker, Johanna" uniqKey="Schleutker J" first="Johanna" last="Schleutker">Johanna Schleutker</name><affiliation><nlm:aff id="Aff15">Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="Aff16">Institute of Biomedical Technology/BioMediTech, University of Tampere and FimLab Laboratories, Tampere, Finland</nlm:aff></affiliation></author><author><name sortKey="Nordestgaard, B Rge G" sort="Nordestgaard, B Rge G" uniqKey="Nordestgaard B" first="B Rge G." last="Nordestgaard">B Rge G. Nordestgaard</name><affiliation><nlm:aff id="Aff17">Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 75, Herlev, DK-2730 Denmark</nlm:aff></affiliation></author><author><name sortKey="Travis, Ruth C" sort="Travis, Ruth C" uniqKey="Travis R" first="Ruth C." last="Travis">Ruth C. Travis</name><affiliation><nlm:aff id="Aff18">Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK</nlm:aff></affiliation></author><author><name sortKey="Pashayan, Nora" sort="Pashayan, Nora" uniqKey="Pashayan N" first="Nora" last="Pashayan">Nora Pashayan</name><affiliation><nlm:aff id="Aff19">Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway Cambridge, UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff20">Department of Applied Health Research, University College London, 1-19 Torrington Place, London, WC1E 7HB UK</nlm:aff></affiliation></author><author><name sortKey="Khaw, Kay Tee" sort="Khaw, Kay Tee" uniqKey="Khaw K" first="Kay-Tee" last="Khaw">Kay-Tee Khaw</name><affiliation><nlm:aff id="Aff21">Cambridge Institute of Public Health, University of Cambridge, Forvie Site, Robinson Way, Cambridge, CB2 0SR UK</nlm:aff></affiliation></author><author><name sortKey="Stanford, Janet L" sort="Stanford, Janet L" uniqKey="Stanford J" first="Janet L." last="Stanford">Janet L. Stanford</name><affiliation><nlm:aff id="Aff22">Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA USA</nlm:aff></affiliation><affiliation><nlm:aff id="Aff23">Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA USA</nlm:aff></affiliation></author><author><name sortKey="Blot, William J" sort="Blot, William J" uniqKey="Blot W" first="William J." last="Blot">William J. Blot</name><affiliation><nlm:aff id="Aff24">International Epidemiology Institute, 1455 Research Blvd., Suite 550, Rockville, MD 20850 USA</nlm:aff></affiliation></author><author><name sortKey="Thibodeau, Stephen" sort="Thibodeau, Stephen" uniqKey="Thibodeau S" first="Stephen" last="Thibodeau">Stephen Thibodeau</name><affiliation><nlm:aff id="Aff25">Mayo Clinic, Rochester, MN USA</nlm:aff></affiliation></author><author><name sortKey="Maier, Christiane" sort="Maier, Christiane" uniqKey="Maier C" first="Christiane" last="Maier">Christiane Maier</name><affiliation><nlm:aff id="Aff26">Department of Urology, University Hospital Ulm, Ulm, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="Aff27">Institute of Human Genetics, University Hospital Ulm, Ulm, Germany</nlm:aff></affiliation></author><author><name sortKey="Kibel, Adam S" sort="Kibel, Adam S" uniqKey="Kibel A" first="Adam S." last="Kibel">Adam S. Kibel</name><affiliation><nlm:aff id="Aff28">Brigham and Women’s Hospital/Dana-Farber Cancer Institute, 45 Francis Street - ASB II-3, Boston, MA 02115 USA</nlm:aff></affiliation><affiliation><nlm:aff id="Aff29">Washington University, St Louis, MO USA</nlm:aff></affiliation></author><author><name sortKey="Cybulski, Cezary" sort="Cybulski, Cezary" uniqKey="Cybulski C" first="Cezary" last="Cybulski">Cezary Cybulski</name><affiliation><nlm:aff id="Aff30">International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland</nlm:aff></affiliation></author><author><name sortKey="Cannon Albright, Lisa" sort="Cannon Albright, Lisa" uniqKey="Cannon Albright L" first="Lisa" last="Cannon-Albright">Lisa Cannon-Albright</name><affiliation><nlm:aff id="Aff31">Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT USA</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="Aff32">Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="Aff33">Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="Aff34">German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Park, Jong" sort="Park, Jong" uniqKey="Park J" first="Jong" last="Park">Jong Park</name><affiliation><nlm:aff id="Aff35">Division of Cancer Prevention and Control, H. Lee Moffitt Cancer Center, 12902 Magnolia Dr., Tampa, FL USA</nlm:aff></affiliation></author><author><name sortKey="Kaneva, Radka" sort="Kaneva, Radka" uniqKey="Kaneva R" first="Radka" last="Kaneva">Radka Kaneva</name><affiliation><nlm:aff id="Aff36">Molecular Medicine Center and Department of Medical Chemistry and Biochemistry, Medical University-Sofia, 2 Zdrave St., Sofia, 1431 Bulgaria</nlm:aff></affiliation></author><author><name sortKey="Batra, Jyotsna" sort="Batra, Jyotsna" uniqKey="Batra J" first="Jyotsna" last="Batra">Jyotsna Batra</name><affiliation><nlm:aff id="Aff37">Australian Prostate Cancer Research Centre – Qld, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia</nlm:aff></affiliation></author><author><name sortKey="Teixeira, Manuel R" sort="Teixeira, Manuel R" uniqKey="Teixeira M" first="Manuel R." last="Teixeira">Manuel R. Teixeira</name><affiliation><nlm:aff id="Aff38">Department of Genetics, Portuguese Oncology Institute, Porto, Portugal</nlm:aff></affiliation><affiliation><nlm:aff id="Aff39">Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal</nlm:aff></affiliation></author><author><name sortKey="Pandha, Hardev" sort="Pandha, Hardev" uniqKey="Pandha H" first="Hardev" last="Pandha">Hardev Pandha</name><affiliation><nlm:aff id="Aff40">The University of Surrey, Guildford, Surrey GU2 7XH UK</nlm:aff></affiliation></author><author><name sortKey="Lathrop, Mark" sort="Lathrop, Mark" uniqKey="Lathrop M" first="Mark" last="Lathrop">Mark Lathrop</name><affiliation><nlm:aff id="Aff41">Commissariat à l’Energie Atomique, Center National de Génotypage, Evry, France</nlm:aff></affiliation><affiliation><nlm:aff id="Aff42">McGill University-Génome Québec Innovation Centre, Montreal, Canada</nlm:aff></affiliation></author><author><name sortKey="Davey Smith, George" sort="Davey Smith, George" uniqKey="Davey Smith G" first="George" last="Davey Smith">George Davey Smith</name><affiliation><nlm:aff id="Aff1">School of Social and Community Medicine, University of Bristol, Bristol, UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff2">MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27044414</idno><idno type="pmc">4820939</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820939</idno><idno type="RBID">PMC:4820939</idno><idno type="doi">10.1186/s12916-016-0602-x</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000B03</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000B03</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Pubertal development and prostate cancer risk: Mendelian randomization study in a population-based cohort</title><author><name sortKey="Bonilla, Carolina" sort="Bonilla, Carolina" uniqKey="Bonilla C" first="Carolina" last="Bonilla">Carolina Bonilla</name><affiliation><nlm:aff id="Aff1">School of Social and Community Medicine, University of Bristol, Bristol, UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff2">MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK</nlm:aff></affiliation></author><author><name sortKey="Lewis, Sarah J" sort="Lewis, Sarah J" uniqKey="Lewis S" first="Sarah J." last="Lewis">Sarah J. Lewis</name><affiliation><nlm:aff id="Aff1">School of Social and Community Medicine, University of Bristol, Bristol, UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff2">MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK</nlm:aff></affiliation></author><author><name sortKey="Martin, Richard M" sort="Martin, Richard M" uniqKey="Martin R" first="Richard M." last="Martin">Richard M. Martin</name><affiliation><nlm:aff id="Aff1">School of Social and Community Medicine, University of Bristol, Bristol, UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff2">MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff3">National Institute for Health Research, Bristol Biomedical Research Unit in Nutrition, Bristol, UK</nlm:aff></affiliation></author><author><name sortKey="Donovan, Jenny L" sort="Donovan, Jenny L" uniqKey="Donovan J" first="Jenny L." last="Donovan">Jenny L. Donovan</name><affiliation><nlm:aff id="Aff1">School of Social and Community Medicine, University of Bristol, Bristol, UK</nlm:aff></affiliation></author><author><name sortKey="Hamdy, Freddie C" sort="Hamdy, Freddie C" uniqKey="Hamdy F" first="Freddie C." last="Hamdy">Freddie C. Hamdy</name><affiliation><nlm:aff id="Aff4">Nuffield Department of Surgery, University of Oxford, Oxford, UK</nlm:aff></affiliation></author><author><name sortKey="Neal, David E" sort="Neal, David E" uniqKey="Neal D" first="David E." last="Neal">David E. Neal</name><affiliation><nlm:aff id="Aff4">Nuffield Department of Surgery, University of Oxford, Oxford, UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff5">Surgical Oncology (Uro-Oncology: S4), University of Cambridge, Box 279, Addenbrooke’s Hospital, Hills Road, Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Eeles, Rosalind" sort="Eeles, Rosalind" uniqKey="Eeles R" first="Rosalind" last="Eeles">Rosalind Eeles</name><affiliation><nlm:aff id="Aff6">The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG Surrey UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff7">The Royal Marsden NHS Foundation Trust, Fulham and Sutton London and Surrey, UK</nlm:aff></affiliation></author><author><name sortKey="Easton, Doug" sort="Easton, Doug" uniqKey="Easton D" first="Doug" last="Easton">Doug Easton</name><affiliation><nlm:aff id="Aff8">Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Kote Jarai, Zsofia" sort="Kote Jarai, Zsofia" uniqKey="Kote Jarai Z" first="Zsofia" last="Kote-Jarai">Zsofia Kote-Jarai</name><affiliation><nlm:aff id="Aff6">The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG Surrey UK</nlm:aff></affiliation></author><author><name sortKey="Al Olama, Ali Amin" sort="Al Olama, Ali Amin" uniqKey="Al Olama A" first="Ali Amin" last="Al Olama">Ali Amin Al Olama</name><affiliation><nlm:aff id="Aff8">Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Benlloch, Sara" sort="Benlloch, Sara" uniqKey="Benlloch S" first="Sara" last="Benlloch">Sara Benlloch</name><affiliation><nlm:aff id="Aff8">Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway Cambridge, UK</nlm:aff></affiliation></author><author><name sortKey="Muir, Kenneth" sort="Muir, Kenneth" uniqKey="Muir K" first="Kenneth" last="Muir">Kenneth Muir</name><affiliation><nlm:aff id="Aff9">University of Warwick, Coventry, UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff10">Institute of Population Health, The University of Manchester, Manchester, M13 9PL UK</nlm:aff></affiliation></author><author><name sortKey="Giles, Graham G" sort="Giles, Graham G" uniqKey="Giles G" first="Graham G." last="Giles">Graham G. Giles</name><affiliation><nlm:aff id="Aff11">The Cancer Council Victoria, 615 St. Kilda Road, Melbourne, Victoria 3004 Australia</nlm:aff></affiliation><affiliation><nlm:aff id="Aff12">Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria 3010 Australia</nlm:aff></affiliation></author><author><name sortKey="Wiklund, Fredrik" sort="Wiklund, Fredrik" uniqKey="Wiklund F" first="Fredrik" last="Wiklund">Fredrik Wiklund</name><affiliation><nlm:aff id="Aff13">Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden</nlm:aff></affiliation></author><author><name sortKey="Gronberg, Henrik" sort="Gronberg, Henrik" uniqKey="Gronberg H" first="Henrik" last="Gronberg">Henrik Gronberg</name><affiliation><nlm:aff id="Aff13">Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden</nlm:aff></affiliation></author><author><name sortKey="Haiman, Christopher A" sort="Haiman, Christopher A" uniqKey="Haiman C" first="Christopher A." last="Haiman">Christopher A. Haiman</name><affiliation><nlm:aff id="Aff14">Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA USA</nlm:aff></affiliation></author><author><name sortKey="Schleutker, Johanna" sort="Schleutker, Johanna" uniqKey="Schleutker J" first="Johanna" last="Schleutker">Johanna Schleutker</name><affiliation><nlm:aff id="Aff15">Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="Aff16">Institute of Biomedical Technology/BioMediTech, University of Tampere and FimLab Laboratories, Tampere, Finland</nlm:aff></affiliation></author><author><name sortKey="Nordestgaard, B Rge G" sort="Nordestgaard, B Rge G" uniqKey="Nordestgaard B" first="B Rge G." last="Nordestgaard">B Rge G. Nordestgaard</name><affiliation><nlm:aff id="Aff17">Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 75, Herlev, DK-2730 Denmark</nlm:aff></affiliation></author><author><name sortKey="Travis, Ruth C" sort="Travis, Ruth C" uniqKey="Travis R" first="Ruth C." last="Travis">Ruth C. Travis</name><affiliation><nlm:aff id="Aff18">Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK</nlm:aff></affiliation></author><author><name sortKey="Pashayan, Nora" sort="Pashayan, Nora" uniqKey="Pashayan N" first="Nora" last="Pashayan">Nora Pashayan</name><affiliation><nlm:aff id="Aff19">Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway Cambridge, UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff20">Department of Applied Health Research, University College London, 1-19 Torrington Place, London, WC1E 7HB UK</nlm:aff></affiliation></author><author><name sortKey="Khaw, Kay Tee" sort="Khaw, Kay Tee" uniqKey="Khaw K" first="Kay-Tee" last="Khaw">Kay-Tee Khaw</name><affiliation><nlm:aff id="Aff21">Cambridge Institute of Public Health, University of Cambridge, Forvie Site, Robinson Way, Cambridge, CB2 0SR UK</nlm:aff></affiliation></author><author><name sortKey="Stanford, Janet L" sort="Stanford, Janet L" uniqKey="Stanford J" first="Janet L." last="Stanford">Janet L. Stanford</name><affiliation><nlm:aff id="Aff22">Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA USA</nlm:aff></affiliation><affiliation><nlm:aff id="Aff23">Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA USA</nlm:aff></affiliation></author><author><name sortKey="Blot, William J" sort="Blot, William J" uniqKey="Blot W" first="William J." last="Blot">William J. Blot</name><affiliation><nlm:aff id="Aff24">International Epidemiology Institute, 1455 Research Blvd., Suite 550, Rockville, MD 20850 USA</nlm:aff></affiliation></author><author><name sortKey="Thibodeau, Stephen" sort="Thibodeau, Stephen" uniqKey="Thibodeau S" first="Stephen" last="Thibodeau">Stephen Thibodeau</name><affiliation><nlm:aff id="Aff25">Mayo Clinic, Rochester, MN USA</nlm:aff></affiliation></author><author><name sortKey="Maier, Christiane" sort="Maier, Christiane" uniqKey="Maier C" first="Christiane" last="Maier">Christiane Maier</name><affiliation><nlm:aff id="Aff26">Department of Urology, University Hospital Ulm, Ulm, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="Aff27">Institute of Human Genetics, University Hospital Ulm, Ulm, Germany</nlm:aff></affiliation></author><author><name sortKey="Kibel, Adam S" sort="Kibel, Adam S" uniqKey="Kibel A" first="Adam S." last="Kibel">Adam S. Kibel</name><affiliation><nlm:aff id="Aff28">Brigham and Women’s Hospital/Dana-Farber Cancer Institute, 45 Francis Street - ASB II-3, Boston, MA 02115 USA</nlm:aff></affiliation><affiliation><nlm:aff id="Aff29">Washington University, St Louis, MO USA</nlm:aff></affiliation></author><author><name sortKey="Cybulski, Cezary" sort="Cybulski, Cezary" uniqKey="Cybulski C" first="Cezary" last="Cybulski">Cezary Cybulski</name><affiliation><nlm:aff id="Aff30">International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland</nlm:aff></affiliation></author><author><name sortKey="Cannon Albright, Lisa" sort="Cannon Albright, Lisa" uniqKey="Cannon Albright L" first="Lisa" last="Cannon-Albright">Lisa Cannon-Albright</name><affiliation><nlm:aff id="Aff31">Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT USA</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="Aff32">Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="Aff33">Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="Aff34">German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Park, Jong" sort="Park, Jong" uniqKey="Park J" first="Jong" last="Park">Jong Park</name><affiliation><nlm:aff id="Aff35">Division of Cancer Prevention and Control, H. Lee Moffitt Cancer Center, 12902 Magnolia Dr., Tampa, FL USA</nlm:aff></affiliation></author><author><name sortKey="Kaneva, Radka" sort="Kaneva, Radka" uniqKey="Kaneva R" first="Radka" last="Kaneva">Radka Kaneva</name><affiliation><nlm:aff id="Aff36">Molecular Medicine Center and Department of Medical Chemistry and Biochemistry, Medical University-Sofia, 2 Zdrave St., Sofia, 1431 Bulgaria</nlm:aff></affiliation></author><author><name sortKey="Batra, Jyotsna" sort="Batra, Jyotsna" uniqKey="Batra J" first="Jyotsna" last="Batra">Jyotsna Batra</name><affiliation><nlm:aff id="Aff37">Australian Prostate Cancer Research Centre – Qld, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia</nlm:aff></affiliation></author><author><name sortKey="Teixeira, Manuel R" sort="Teixeira, Manuel R" uniqKey="Teixeira M" first="Manuel R." last="Teixeira">Manuel R. Teixeira</name><affiliation><nlm:aff id="Aff38">Department of Genetics, Portuguese Oncology Institute, Porto, Portugal</nlm:aff></affiliation><affiliation><nlm:aff id="Aff39">Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal</nlm:aff></affiliation></author><author><name sortKey="Pandha, Hardev" sort="Pandha, Hardev" uniqKey="Pandha H" first="Hardev" last="Pandha">Hardev Pandha</name><affiliation><nlm:aff id="Aff40">The University of Surrey, Guildford, Surrey GU2 7XH UK</nlm:aff></affiliation></author><author><name sortKey="Lathrop, Mark" sort="Lathrop, Mark" uniqKey="Lathrop M" first="Mark" last="Lathrop">Mark Lathrop</name><affiliation><nlm:aff id="Aff41">Commissariat à l’Energie Atomique, Center National de Génotypage, Evry, France</nlm:aff></affiliation><affiliation><nlm:aff id="Aff42">McGill University-Génome Québec Innovation Centre, Montreal, Canada</nlm:aff></affiliation></author><author><name sortKey="Davey Smith, George" sort="Davey Smith, George" uniqKey="Davey Smith G" first="George" last="Davey Smith">George Davey Smith</name><affiliation><nlm:aff id="Aff1">School of Social and Community Medicine, University of Bristol, Bristol, UK</nlm:aff></affiliation><affiliation><nlm:aff id="Aff2">MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK</nlm:aff></affiliation></author></analytic><series><title level="j">BMC Medicine</title><idno type="eISSN">1741-7015</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>Epidemiological studies have observed a positive association between an earlier age at sexual development and prostate cancer, but markers of sexual maturation in boys are imprecise and observational estimates are likely to suffer from a degree of uncontrolled confounding. To obtain causal estimates, we examined the role of pubertal development in prostate cancer using genetic polymorphisms associated with Tanner stage in adolescent boys in a Mendelian randomization (MR) approach.</p></sec><sec><title>Methods</title><p>We derived a weighted genetic risk score for pubertal development, combining 13 SNPs associated with male Tanner stage. A higher score indicated a later puberty onset. We examined the association of this score with prostate cancer risk, stage and grade in the UK-based ProtecT case-control study (<italic>n</italic> = 2,927), and used the PRACTICAL consortium (<italic>n</italic> = 43,737) as a replication sample.</p></sec><sec><title>Results</title><p>In ProtecT, the puberty genetic score was inversely associated with prostate cancer grade (odds ratio (OR) of high- vs. low-grade cancer, per tertile of the score: 0.76; 95 % CI, 0.64–0.89). In an instrumental variable estimation of the causal OR, later physical development in adolescence (equivalent to a difference of one Tanner stage between pubertal boys of the same age) was associated with a 77 % (95 % CI, 43–91 %) reduced odds of high Gleason prostate cancer. In PRACTICAL, the puberty genetic score was associated with prostate cancer stage (OR of advanced vs. localized cancer, per tertile: 0.95; 95 % CI, 0.91–1.00) and prostate cancer-specific mortality (hazard ratio amongst cases, per tertile: 0.94; 95 % CI, 0.90–0.98), but not with disease grade.</p></sec><sec><title>Conclusions</title><p>Older age at sexual maturation is causally linked to a reduced risk of later prostate cancer, especially aggressive disease.</p></sec><sec><title>Electronic supplementary material</title><p>The online version of this article (doi:10.1186/s12916-016-0602-x) contains supplementary material, which is available to authorized users.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Jemal, A" uniqKey="Jemal A">A Jemal</name></author><author><name sortKey="Bray, F" uniqKey="Bray F">F Bray</name></author><author><name sortKey="Center, Mm" uniqKey="Center M">MM Center</name></author><author><name 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<front><journal-meta><journal-id journal-id-type="nlm-ta">BMC Med</journal-id><journal-id journal-id-type="iso-abbrev">BMC Med</journal-id><journal-title-group><journal-title>BMC Medicine</journal-title></journal-title-group><issn pub-type="epub">1741-7015</issn><publisher><publisher-name>BioMed Central</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">27044414</article-id><article-id pub-id-type="pmc">4820939</article-id><article-id pub-id-type="publisher-id">602</article-id><article-id pub-id-type="doi">10.1186/s12916-016-0602-x</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group></article-categories><title-group><article-title>Pubertal development and prostate cancer risk: Mendelian randomization study in a population-based cohort</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Bonilla</surname><given-names>Carolina</given-names></name><address><email>c.bonilla@bristol.ac.uk</email></address><xref ref-type="aff" rid="Aff1"></xref><xref ref-type="aff" rid="Aff2"></xref></contrib><contrib contrib-type="author"><name><surname>Lewis</surname><given-names>Sarah J.</given-names></name><xref ref-type="aff" rid="Aff1"></xref><xref ref-type="aff" rid="Aff2"></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Martin</surname><given-names>Richard M.</given-names></name><address><phone>+44 117 928 7321</phone><email>richard.martin@bristol.ac.uk</email></address><xref ref-type="aff" rid="Aff1"></xref><xref ref-type="aff" rid="Aff2"></xref><xref ref-type="aff" rid="Aff3"></xref></contrib><contrib contrib-type="author"><name><surname>Donovan</surname><given-names>Jenny L.</given-names></name><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Hamdy</surname><given-names>Freddie C.</given-names></name><xref ref-type="aff" rid="Aff4"></xref></contrib><contrib contrib-type="author"><name><surname>Neal</surname><given-names>David E.</given-names></name><xref ref-type="aff" rid="Aff4"></xref><xref ref-type="aff" rid="Aff5"></xref></contrib><contrib contrib-type="author"><name><surname>Eeles</surname><given-names>Rosalind</given-names></name><xref ref-type="aff" rid="Aff6"></xref><xref ref-type="aff" rid="Aff7"></xref></contrib><contrib contrib-type="author"><name><surname>Easton</surname><given-names>Doug</given-names></name><xref ref-type="aff" rid="Aff8"></xref></contrib><contrib contrib-type="author"><name><surname>Kote-Jarai</surname><given-names>Zsofia</given-names></name><xref ref-type="aff" rid="Aff6"></xref></contrib><contrib contrib-type="author"><name><surname>Al Olama</surname><given-names>Ali Amin</given-names></name><xref ref-type="aff" rid="Aff8"></xref></contrib><contrib contrib-type="author"><name><surname>Benlloch</surname><given-names>Sara</given-names></name><xref ref-type="aff" rid="Aff8"></xref></contrib><contrib contrib-type="author"><name><surname>Muir</surname><given-names>Kenneth</given-names></name><xref ref-type="aff" rid="Aff9"></xref><xref ref-type="aff" rid="Aff10"></xref></contrib><contrib contrib-type="author"><name><surname>Giles</surname><given-names>Graham G.</given-names></name><xref ref-type="aff" rid="Aff11"></xref><xref ref-type="aff" rid="Aff12"></xref></contrib><contrib contrib-type="author"><name><surname>Wiklund</surname><given-names>Fredrik</given-names></name><xref ref-type="aff" rid="Aff13"></xref></contrib><contrib contrib-type="author"><name><surname>Gronberg</surname><given-names>Henrik</given-names></name><xref ref-type="aff" rid="Aff13"></xref></contrib><contrib contrib-type="author"><name><surname>Haiman</surname><given-names>Christopher A.</given-names></name><xref ref-type="aff" rid="Aff14"></xref></contrib><contrib contrib-type="author"><name><surname>Schleutker</surname><given-names>Johanna</given-names></name><xref ref-type="aff" rid="Aff15"></xref><xref ref-type="aff" rid="Aff16"></xref></contrib><contrib contrib-type="author"><name><surname>Nordestgaard</surname><given-names>Børge G.</given-names></name><xref ref-type="aff" rid="Aff17"></xref></contrib><contrib contrib-type="author"><name><surname>Travis</surname><given-names>Ruth C.</given-names></name><xref ref-type="aff" rid="Aff18"></xref></contrib><contrib contrib-type="author"><name><surname>Pashayan</surname><given-names>Nora</given-names></name><xref ref-type="aff" rid="Aff19"></xref><xref ref-type="aff" rid="Aff20"></xref></contrib><contrib contrib-type="author"><name><surname>Khaw</surname><given-names>Kay-Tee</given-names></name><xref ref-type="aff" rid="Aff21"></xref></contrib><contrib contrib-type="author"><name><surname>Stanford</surname><given-names>Janet L.</given-names></name><xref ref-type="aff" rid="Aff22"></xref><xref ref-type="aff" rid="Aff23"></xref></contrib><contrib contrib-type="author"><name><surname>Blot</surname><given-names>William J.</given-names></name><xref ref-type="aff" rid="Aff24"></xref></contrib><contrib contrib-type="author"><name><surname>Thibodeau</surname><given-names>Stephen</given-names></name><xref ref-type="aff" rid="Aff25"></xref></contrib><contrib contrib-type="author"><name><surname>Maier</surname><given-names>Christiane</given-names></name><xref ref-type="aff" rid="Aff26"></xref><xref ref-type="aff" rid="Aff27"></xref></contrib><contrib contrib-type="author"><name><surname>Kibel</surname><given-names>Adam S.</given-names></name><xref ref-type="aff" rid="Aff28"></xref><xref ref-type="aff" rid="Aff29"></xref></contrib><contrib contrib-type="author"><name><surname>Cybulski</surname><given-names>Cezary</given-names></name><xref ref-type="aff" rid="Aff30"></xref></contrib><contrib contrib-type="author"><name><surname>Cannon-Albright</surname><given-names>Lisa</given-names></name><xref ref-type="aff" rid="Aff31"></xref></contrib><contrib contrib-type="author"><name><surname>Brenner</surname><given-names>Hermann</given-names></name><xref ref-type="aff" rid="Aff32"></xref><xref ref-type="aff" rid="Aff33"></xref><xref ref-type="aff" rid="Aff34"></xref></contrib><contrib contrib-type="author"><name><surname>Park</surname><given-names>Jong</given-names></name><xref ref-type="aff" rid="Aff35"></xref></contrib><contrib contrib-type="author"><name><surname>Kaneva</surname><given-names>Radka</given-names></name><xref ref-type="aff" rid="Aff36"></xref></contrib><contrib contrib-type="author"><name><surname>Batra</surname><given-names>Jyotsna</given-names></name><xref ref-type="aff" rid="Aff37"></xref></contrib><contrib contrib-type="author"><name><surname>Teixeira</surname><given-names>Manuel R.</given-names></name><xref ref-type="aff" rid="Aff38"></xref><xref ref-type="aff" rid="Aff39"></xref></contrib><contrib contrib-type="author"><name><surname>Pandha</surname><given-names>Hardev</given-names></name><xref ref-type="aff" rid="Aff40"></xref></contrib><contrib contrib-type="author"><name><surname>Lathrop</surname><given-names>Mark</given-names></name><xref ref-type="aff" rid="Aff41"></xref><xref ref-type="aff" rid="Aff42"></xref></contrib><contrib contrib-type="author"><name><surname>Davey Smith</surname><given-names>George</given-names></name><xref ref-type="aff" rid="Aff1"></xref><xref ref-type="aff" rid="Aff2"></xref></contrib><contrib contrib-type="author"><collab>The PRACTICAL consortium</collab></contrib><aff id="Aff1"><label></label>School of Social and Community Medicine, University of Bristol, Bristol, UK</aff><aff id="Aff2"><label></label>MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK</aff><aff id="Aff3"><label></label>National Institute for Health Research, Bristol Biomedical Research Unit in Nutrition, Bristol, UK</aff><aff id="Aff4"><label></label>Nuffield Department of Surgery, University of Oxford, Oxford, UK</aff><aff id="Aff5"><label></label>Surgical Oncology (Uro-Oncology: S4), University of Cambridge, Box 279, Addenbrooke’s Hospital, Hills Road, Cambridge, UK</aff><aff id="Aff6"><label></label>The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG Surrey UK</aff><aff id="Aff7"><label></label>The Royal Marsden NHS Foundation Trust, Fulham and Sutton London and Surrey, UK</aff><aff id="Aff8"><label></label>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway Cambridge, UK</aff><aff id="Aff9"><label></label>University of Warwick, Coventry, UK</aff><aff id="Aff10"><label></label>Institute of Population Health, The University of Manchester, Manchester, M13 9PL UK</aff><aff id="Aff11"><label></label>The Cancer Council Victoria, 615 St. Kilda Road, Melbourne, Victoria 3004 Australia</aff><aff id="Aff12"><label></label>Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria 3010 Australia</aff><aff id="Aff13"><label></label>Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden</aff><aff id="Aff14"><label></label>Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA USA</aff><aff id="Aff15"><label></label>Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland</aff><aff id="Aff16"><label></label>Institute of Biomedical Technology/BioMediTech, University of Tampere and FimLab Laboratories, Tampere, Finland</aff><aff id="Aff17"><label></label>Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 75, Herlev, DK-2730 Denmark</aff><aff id="Aff18"><label></label>Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK</aff><aff id="Aff19"><label></label>Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway Cambridge, UK</aff><aff id="Aff20"><label></label>Department of Applied Health Research, University College London, 1-19 Torrington Place, London, WC1E 7HB UK</aff><aff id="Aff21"><label></label>Cambridge Institute of Public Health, University of Cambridge, Forvie Site, Robinson Way, Cambridge, CB2 0SR UK</aff><aff id="Aff22"><label></label>Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA USA</aff><aff id="Aff23"><label></label>Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA USA</aff><aff id="Aff24"><label></label>International Epidemiology Institute, 1455 Research Blvd., Suite 550, Rockville, MD 20850 USA</aff><aff id="Aff25"><label></label>Mayo Clinic, Rochester, MN USA</aff><aff id="Aff26"><label></label>Department of Urology, University Hospital Ulm, Ulm, Germany</aff><aff id="Aff27"><label></label>Institute of Human Genetics, University Hospital Ulm, Ulm, Germany</aff><aff id="Aff28"><label></label>Brigham and Women’s Hospital/Dana-Farber Cancer Institute, 45 Francis Street - ASB II-3, Boston, MA 02115 USA</aff><aff id="Aff29"><label></label>Washington University, St Louis, MO USA</aff><aff id="Aff30"><label></label>International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland</aff><aff id="Aff31"><label></label>Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT USA</aff><aff id="Aff32"><label></label>Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany</aff><aff id="Aff33"><label></label>Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany</aff><aff id="Aff34"><label></label>German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany</aff><aff id="Aff35"><label></label>Division of Cancer Prevention and Control, H. Lee Moffitt Cancer Center, 12902 Magnolia Dr., Tampa, FL USA</aff><aff id="Aff36"><label></label>Molecular Medicine Center and Department of Medical Chemistry and Biochemistry, Medical University-Sofia, 2 Zdrave St., Sofia, 1431 Bulgaria</aff><aff id="Aff37"><label></label>Australian Prostate Cancer Research Centre – Qld, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia</aff><aff id="Aff38"><label></label>Department of Genetics, Portuguese Oncology Institute, Porto, Portugal</aff><aff id="Aff39"><label></label>Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal</aff><aff id="Aff40"><label></label>The University of Surrey, Guildford, Surrey GU2 7XH UK</aff><aff id="Aff41"><label></label>Commissariat à l’Energie Atomique, Center National de Génotypage, Evry, France</aff><aff id="Aff42"><label></label>McGill University-Génome Québec Innovation Centre, Montreal, Canada</aff></contrib-group><pub-date pub-type="epub"><day>4</day><month>4</month><year>2016</year></pub-date><pub-date pub-type="pmc-release"><day>4</day><month>4</month><year>2016</year></pub-date><pub-date pub-type="collection"><year>2016</year></pub-date><volume>14</volume><elocation-id>66</elocation-id><history><date date-type="received"><day>20</day><month>11</month><year>2015</year></date><date date-type="accepted"><day>16</day><month>3</month><year>2016</year></date></history><permissions><copyright-statement>© Bonilla et al. 2016</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold>This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>) applies to the data made available in this article, unless otherwise stated.</license-p></license></permissions><abstract id="Abs1"><sec><title>Background</title><p>Epidemiological studies have observed a positive association between an earlier age at sexual development and prostate cancer, but markers of sexual maturation in boys are imprecise and observational estimates are likely to suffer from a degree of uncontrolled confounding. To obtain causal estimates, we examined the role of pubertal development in prostate cancer using genetic polymorphisms associated with Tanner stage in adolescent boys in a Mendelian randomization (MR) approach.</p></sec><sec><title>Methods</title><p>We derived a weighted genetic risk score for pubertal development, combining 13 SNPs associated with male Tanner stage. A higher score indicated a later puberty onset. We examined the association of this score with prostate cancer risk, stage and grade in the UK-based ProtecT case-control study (<italic>n</italic> = 2,927), and used the PRACTICAL consortium (<italic>n</italic> = 43,737) as a replication sample.</p></sec><sec><title>Results</title><p>In ProtecT, the puberty genetic score was inversely associated with prostate cancer grade (odds ratio (OR) of high- vs. low-grade cancer, per tertile of the score: 0.76; 95 % CI, 0.64–0.89). In an instrumental variable estimation of the causal OR, later physical development in adolescence (equivalent to a difference of one Tanner stage between pubertal boys of the same age) was associated with a 77 % (95 % CI, 43–91 %) reduced odds of high Gleason prostate cancer. In PRACTICAL, the puberty genetic score was associated with prostate cancer stage (OR of advanced vs. localized cancer, per tertile: 0.95; 95 % CI, 0.91–1.00) and prostate cancer-specific mortality (hazard ratio amongst cases, per tertile: 0.94; 95 % CI, 0.90–0.98), but not with disease grade.</p></sec><sec><title>Conclusions</title><p>Older age at sexual maturation is causally linked to a reduced risk of later prostate cancer, especially aggressive disease.</p></sec><sec><title>Electronic supplementary material</title><p>The online version of this article (doi:10.1186/s12916-016-0602-x) contains supplementary material, which is available to authorized users.</p></sec></abstract><kwd-group xml:lang="en"><title>Keywords</title><kwd>Boys</kwd><kwd>Mendelian randomization</kwd><kwd>Prostate cancer</kwd><kwd>Puberty</kwd><kwd>Tanner scale</kwd></kwd-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/501100000321</institution-id><institution>World Cancer Research Fund</institution></institution-wrap></funding-source><award-id>2011/419</award-id><principal-award-recipient><name><surname>Martin</surname><given-names>Richard M.</given-names></name></principal-award-recipient></award-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/501100000289</institution-id><institution>Cancer Research UK</institution></institution-wrap></funding-source><award-id>C18281/A19169</award-id><principal-award-recipient><name><surname>Martin</surname><given-names>Richard M.</given-names></name></principal-award-recipient></award-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/501100000265</institution-id><institution>Medical Research Council</institution></institution-wrap></funding-source><award-id>G0600705; MC_UU_12013/19</award-id></award-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/501100000664</institution-id><institution>Health Technology Assessment Programme</institution></institution-wrap></funding-source><award-id>HTA 96/20/99; ISRCTN20141297</award-id></award-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/501100004963</institution-id><institution>Seventh Framework Programme</institution></institution-wrap></funding-source><award-id>223175/HEALTH-F2-2009-223175</award-id></award-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/501100000289</institution-id><institution>Cancer Research UK</institution></institution-wrap></funding-source><award-id>C1287/A10118; C1287/A10710; C12292/A11174; C1281/A12014; C5047/A8384; C5047/A15007; C5047/A10692; C8197/A16565</award-id></award-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/100000002</institution-id><institution>National Institutes of Health</institution></institution-wrap></funding-source><award-id>CA128978</award-id></award-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/100000005</institution-id><institution>U.S. Department of Defense</institution></institution-wrap></funding-source><award-id>W81XWH-10-1-0341</award-id></award-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/501100000024</institution-id><institution>Canadian Institutes of Health Research (CA)</institution></institution-wrap></funding-source></award-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/100000869</institution-id><institution>Susan G. Komen for the Cure</institution></institution-wrap></funding-source></award-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/100001006</institution-id><institution>Breast Cancer Research Foundation</institution></institution-wrap></funding-source></award-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/100001282</institution-id><institution>Ovarian Cancer Research Fund</institution></institution-wrap></funding-source></award-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/501100000272</institution-id><institution>National Institute for Health Research</institution></institution-wrap></funding-source></award-group><award-group><funding-source><institution>Post-Cancer GWAS initiative</institution></funding-source><award-id>1U19 CA148537; 1U19 CA148065; 1U19 CA148112</award-id></award-group><award-group><funding-source><institution>The University of Bristol</institution></funding-source></award-group></funding-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2016</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="Sec1"><title>Background</title><p>Prostate cancer is now the most frequently detected cancer among men in Westernized countries [<xref ref-type="bibr" rid="CR1">1</xref>]. Prostatic intraepithelial neoplasia, a precursor of prostate cancer, has been observed among men in their 20s, suggesting that early-life exposures may play a role in the development of prostate cancer [<xref ref-type="bibr" rid="CR2">2</xref>] and provide novel opportunities for prostate cancer prevention [<xref ref-type="bibr" rid="CR3">3</xref>].</p><p>Circulating hormones, which rise during puberty, in particular androgens and insulin-like growth factors (IGFs), may play a role in prostate cancer initiation and progression [<xref ref-type="bibr" rid="CR4">4</xref>, <xref ref-type="bibr" rid="CR5">5</xref>], although the relevance of serum androgen levels has recently been called into question [<xref ref-type="bibr" rid="CR6">6</xref>]. Age at onset of puberty may be a risk factor for prostate adenocarcinoma in men given that exposure to high levels of hormones takes place during the critical window of prostate development in adolescence [<xref ref-type="bibr" rid="CR3">3</xref>]. Age of menarche is a well-known risk factor for breast cancer [<xref ref-type="bibr" rid="CR7">7</xref>], but it is yet unclear whether sexual maturation similarly influences later life cancer events in men. However, timing of puberty in boys is difficult to measure as it is not defined by a specific event as in women (menarche); thus, assessing it as a risk factor for prostate cancer in men is challenging.</p><p>We investigated whether pubertal development influences risk of prostate cancer in a population-based cohort. We used a genetic score comprised of single nucleotide polymorphisms (SNPs) associated with Tanner genital stage in adolescent boys [<xref ref-type="bibr" rid="CR8">8</xref>, <xref ref-type="bibr" rid="CR9">9</xref>], as a surrogate for the onset and progression of pubertal changes, and we determined associations of this genetic score with prostate cancer risk, stage and grade. The Tanner scale is a widely used 5-point scale that rates breast development in girls, genital development in boys, and pubic hair growth in both [<xref ref-type="bibr" rid="CR10">10</xref>]. Using a genetic score instead of directly assessed Tanner stage, in an approach known as Mendelian randomization (MR) [<xref ref-type="bibr" rid="CR11">11</xref>], allows stronger causal inferences because genetic variants are usually unaffected by non-genetic confounding, reverse causality, or measurement error, which underlie the problematic interpretation of observational studies [<xref ref-type="bibr" rid="CR11">11</xref>, <xref ref-type="bibr" rid="CR12">12</xref>].</p></sec><sec id="Sec2"><title>Methods</title><sec id="Sec3"><title>Subjects</title><p>This is a case-control study nested within a multicenter randomized controlled trial of treatments for prostate-specific antigen (PSA)-detected prostate cancer: the Prostate Testing for cancer and Treatment (ProtecT) study (ISRCTN20141297) [<xref ref-type="bibr" rid="CR13">13</xref>]. During recruitment to the ProtecT study between 2001 and 2009, over 100,000 men aged 50–69 years at 337 general practices in nine UK centres (Birmingham, Bristol, Cambridge, Cardiff, Edinburgh, Leeds, Leicester, Newcastle, Sheffield) were offered a PSA test at a community-based ‘prostate check clinic’, and those with raised levels (≥3 ng/mL) were offered a diagnostic biopsy [<xref ref-type="bibr" rid="CR14">14</xref>]. Detected tumours were all histologically confirmed and clinically staged using the TNM system [<xref ref-type="bibr" rid="CR15">15</xref>]. In the current analysis, cancer stages T1-T2 were categorized as ‘localized’; and T3-T4 as ‘locally advanced’, because few tumors had metastasized. Histologic material obtained at biopsy was assigned a Gleason score by specialist uropathologists following a standard proforma and, for the purposes of this study, categorized as low- (score ≤6) or high-grade (score ≥7) cancers. All men without evidence of prostate cancer were eligible for selection as controls; that is, men with a PSA <3 ng/mL or a raised PSA (≥3 ng/mL) combined with at least one negative biopsy and no subsequent prostate cancer diagnosis during the follow-up protocol. We selected one stratum-matched control for each case from those men who had provided a non-fasting blood sample at the prostate check clinic. Controls were randomly selected from the same stratum, i.e. 5-year age-band (age at PSA test) and GP/family practice, as cases.</p><p>The working dataset consisted of 2,927 individuals (1,136 cases, 1,791 controls) of European descent with available genotype and phenotype information. All men provided written informed consent prior to inclusion in the study. Trent Multicentre Research Ethics Committee (MREC) approved the ProtecT study (MREC/01/4/025) and the associated ProMPT study which collected biological material (MREC/01/4/061; see Additional file <xref rid="MOESM1" ref-type="media">1</xref>: Supplementary Methods for further details).</p></sec><sec id="Sec4"><title>Genetic risk score</title><p>We derived a genetic risk score for pubertal development in boys based on associations between 13 SNPs and Tanner genital stage in males between 12.6 and 15 years of age described in two recent genome-wide association studies (GWAS) of sexual maturation [<xref ref-type="bibr" rid="CR8">8</xref>, <xref ref-type="bibr" rid="CR9">9</xref>]. All SNPs in the score were associated with Tanner stage in boys (independently of whether they were also associated with Tanner stage in girls or in a combined sample of boys and girls), and they had previously been associated with age at menarche [<xref ref-type="bibr" rid="CR8">8</xref>, <xref ref-type="bibr" rid="CR16">16</xref>], although not always in the direction consistent with their association with Tanner genital stage [<xref ref-type="bibr" rid="CR9">9</xref>]. Variants in the same gene were included in the score provided their linkage disequilibrium, r<sup>2</sup>, was lower than 0.8.</p><p>Scores are used instead of individual genetic variants because they are likely to explain a larger proportion of trait variability and therefore represent stronger proxies for the exposure [<xref ref-type="bibr" rid="CR12">12</xref>]. Scores were calculated by summing up the dosages of the risk alleles at all 13 SNPs in each individual, weighted by the effect size of the variant in males as reported in the discovery GWAS [<xref ref-type="bibr" rid="CR8">8</xref>, <xref ref-type="bibr" rid="CR9">9</xref>], in such a way that a unit increase in the score corresponded approximately to one risk allele. Risk alleles were those associated with a lower Tanner stage (i.e. delayed pubertal development). Polymorphisms included in the score are shown in Table <xref rid="Tab1" ref-type="table">1</xref>.<table-wrap id="Tab1"><label>Table 1</label><caption><p>SNPs included in the pubertal development genetic risk score in the ProtecT study</p></caption><table frame="hsides" rules="groups"><thead><tr><th>SNP</th><th>Nearest gene (distance)</th><th>Chr</th><th>Position<sup>a</sup></th><th>Tanner stage decreasing/other allele</th><th>Tanner stage decreasing allele frequency (ProtecT controls)<sup>b</sup></th><th>Tanner stage decreasing allele frequency (CEU)</th><th>Hardy–Weinberg equilibrium<break></break><italic>P</italic> value</th><th>Gene function</th></tr></thead><tbody><tr><td>rs2274465</td><td><italic>KDM4A</italic></td><td>1</td><td>44121557</td><td>C/G</td><td char="." align="char">0.664</td><td char="." align="char">0.676</td><td char="." align="char">0.9</td><td>Histone demethylation</td></tr><tr><td>rs6427782</td><td><italic>NR5A2</italic> (+198 kb)</td><td>1</td><td>199798339</td><td>A/G</td><td char="." align="char">0.510</td><td char="." align="char">0.556</td><td char="." align="char">0.005</td><td>DNA binding/steroid hormone receptor activity</td></tr><tr><td>rs6762477</td><td><italic>RBM6</italic></td><td>3</td><td>50093209</td><td>A/G</td><td char="." align="char">0.547</td><td char="." align="char">0.551</td><td char="." align="char">0.6</td><td>Regulation of alternative splicing</td></tr><tr><td>rs2153127</td><td><italic>LIN28B</italic> (+36 kb)</td><td>6</td><td>105348544</td><td>T/C</td><td char="." align="char">0.530</td><td char="." align="char">0.515</td><td char="." align="char">0.8</td><td>Cell reprogramming</td></tr><tr><td>rs7759938</td><td><italic>LIN28B</italic> (+6 kb)</td><td>6</td><td>105378954</td><td>C/T</td><td char="." align="char">0.318</td><td char="." align="char">0.373</td><td char="." align="char">1.0</td><td>Cell reprogramming</td></tr><tr><td>rs7821178</td><td><italic>PEX2</italic> (–181 kb)</td><td>8</td><td>78093837</td><td>C/A</td><td char="." align="char">0.665</td><td char="." align="char">0.658</td><td char="." align="char">0.1</td><td>Peroxisome biogenesis</td></tr><tr><td>rs10453225</td><td><italic>TMEM38B</italic> (–381 kb)</td><td>9</td><td>108920220</td><td>G/T</td><td char="." align="char">0.681</td><td char="." align="char">0.700</td><td char="." align="char">0.2</td><td>Maintenance of intracellular calcium release</td></tr><tr><td>rs2090409</td><td><italic>TMEM38B</italic> (–428 kb)</td><td>9</td><td>108967088</td><td>C/A</td><td char="." align="char">0.680</td><td char="." align="char">0.688</td><td char="." align="char">0.3</td><td>Maintenance of intracellular calcium release</td></tr><tr><td>rs10739221</td><td><italic>TMEM38B</italic> (–522 kb)</td><td>9</td><td>109060830</td><td>C/T</td><td char="." align="char">0.772</td><td char="." align="char">0.770</td><td char="." align="char">0.5</td><td>Maintenance of intracellular calcium release</td></tr><tr><td>rs1324913</td><td><italic>KLF12</italic></td><td>13</td><td>74635588</td><td>T/G</td><td char="." align="char">0.338</td><td char="." align="char">0.312</td><td char="." align="char">0.6</td><td>Transcription factor/gene expression regulation</td></tr><tr><td>rs12915845</td><td><italic>DET1</italic></td><td>15</td><td>89042467</td><td>C/T</td><td char="." align="char">0.587</td><td char="." align="char">0.582</td><td char="." align="char">0.1</td><td>Development regulation</td></tr><tr><td>rs246185</td><td><italic>MKL2</italic> (–35 kb)</td><td>16</td><td>14395432</td><td>C/T</td><td char="." align="char">0.313</td><td char="." align="char">0.300</td><td char="." align="char">0.6</td><td>Regulation of immediate early genes/muscle genes</td></tr><tr><td>rs12446632</td><td><italic>GPRC5B</italic> (–38 kb)</td><td>16</td><td>19935389</td><td>A/G</td><td char="." align="char">0.146</td><td char="." align="char">0.127</td><td char="." align="char">0.8</td><td>Modulation of insulin secretion</td></tr></tbody></table><table-wrap-foot><p><sup>a</sup>Position based on GRCh37.p13 assembly</p><p><sup>b</sup><italic>n</italic> = 1,791</p></table-wrap-foot></table-wrap></p></sec><sec id="Sec5"><title>Statistical analysis</title><p>Associations of individual SNPs and the multiple SNP score for pubertal development with case/control status and other binary outcomes (localized [reference] vs. locally advanced stage and low [reference] vs. high grade) were determined using logistic regression, with adjustment for age, study center, and the 10 principal components which defined the population structure.</p><p>The genetic score was entered into the regression models as a categorical variable with three levels (tertiles). We also used this variable to test for linearity of effect and compare prostate cancer risk among men in the lowest and highest tertiles (i.e. with the earliest and latest sexual maturation, respectively). All analyses were carried out in Stata 13 (StataCorp LP, College Station, TX).</p><p>We plotted the effect of each SNP in the genetic score on Tanner stage in approximately 13- to 15-year-old boys against the corresponding effect on high-grade prostate cancer, the disease outcome with the strongest association with the score. The likelihood of bias due to overall directional pleiotropy was formally evaluated with MR-Egger regression [<xref ref-type="bibr" rid="CR17">17</xref>]. MR-Egger regression also provides an unbiased effect estimate (see definitions in Additional file <xref rid="MOESM1" ref-type="media">1</xref>: Supplementary Methods).</p><p>We did not have data on Tanner stage measured in adolescence in ProtecT men, and therefore could not estimate its association with the genetic score in ProtecT, in order to run a typical instrumental variable analysis. However, we used a recently developed MR method (summarized data allele score with correlated variants) that provides an estimate of the causal effect of the exposure (i.e. Tanner stage) on the outcome of interest (i.e. prostate cancer) using information on the association of individual SNPs in the score with exposure and outcome [<xref ref-type="bibr" rid="CR18">18</xref>]. We obtained the effect estimates of SNPs on Tanner stage at approximately 13–15 years from published GWAS data [<xref ref-type="bibr" rid="CR8">8</xref>, <xref ref-type="bibr" rid="CR9">9</xref>].</p><p>Replication analyses were carried out in the PRACTICAL consortium (PRostate cancer AssoCiation group To Investigate Cancer-Associated aLterations in the genome) to test the association of the puberty genetic score with prostate cancer risk and progression. Overall, there were 45,928 individuals of European ancestry, of which 22,160 prostate cancer cases and 21,577 controls had genotype data available after applying quality control procedures. Additionally, amongst men with prostate cancer in PRACTICAL, we estimated associations of the puberty score with 15-year all-cause and prostate cancer-specific mortality (as an indication of long-term survival) using Cox proportional hazards regression with date at diagnosis as the start date and date at death or final follow-up as the exit date, adjusted for age at diagnosis and 15 principal components, with robust standard errors to account for within study clustering. All studies in the consortium have the relevant Institutional Review Board approval in each country in accordance with the Declaration of Helsinki. More detailed information is provided in the consortium website (<ext-link ext-link-type="uri" xlink:href="http://practical.ccge.medschl.cam.ac.uk">http://practical.ccge.medschl.cam.ac.uk</ext-link>) and Additional file <xref rid="MOESM1" ref-type="media">1</xref>: Supplementary Methods and Tables S1 and S2.</p></sec></sec><sec id="Sec6"><title>Results</title><sec id="Sec7"><title>ProtecT</title><p>Men with prostate cancer were on average older, had less benign prostatic hyperplasia (BPH), a lower body mass index (BMI), more relatives with prostate cancer, lower IGF-I, and higher IGF-II and IGF binding protein (BP)-3 levels than controls (Table <xref rid="Tab2" ref-type="table">2</xref>). The IGF-I:IGFBP-3 molar ratio, an indicator of bioavailable IGF-I, was consequently lower in patients; 30 % of men with prostate cancer were classified as having high-grade disease (Gleason score ≥7), and 12 % as having locally advanced disease (TNM stages T3-T4).<table-wrap id="Tab2"><label>Table 2</label><caption><p>Clinical characteristics of prostate cancer cases and controls in the ProtecT study</p></caption><table frame="hsides" rules="groups"><thead><tr><th></th><th>Cases</th><th>Controls</th><th>n</th><th><italic>P</italic> value</th></tr></thead><tbody><tr><td>Total, n</td><td>1,136</td><td>1,791</td><td>2,927</td><td></td></tr><tr><td>Age, years</td><td>62.2 ± 5.1</td><td>61.6 ± 5.2</td><td>2,927</td><td>0.003</td></tr><tr><td>PSA, ng/mL</td><td>8.5 ± 15.4</td><td>1.1 ± 1.3</td><td>2,925</td><td><0.001</td></tr><tr><td>Gleason grade, % (<7/≥7)</td><td>70.0/30.0</td><td>n/a</td><td>1,135</td><td></td></tr><tr><td>TNM stage, % (localized/advanced)</td><td>88.4/11.6</td><td>n/a</td><td>1,136</td><td></td></tr><tr><td>BPH, % (no/yes)<sup>a</sup></td><td>92.7/7.3</td><td>89.0/11.0</td><td>1,363</td><td>0.02</td></tr><tr><td>BMI, kg/m<sup>2</sup></td><td>27.0 ± 3.7</td><td>27.5 ± 4.1</td><td>1,973</td><td>0.01</td></tr><tr><td>Height, cm</td><td>176.4 ± 7.0</td><td>175.9 ± 6.9</td><td>2,078</td><td>0.2</td></tr><tr><td>Weight, kg</td><td>84.5 ± 13.0</td><td>85.9 ± 14.6</td><td>2,677</td><td>0.02</td></tr><tr><td>leg length, cm</td><td>76.7 ± 4.8</td><td>76.5 ± 4.6</td><td>2,055</td><td>0.3</td></tr><tr><td>Birthweight, g</td><td>3,437.2 ± 744.9</td><td>3,476.1 ± 663.4</td><td>939</td><td>0.4</td></tr><tr><td>Family history, % (no/yes)<sup>b</sup></td><td>92.7/7.3</td><td>95.0/5.0</td><td>2,908</td><td>0.01</td></tr><tr><td>Diabetes, % (no/yes)<sup>c</sup></td><td>92.8/7.2</td><td>91.1/8.9</td><td>1,895</td><td>0.2</td></tr><tr><td>IGF-I, ng/mL</td><td>156.1 ± 55.8</td><td>163.2 ± 57.0</td><td>1,756</td><td>0.01</td></tr><tr><td>IGF-II, ng/mL</td><td>862.1 ± 323.6</td><td>733.7 ± 265.3</td><td>1,720</td><td><0.001</td></tr><tr><td>IGFBP-2, ng/mL</td><td>731.5 ± 426.0</td><td>726.2 ± 444.7</td><td>1,745</td><td>0.5<sup>d</sup></td></tr><tr><td>IGFBP-3, ng/mL</td><td>4,673.6 ± 1,041.9</td><td>4,370.8 ± 1,055.7</td><td>1,711</td><td><0.001</td></tr><tr><td>IGF-I:IGFBP-3 molar ratio<sup>e</sup></td><td>0.12 ± 0.04</td><td>0.14 ± 0.06</td><td>1,711</td><td><0.001<sup>d</sup></td></tr></tbody></table><table-wrap-foot><p>Continuous variables: mean ± SD</p><p>Two-sided <italic>t</italic>-tests and χ<sup>2</sup> tests were used to analyze continuous and categorical variables, respectively</p><p><italic>PSA</italic> Prostate-specific antigen, <italic>BMI</italic> Body mass index, <italic>BPH</italic> Benign prostatic hyperplasia, <italic>IGF</italic> Insulin-like growth factor, <italic>IGFBP</italic> Insulin-like growth factor binding protein</p><p><sup>a</sup>n cases = 682, n controls = 681</p><p><sup>b</sup>n cases = 1,131, n controls = 1,777</p><p><sup>c</sup>n cases = 735, n controls = 1,160</p><p><sup>d</sup><italic>P</italic> value obtained from analysis of natural log transformed variable</p><p><sup>e</sup>IGF-I:IGFBP-3 molar ratio = 0.13*[IGF-I]:0.036*[IGFBP-3]</p></table-wrap-foot></table-wrap></p><p>The genetic score was normally distributed (Additional file <xref rid="MOESM1" ref-type="media">1</xref>: Figure S1) and for the most part not correlated with population stratification axes (data not shown).</p><p>We found evidence of an inverse association between our genetic score for pubertal development in boys and prostate cancer, i.e. the higher the score and, thus, the later the sexual maturation, the lower the risk for prostate cancer. The association was particularly strong for Gleason grade (odds ratio (OR) low- vs. high-grade disease, per tertile: 0.76; 95 % CI, 0.64–0.89; <italic>P</italic> = 0.001; Table <xref rid="Tab3" ref-type="table">3</xref>). A dose-response effect of the genetic score in tertiles on high-grade prostate cancer was observed. Men in the highest score tertile (representing the most sexually immature individuals at a specific age) had a 43 % (95 % CI, 21–59 %) lower risk of high- versus low-grade disease than men in the lowest tertile (Table <xref rid="Tab4" ref-type="table">4</xref>).<table-wrap id="Tab3"><label>Table 3</label><caption><p>Pubertal development genetic risk score and prostate cancer risk, stage and grade in the ProtecT study</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Trait</th><th>n</th><th>OR</th><th>95 % CI</th><th><italic>P</italic> value</th></tr></thead><tbody><tr><td>Control/case (0/1)</td><td>2,927</td><td char="." align="char">0.95</td><td>0.87–1.04</td><td char="." align="char">0.3</td></tr><tr><td>Gleason score (0:≤6/1:≥7)<sup>a</sup></td><td>1,135</td><td char="." align="char">0.76</td><td>0.64–0.89</td><td char="." align="char">0.001</td></tr><tr><td>Stage (0:localised/1:locally advanced)</td><td>1,136</td><td char="." align="char">0.80</td><td>0.64–1.01</td><td char="." align="char">0.06</td></tr><tr><td>BPH (0:no/1:yes)</td><td>1,363</td><td char="." align="char">1.11</td><td>0.88–1.40</td><td char="." align="char">0.4</td></tr></tbody></table><table-wrap-foot><p>ORs indicate effects per tertile increase in the genetic score, adjusted by age, recruitment centre and 10 principal components for population structure</p><p><sup>a</sup>0 corresponds to the reference category</p><p><italic>BPH</italic> Benign prostatic hyperplasia, <italic>CI</italic> Confidence intervals, <italic>OR</italic> Odds ratio</p></table-wrap-foot></table-wrap><table-wrap id="Tab4"><label>Table 4</label><caption><p>Odds ratios (ORs) for high- vs low-grade prostate cancer by pubertal development genetic risk score tertiles in the ProtecT study</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Genetic score tertiles</th><th>OR</th><th>95 % CI</th><th><italic>P</italic> value</th></tr></thead><tbody><tr><td>T1</td><td>Reference</td><td></td><td>0.003</td></tr><tr><td>T2</td><td>0.79</td><td>0.58–1.07</td><td></td></tr><tr><td>T3</td><td>0.57</td><td>0.41–0.79</td><td></td></tr></tbody></table><table-wrap-foot><p>High-grade prostate cancer = Gleason ≥7</p><p>Low-grade prostate cancer = Gleason ≤6</p><p>OR adjusted by age, recruitment centre and 10 principal components for population structure</p><p><italic>n</italic> = 1,135</p><p><italic>CI</italic> Confidence intervals</p></table-wrap-foot></table-wrap></p><p>The reported effect of each SNP in the score on Tanner stage in boys [<xref ref-type="bibr" rid="CR8">8</xref>, <xref ref-type="bibr" rid="CR9">9</xref>] was correlated with the corresponding effect on having high-, compared to low-grade, prostate cancer (R<sup>2</sup> ~ 31 %; Additional file <xref rid="MOESM1" ref-type="media">1</xref>: Table S3, Fig. <xref rid="Fig1" ref-type="fig">1</xref>).<fig id="Fig1"><label>Fig. 1</label><caption><p>Effect of Tanner stage change in boys on the risk of developing high-grade prostate cancer. In ProtecT, proportional risk reduction for high-grade prostate cancer (Gleason ≥7) for each SNP plotted against each SNP’s absolute effect on lowering Tanner stage. The trend line, set to intercept the axes at the origin, represents the percentage risk reduction for high-grade disease per unit decrease in Tanner stage. Excluding SNP rs6427782, which was out of Hardy–Weinberg equilibrium pre-Bonferroni correction for multiple testing, from the plot did not produce an appreciable change in the results. Tanner genital stage in boys was treated as a quantitative trait on a scale of 1–5, according to the studies where the associated SNPs were first described [<xref ref-type="bibr" rid="CR8">8</xref>, <xref ref-type="bibr" rid="CR9">9</xref>]</p></caption><graphic xlink:href="12916_2016_602_Fig1_HTML" id="MO1"></graphic></fig></p><p>Overall, there was no evidence of an association between the genetic score and potential confounders among controls, such as age, BMI, weight, birthweight, BPH, family history of prostate cancer, or diabetes. No association between the genetic score and PSA was found either. Marginal positive associations with leg length, a trait affected by the timing of puberty [<xref ref-type="bibr" rid="CR19">19</xref>], and adult height were detected. In addition, we uncovered weak associations with IGFBP-2 and IGFBP-3 serum levels, as well as with the IGF-I:IGBP-3 molar ratio (Additional file <xref rid="MOESM1" ref-type="media">1</xref>: Table S4).</p><p>Using an estimated genetic score with summarized data [<xref ref-type="bibr" rid="CR18">18</xref>] we determined that there would be a substantial reduction in high-grade (compared to low-grade) prostate cancer per unit decrease in Tanner stage in relation to peers (OR: 0.23; 95 % CI, 0.09–0.57; <italic>P</italic> = 0.002). The MR-Egger’s test did not suggest the presence of directional pleiotropy (<italic>P</italic> for intercept >0.05; see symmetrical funnel plot in Additional file <xref rid="MOESM1" ref-type="media">1</xref>: Figure S2), and gave a similar causal estimate to that obtained with the allele score with the summarized data method (OR: 0.16; 95 % CI, 0.04–2.94; <italic>P</italic> = 0.2). No heterogeneity was apparent in the causal estimates obtained from each genetic variant individually (I<sup>2</sup> = 0.0 %, <italic>P</italic> = 1.0).</p></sec><sec id="Sec8"><title>PRACTICAL</title><p>We created a weighted genetic score with 12 of the 13 SNPs used in ProtecT, as rs1324913 was not available in PRACTICAL. Information on SNPs in the score is provided in Additional file <xref rid="MOESM1" ref-type="media">1</xref>: Table S5, and the score distribution is shown in Additional file <xref rid="MOESM1" ref-type="media">1</xref>: Figure S1. No correlation between the Tanner score and principal components was evident, and similarly, the score was not associated with age at diagnosis, family history, or method of disease detection (not shown).</p><p>In a meta-analysis of 21 studies included in PRACTICAL, the genetic score was associated with prostate cancer risk, such that a higher score – and therefore, a delayed maturation – showed a protective effect (OR per tertile: 0.97; 95 % CI, 0.94–1.00; <italic>P</italic> = 0.03). A slightly bigger effect was found with prostate cancer stage (localized vs. advanced, OR per tertile: 0.95; 95 % CI, 0.91–1.00; <italic>P</italic> = 0.03; Fig. <xref rid="Fig2" ref-type="fig">2</xref>) but not with grade (low vs. high grade, OR per tertile: 0.98; 95 % CI, 0.95–1.02; <italic>P</italic> = 0.4; Additional file <xref rid="MOESM1" ref-type="media">1</xref>: Table S6). Heterogeneity between studies was low (I<sup>2</sup> < 33 %; <italic>P</italic> >0.05).<fig id="Fig2"><label>Fig. 2</label><caption><p>Pubertal development genetic risk score and prostate cancer risk (top) and stage (bottom) in the PRACTICAL consortium</p></caption><graphic xlink:href="12916_2016_602_Fig2_HTML" id="MO2"></graphic></fig></p><p>There were 15 studies with mortality data in PRACTICAL. Overall, the average time to death or final follow-up was 7 years, with a maximum ranging from approximately 6 (in PCMUS) to 38 years (in Tampere). The genetic score was associated with 15-year prostate cancer-specific mortality amongst men with prostate cancer (hazard ratio (HR) per tertile: 0.94; 95 % CI, 0.90–0.98; <italic>P</italic> = 0.01), and marginally with 15-year all-cause mortality (HR per tertile: 0.97; 95 % CI, 0.95–1.00; <italic>P</italic> = 0.04). The proportional hazards assumption was not met (<italic>P</italic> <0.001), probably due to the fact that up to 5 years post-diagnosis there do not appear to be differences in survival between individuals with different numbers of risk alleles (i.e. alleles associated with later pubertal timing; Additional file <xref rid="MOESM1" ref-type="media">1</xref>: Figure S3).</p><p>We estimated the effect of being ranked a unit lower in the Tanner stage (for the same age) on 15-year prostate cancer-specific mortality as HR 0.62 (95 % CI, 0.49–0.78; <italic>P</italic> <0.001). The corresponding funnel plot and MR-Egger results, which did not uncover evidence of pleiotropy, are shown in Additional file <xref rid="MOESM1" ref-type="media">1</xref>: Figure S4.</p></sec></sec><sec id="Sec9"><title>Discussion</title><sec id="Sec10"><title>Main findings</title><p>In a study of PSA-detected prostate cancer cases and controls we found strong evidence that a genetic score, comprised of SNPs associated with Tanner stage in approximately 13- to 15-year-old boys, was inversely associated with prostate cancer progression. A later pubertal development (expected among those with higher genetic score values) lowered the risk of developing high-grade disease, a possible clinically relevant subtype because of its stronger relationship than low-grade disease to progression.</p><p>Replication analysis using 21 prostate cancer studies across Europe, the USA and Australia in the PRACTICAL consortium, uncovered a weak inverse association between prostate cancer risk and stage and the puberty genetic score, with a reduced effect detected on disease grade. However, we found a stronger association of the score with prostate cancer-specific mortality up to 15 years after diagnosis, indicating that (on average) men whose sexual maturation was later than their peers were less likely to die due to the disease than those whose onset of puberty was earlier. This is in agreement with our findings in ProtecT, regarding the association of earlier puberty with high-grade disease, as men with more aggressive cancer tend to have a poorer prognosis [<xref ref-type="bibr" rid="CR20">20</xref>]. It is possible that differing definitions of low- and high-grade prostate cancer across studies may have prevented the detection of an effect of the puberty score on this phenotype, with mortality being a stronger and more clear-cut marker of an aggressive disease. There were also differences between studies in method of disease detection: the cases enrolled in ProtecT were PSA-detected, whereas the majority of men in the PRACTICAL studies were clinically identified. Additionally, in PRACTICAL, there was a wide variation in the proportion of men with a positive family history of prostate cancer, which ranged from as low as 2.4 % in EPIC to 42.4 % in WUGS (conversely, the proportion of men with a positive family history in ProtecT was ~6 %).</p></sec><sec id="Sec11"><title>Mechanisms explaining the observed associations</title><p>It has been suggested that endogenous androgen and IGF-I hormones may underlie the relationship between puberty timing and prostate cancer risk [<xref ref-type="bibr" rid="CR4">4</xref>, <xref ref-type="bibr" rid="CR5">5</xref>]. The concentrations of these hormones increases markedly during puberty and are likely to be especially influential on the prostate gland as it becomes fully developed at this time [<xref ref-type="bibr" rid="CR21">21</xref>]. Because the prostate is still maturing, puberty may be an important biological window at which early life exposures could have long-term effects on the prostate [<xref ref-type="bibr" rid="CR3">3</xref>].</p><p>Androgens play a central role in the etiology of prostate cancer, as prostate cancer is dependent on androgen receptor activation for growth and survival [<xref ref-type="bibr" rid="CR22">22</xref>]. A delayed pubertal onset may reduce the length of time an individual is exposed to high androgen levels during a period when the prostate is particularly susceptible to carcinogenic exposures [<xref ref-type="bibr" rid="CR3">3</xref>].</p><p>IGF-I is a potent mitogen and inhibitor of apoptosis that mediates growth during childhood and adolescence and, consequently, stimulates carcinogenesis. IGF-I levels increase from birth to a pubertal peak before declining steadily from young adulthood [<xref ref-type="bibr" rid="CR23">23</xref>, <xref ref-type="bibr" rid="CR24">24</xref>]. It is possible that a younger age at the initiation of puberty is linked to an increase in prostate cancer risk by its association with higher IGF-I levels. Serum IGF-I has been positively associated with an earlier pubertal age in an observational study examining adult IGF-I levels, suggesting that higher pre-pubertal IGF-I (if reflected by higher adult IGF-I) may accelerate childhood growth and the start of puberty [<xref ref-type="bibr" rid="CR24">24</xref>].</p><p>In our study, the puberty genetic score was not associated with circulating IGF-I, although the effect appeared to be in the direction anticipated [<xref ref-type="bibr" rid="CR24">24</xref>], but we observed an inverse association with the IGF-I:IGFBP-3 molar ratio, suggesting that an earlier pubertal development may be influenced by higher levels of bioavailable IGF-I.</p><p>The weakly positive association of the genetic score with adult leg length and height agrees with studies that showed that earlier age at puberty was associated with shorter stature, primarily attributable to shorter leg length, in US women [<xref ref-type="bibr" rid="CR25">25</xref>] and Swedish men [<xref ref-type="bibr" rid="CR19">19</xref>]. Growth in leg length, an indicator of pre-pubertal living conditions, on the other hand, has been positively associated with IGF-I levels in UK children, particularly boys [<xref ref-type="bibr" rid="CR26">26</xref>].</p><p>Our finding that a younger age at sexual maturation increases the risk of developing high-grade prostate cancer, and of dying due to the disease, strengthens the idea of the existence of trade-offs between reproductive success and health. MR analysis suggests that there may be a causal relationship between early life environments that promote an accelerated onset of puberty under conditions of uncertainty (e.g. in cases of familial stress due to low income, marital conflict or father absence), so as to favour reproduction, and a detrimental effect on health and longevity in the long term [<xref ref-type="bibr" rid="CR27">27</xref>, <xref ref-type="bibr" rid="CR28">28</xref>].</p></sec><sec id="Sec12"><title>Strengths and limitations</title><p>Studies of puberty in men are problematic because its initiation is not defined as a single event in the way that menarche is. In addition, in studies of middle aged and elderly men, an attempt to measure puberty is likely to suffer from recall bias. The genetic score represents a more accurate instrument to assess the causality of the association of pubertal development and prostate cancer risk. The association with leg length provides to some extent a validation of the genetic score in the ProtecT population.</p><p>A genetic score is unlikely to be associated with non-genetic confounders, which frequently obscure the interpretation of observational data, and this is, in fact, the case in our study with respect to a few measured confounders.</p><p>As the genetic score in our study was not associated with age, PSA, BMI, diabetes, or BPH, we believe that its association with prostate cancer does not represent an artefact of detection due to, for instance, men who are seen more frequently by a doctor having an incidental diagnosis of prostate cancer.</p><p>One important assumption in MR is that the instrument (i.e. the genetic score) should be associated with the outcome of interest (i.e. prostate cancer) only via the exposure (i.e. pubertal development). Some SNPs in the score have been associated with height <italic>(P</italic> <0.05, <ext-link ext-link-type="uri" xlink:href="http://www.gwascentral.org/index">http://www.gwascentral.org/index</ext-link>) while four of them are located near genes (<italic>LIN28B</italic> and <italic>TMEM38B</italic>) recently associated with sitting height ratio and found to disproportionately affect leg length [<xref ref-type="bibr" rid="CR29">29</xref>]. However, this could be an example of mediated pleiotropy (where a single process influences a cascade of events) [<xref ref-type="bibr" rid="CR30">30</xref>] and as such it does not undermine our findings. Furthermore, a formal test of the assumption of no pleiotropy, implemented using MR-Egger’s regression, found no evidence of a violation of this principle.</p><p>Replication of our findings as well as uncovering the potential mechanisms through which the timing of puberty might affect the progression of prostate cancer were likely hindered by differences in phenotype ascertainment in PRACTICAL studies.</p></sec><sec id="Sec13"><title>Comparison with existing literature</title><p>Few studies have examined the role that pubertal development has on the initiation and progression of prostate cancer, in contrast to the more extensive research on age at menarche and breast cancer. This research shows that an earlier age at menarche is reliably associated with greater breast cancer risk [<xref ref-type="bibr" rid="CR31">31</xref>]. Given the difficulties in defining puberty among males, studies have used a variety of traits as proxies, mainly age at different life events such as shaving initiation [<xref ref-type="bibr" rid="CR21">21</xref>, <xref ref-type="bibr" rid="CR32">32</xref>], first sexual intercourse [<xref ref-type="bibr" rid="CR33">33</xref>–<xref ref-type="bibr" rid="CR36">36</xref>], first ejaculation [<xref ref-type="bibr" rid="CR37">37</xref>], peak height velocity [<xref ref-type="bibr" rid="CR24">24</xref>], attainment of adult height [<xref ref-type="bibr" rid="CR38">38</xref>], as well as the well-established Tanner scale [<xref ref-type="bibr" rid="CR10">10</xref>]. Results from studies that assessed these variables with respect to prostate cancer showed that later growth relative to peers [<xref ref-type="bibr" rid="CR37">37</xref>], height attainment [<xref ref-type="bibr" rid="CR38">38</xref>], age at first sexual intercourse [<xref ref-type="bibr" rid="CR33">33</xref>–<xref ref-type="bibr" rid="CR36">36</xref>], and being older than 16 at first ejaculation [<xref ref-type="bibr" rid="CR37">37</xref>] were all associated in a protective direction with prostate cancer. Older age at initiation of shaving was also protective but only among African Americans [<xref ref-type="bibr" rid="CR21">21</xref>]. As far as we know, no observational study to date has used Tanner stage to investigate the relationship between pubertal development and prostate cancer, so a comparison with our MR findings is not possible.</p></sec></sec><sec id="Sec14"><title>Conclusions</title><p>Using an MR approach, we have found evidence that experiencing a later sexual maturation reduces prostate cancer risk, especially that of aggressive prostate cancer, as well as mortality owing to the disease. The mechanisms that underlie this relationship may involve the androgenic or IGF pathways, but additional MR studies, using specific instruments for these exposures, should be carried out to investigate this further. Although altering pubertal timing is not a viable prostate cancer prevention strategy there is public health value in identifying those individuals who are more likely to have a worse prognosis [<xref ref-type="bibr" rid="CR3">3</xref>]. On the other hand, if pubertal development is shown to be driven by increased IGF-I levels, then dietary interventions to regulate its course could potentially be considered.</p></sec><sec id="Sec15" sec-type="materials|methods"><title>Availability of data and materials</title><p>Summary data is provided in Additional file <xref rid="MOESM2" ref-type="media">2</xref>.</p></sec></body><back><app-group><app id="App1"><sec id="Sec16"><title>Additional files</title><p><media position="anchor" xlink:href="12916_2016_602_MOESM1_ESM.docx" id="MOESM1"><label>Additional file 1: Tables S1 – S6.</label><caption><p>Figures S1–S4. Supplementary Methods. Definitions. Supplementary References. (DOCX 214 kb)</p></caption></media><media position="anchor" xlink:href="12916_2016_602_MOESM2_ESM.xlsx" id="MOESM2"><label>Additional file 2:</label><caption><p>Summary data of the association of each SNP in the pubertal development genetic risk score with exposure and outcomes in the PRACTICAL consortium. (XLSX 13 kb)</p></caption></media></p></sec></app></app-group><glossary><title>Abbreviations</title><def-list><def-item><term>BMI</term><def><p>Body mass index</p></def></def-item><def-item><term>BPH</term><def><p>Benign prostatic hyperplasia</p></def></def-item><def-item><term>GWAS</term><def><p>Genome-wide association study</p></def></def-item><def-item><term>IGF</term><def><p>Insulin-like growth factor</p></def></def-item><def-item><term>IGFBP</term><def><p>Insulin-like growth factor binding protein</p></def></def-item><def-item><term>LD</term><def><p>Linkage disequilibrium</p></def></def-item><def-item><term>MR</term><def><p>Mendelian randomization</p></def></def-item><def-item><term>PSA</term><def><p>Prostate-specific antigen</p></def></def-item><def-item><term>SNP</term><def><p>Single nucleotide polymorphism</p></def></def-item></def-list></glossary><fn-group><fn><p><bold>Competing interests</bold></p><p>The authors declare that they have no competing interests.</p></fn><fn><p><bold>Authors’ contributions</bold></p><p>RMM, SJL and GDS developed the hypothesis and secured funding. CB carried out statistical analyses. CB, SJL and RMM wrote the first draft of the paper. ML organized the genome-wide genotyping of participants in the ProtecT study. JLD, FCH and DEN are PIs of the ProtecT (Prostate Testing for Cancer and Treatment) study. The remaining authors are PIs of the studies contributing to the PRACTICAL consortium. All PIs contributed to the conception, design, and management of each study and of the consortium as a whole. All authors critically commented on and approved the final submitted version of the paper.</p></fn><fn><p><bold>Authors’ information</bold></p><p>JLD, FCH and DEN are NIHR Senior Investigators.</p></fn></fn-group><ack><p>The authors thank the tremendous contribution of all members of the ProtecT study research group, and especially the following, who were involved in this research (Prasad Bollina, Sue Bonnington, Lynn Bradshaw, James Catto, Debbie Cooper, Michael Davis, Liz Down, Andrew Doble, Alan Doherty, Garrett Durkan, Emma Elliott, David Gillatt, Pippa Herbert, Peter Holding, Joanne Howson, Mandy Jones, Roger Kockelbergh, Howard Kynaston, Teresa Lennon, Norma Lyons, Hing Leung, Malcolm Mason, Hilary Moody, Philip Powell, Alan Paul, Stephen Prescott, Derek Rosario, Patricia O’Sullivan, Pauline Thompson, Sarah Tidball). We thank Gemma Marsden and Luke Marsden, who processed the blood samples at the biorepository, and Rajeev Kumar, data manager. We also would like to thank the Center National de Génotypage, Evry, France, for genotyping the ProtecT samples. We also thank Stephen Burgess for his help with some of the Mendelian randomization analyses, and Theresa Redaniel for assistance with the survival analysis.</p><p>The authors are grateful for the provision of the additional epidemiological data by the NHS R&D Directorate supported Prodigal study and the ProMPT (Prostate Mechanisms of Progression and Treatment) collaboration which is supported by the National Cancer Research Institute (NCRI) formed by the Department of Health, the Medical Research Council and Cancer Research UK (G0500966/75466).</p><p>The Collaborative Oncological Gene-environment Study (COGS), within which the PRACTICAL consortium was assembled, would not have been possible without the contributions of the following: Per Hall (COGS), Douglas F. Easton, Paul Pharoah, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang (BCAC), Andrew Berchuck (OCAC), Rosalind A. Eeles, Douglas F. Easton, Ali Amin Al Olama, Zsofia Kote-Jarai, Sara Benlloch (PRACTICAL), Georgia Chenevix-Trench, Antonis Antoniou, Lesley McGuffog, Fergus Couch, Ken Offit (CIMBA), Joe Dennis, Alison M. Dunning, Andrew Lee, Ed Dicks, Craig Luccarini, and the staff of the Centre for Genetic Epidemiology Laboratory; Javier Benitez, Anna Gonzalez-Neira, and the staff of the CNIO genotyping unit; Jacques Simard, Daniel C. Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissière, Frederic Robidoux, and the staff of the McGill University and Génome Québec Innovation Centre; Stig E. Bojesen, Sune F. Nielsen, Maren Weischer, Børge G. Nordestgaard, and the staff of the Copenhagen DNA laboratory; and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer, and the staff of the Mayo Clinic Genotyping Core Facility.</p><p>The funding sources had no role in the design and conduct of the study, collection, management, analysis and interpretation or preparation, review, or approval of the article.</p><sec id="FPar1"><title>Funding</title><p>This work was supported by the World Cancer Research Fund (2011/419) and Cancer Research UK (C18281/A19169). The Integrative Epidemiology Unit (IEU) is supported by the MRC and the University of Bristol (G0600705, MC_UU_12013/19), and the Integrative Cancer Epidemiology Programme is supported by Cancer Research UK programme grant C18281/A19169. The National Institute for Health Research (NIHR) Bristol Nutrition Biomedical Research Unit is funded by the NIHR and is a partnership between University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The ProtecT study is supported by the UK NIHR Health Technology Assessment (HTA) Programme (HTA 96/20/99; ISRCTN20141297). Funding for PRACTICAL and the iCOGS infrastructure came from: the European Community’s Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 – the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. We acknowledge support from the NIHR to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust.</p></sec><sec id="FPar2"><title>The PRACTICAL CONSORTIUM (in addition to those named in the author list)</title><p>Additional members from the consortium are: Margaret Cook<sup>1</sup>, Angela Morga<sup>2</sup>, Artitaya Lophatananon<sup>3,4</sup>, Cyril Fisher<sup>2</sup>, Daniel Leongamornlert<sup>2</sup>, Edward J. Saunders<sup>2</sup>, Emma J. Sawyer<sup>2</sup>, Koveela Govindasami<sup>2</sup>, Malgorzata Tymrakiewicz<sup>2</sup>, Michelle Guy<sup>2</sup>, Naomi Livni<sup>2</sup>, Rosemary Wilkinson<sup>2</sup>, Sara Jugurnauth-Little<sup>2</sup>, Steve Hazel<sup>2</sup>, Tokhir Dadaev<sup>2</sup>, Melissa C. Southey<sup>5</sup>, Liesel M. Fitzgerald<sup>6</sup>, John Pedersen<sup>7</sup>, John Hopper<sup>8</sup>, Ami Karlsson<sup>9</sup>, Carin Cavalli-Bjoerkman<sup>9</sup>, Jan-Erik Johansson<sup>9</sup>, Jan Adolfson<sup>9</sup>, Markus Aly<sup>9,10</sup>, Michael Broms<sup>9</sup>, Paer Stattin<sup>9</sup>, Brian E. Henderson<sup>11</sup>, Fredrick Schumacher<sup>11</sup>, Anssi Auvinen<sup>12</sup>, Kimmo Taari<sup>13</sup>, Liisa Maeaettaenen<sup>14</sup>, Paula Kujala<sup>15</sup>, Teemu Murtola<sup>16,17</sup>, Teuvo LJ Tammela<sup>17</sup>, Csilla Sipeky<sup>18</sup>, Martin Andreas Roder<sup>19</sup>, Peter Iversen<sup>19</sup>, Peter Klarskov<sup>20</sup>, Sune F. Nielsen<sup>21,22</sup>, Maren Weischer<sup>21,22</sup>, Tim J. Key<sup>23</sup>, Hans Wallinder<sup>24</sup>, Sven Gustafsson<sup>24</sup>, Angela Cox<sup>25</sup>, Anne George<sup>26</sup>, Athene Lane<sup>27</sup>, Gemma Marsden<sup>28</sup>, Michael Davis<sup>27</sup>, Paul Brown<sup>27</sup>, Paul Pharoah<sup>29</sup>, Lisa B. Signorello<sup>30,31</sup>, Wei Zheng<sup>32</sup>, Shannon K. McDonnell<sup>33</sup>, Daniel J. Schaid<sup>33</sup>, Liang Wang<sup>33</sup>, Lori Tillmans<sup>33</sup>, Shaun Riska<sup>33</sup>, Thomas Schnoeller<sup>34</sup>, Kathleen Herkommer<sup>35</sup>, Manuel Luedeke<sup>34</sup>, Walther Vogel<sup>36</sup>, Dominika Wokozorczyk<sup>37</sup>, Jan Lubiski<sup>37</sup>, Wojciech Kluzniak<sup>37</sup>, Katja Butterbach<sup>38</sup>, Christa Stegmaier<sup>39</sup>, Bernd Holleczek<sup>39</sup>, Babu Zachariah<sup>40</sup>, Hui-Yi Lim<sup>41</sup>, Hyun Park<sup>40</sup>, James Haley<sup>40</sup>, Julio Pow-Sang<sup>40</sup>, Maria Rincon<sup>40</sup>, Selina Radlein<sup>40</sup>, Thomas Sellers<sup>40</sup>, Chavdar Slavov<sup>42</sup>, Aleksandrina Vlahova<sup>43</sup>, Atanaska Mitkova<sup>44</sup>, Darina Kachakova<sup>44</sup>, Elenko Popov<sup>42</sup>, Svetlana Christova<sup>43</sup>, Tihomir Dikov<sup>43</sup>, Vanio Mitev<sup>44</sup>, Allison Eckert<sup>45</sup>, Angus Collins<sup>45</sup>, Glenn Wood<sup>45</sup>, Greg Malone<sup>45</sup>, Judith A. Clements<sup>45,46</sup>, Kris Kerr<sup>45</sup>, Megan Turner<sup>45</sup>, Pamela Saunders<sup>45</sup>, Peter Heathcote<sup>45</sup>, Gail Risbridger<sup>45</sup>, Wayne Tilley<sup>45</sup>, Lisa Horvath<sup>45</sup>, Trina Yeadon<sup>45</sup>, Srilakshmi Srinivasan<sup>46</sup>, Leire Moya<sup>46</sup>, Amanda Spurdle<sup>47</sup>, Joana Santos<sup>48</sup>, Carmen Jerónimo<sup>48</sup>, Paula Paulo<sup>48</sup>, Pedro Pinto<sup>48</sup>, Rui Henrique<sup>48</sup>, Sofia Maia<sup>48</sup>, Agnieszka Michael<sup>49</sup>, Andrzej Kierzek<sup>49</sup>, and Huihai Wu<sup>49</sup>.</p><p><sup>1</sup>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge CB1 8RN, UK; <sup>2</sup>The Institute of Cancer Research, Sutton, UK; <sup>3</sup>Institute of Population Health, University of Manchester, Manchester, UK; <sup>4</sup>Warwick Medical School, University of Warwick, Coventry, UK; <sup>5</sup>Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Grattan Street, Parkville, Victoria 3010, Australia; <sup>6</sup>Cancer Epidemiology Centre, The Cancer Council Victoria, 615 St Kilda Road, Melbourne, Victoria, Australia; <sup>7</sup>Tissupath Pty Ltd., Melbourne, Victoria 3122, Australia; <sup>8</sup>Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia; <sup>9</sup>Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; <sup>10</sup>Department of Clinical Sciences at Danderyds Hospital, Stockholm, Sweden; <sup>11</sup>Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California, USA, <sup>12</sup>Department of Epidemiology, School of Health Sciences, University of Tampere, Tampere, Finland; <sup>13</sup>Department of Urology, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland; <sup>14</sup>Finnish Cancer Registry, Helsinki, Finland; <sup>15</sup>Fimlab Laboratories, Tampere University Hospital, Tampere, Finland; <sup>16</sup>School of Medicine, University of Tampere, Tampere, Finland; <sup>17</sup>Department of Urology, Tampere University Hospital and Medical School, University of Tampere, Finland; <sup>18</sup>Medical Biochemistry and Genetics, Institute of Biomedicine, University of Turku, Finland; <sup>19</sup>Copenhagen Prostate Cancer Center, Department of Urology, Rigshospitalet, Copenhagen University Hospital, Tagensvej 20, 7521, DK-2200 Copenhagen, Denmark; <sup>20</sup>Department of Urology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark; <sup>21</sup>Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark; <sup>22</sup>Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; <sup>23</sup>Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; <sup>24</sup>Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, UK; <sup>25</sup>CR-UK/YCR Sheffield Cancer Research Centre, University of Sheffield, Sheffield, UK; <sup>26</sup>University of Cambridge, Department of Oncology, Box 279, Addenbrooke’s Hospital, Hills Road Cambridge CB2 0QQ, UK; <sup>27</sup>School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK; <sup>28</sup>Nuffield Department of Surgical Sciences, Faculty of Medical Science, University of Oxford, John Radcliffe Hospital, Oxford, UK; <sup>29</sup>Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge, UK; <sup>30</sup>International Epidemiology Institute, 1555 Research Blvd., Suite 550, Rockville, MD 20850, USA; <sup>31</sup>Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA; <sup>32</sup>Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, 2525 West End Avenue, Suite 800, Nashville, TN 37232, USA; <sup>33</sup>Mayo Clinic, Rochester, MN, USA; <sup>34</sup>Department of Urology, University Hospital Ulm, Germany; <sup>35</sup>Department of Urology, Klinikum rechts der Isar der Technischen Universitaet Muenchen, Munich, Germany; <sup>36</sup>Institute of Human Genetics, University Hospital Ulm, Germany; <sup>37</sup>International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland; <sup>38</sup>Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; <sup>39</sup>Saarland Cancer Registry, 66119 Saarbruecken, Germany; <sup>40</sup>Department of Cancer Epidemiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA, <sup>41</sup>Biostatistics Program, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA; <sup>42</sup>Department of Urology and Alexandrovska University Hospital, Medical University, Sofia, Bulgaria; <sup>43</sup>Department of General and Clinical Pathology, Medical University, Sofia, Bulgaria; <sup>44</sup>Department of Medical Chemistry and Biochemistry, Molecular Medicine Center, Medical University, Sofia, 2 Zdrave Str., 1431 Sofia, Bulgaria; <sup>45</sup>Australian Prostate Cancer BioResource, Brisbane, Australia; <sup>46</sup>Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, Australia; <sup>47</sup>Molecular Cancer Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, Australia; <sup>48</sup>Department of Genetics, Portuguese Oncology Institute, Porto, Portugal; <sup>49</sup>The University of Surrey, Guildford, Surrey, GU2 7XH, UK.</p></sec></ack><ref-list id="Bib1"><title>References</title><ref id="CR1"><label>1.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jemal</surname><given-names>A</given-names></name><name><surname>Bray</surname><given-names>F</given-names></name><name><surname>Center</surname><given-names>MM</given-names></name><name><surname>Ferlay</surname><given-names>J</given-names></name><name><surname>Ward</surname><given-names>E</given-names></name><name><surname>Forman</surname><given-names>D</given-names></name></person-group><article-title>Global cancer statistics</article-title><source>CA Cancer J Clin.</source><year>2011</year><volume>61</volume><fpage>69</fpage><lpage>90</lpage><pub-id pub-id-type="doi">10.3322/caac.20107</pub-id><pub-id pub-id-type="pmid">21296855</pub-id></element-citation></ref><ref id="CR2"><label>2.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sakr</surname><given-names>WA</given-names></name><name><surname>Haas</surname><given-names>GP</given-names></name><name><surname>Cassin</surname><given-names>BF</given-names></name><name><surname>Pontes</surname><given-names>JE</given-names></name><name><surname>Crissman</surname><given-names>JD</given-names></name></person-group><article-title>The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients</article-title><source>J Urol.</source><year>1993</year><volume>150</volume><fpage>379</fpage><lpage>85</lpage><pub-id pub-id-type="pmid">8326560</pub-id></element-citation></ref><ref id="CR3"><label>3.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sutcliffe</surname><given-names>S</given-names></name><name><surname>Colditz</surname><given-names>GA</given-names></name></person-group><article-title>Prostate cancer: is it time to expand the research focus to early-life exposures?</article-title><source>Nat Rev Cancer.</source><year>2013</year><volume>13</volume><fpage>208</fpage><lpage>518</lpage><pub-id pub-id-type="doi">10.1038/nrc3434</pub-id><pub-id pub-id-type="pmid">23363989</pub-id></element-citation></ref><ref id="CR4"><label>4.</label><mixed-citation publication-type="other">Salonia A, Abdollah F, Capitanio U, Suardi N, Gallina A, Castagna G, Clementi MC, Briganti A, Rigatti P, Montorsi F. 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