Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers

Zhang, Yan Dora; Hurson, Amber N.; Zhang, Haoyu; Choudhury, Parichoy Pal; Easton, Douglas F.; Milne, Roger L.; Simard, Jacques; Hall, Per; Michailidou, Kyriaki; Dennis, Joe; Schmidt, Marjanka K.; Chang-Claude, Jenny; Gharahkhani, Puya; Whiteman, David; Campbell, Peter T.; Hoffmeister, Michael; Jenkins, Mark; Peters, Ulrike; Hsu, Li; Gruber, Stephen B.; Casey, Graham; Schmit, Stephanie L.; O’Mara, Tracy A.; Spurdle, Amanda B.; Thompson, Deborah J.; Tomlinson, Ian; De Vivo, Immaculata; Landi, Maria Teresa; Law, Matthew H.; Iles, Mark M.; Demenais, Florence; Kumar, Rajiv; MacGregor, Stuart; Bishop, D. Timothy; Ward, Sarah V.; Bondy, Melissa L.; Houlston, Richard; Wiencke, John K.; Melin, Beatrice; Barnholtz-Sloan, Jill; Kinnersley, Ben; Wrensch, Margaret R.; Amos, Christopher I.; Hung, Rayjean J.; Brennan, Paul; McKay, James; Caporaso, Neil E.; Berndt, Sonja I.; Birmann, Brenda M.; Camp, Nicola J.; Kraft, Peter; Rothman, Nathaniel; Slager, Susan L.; Berchuck, Andrew; Pharoah, Paul D. P.; Sellers, Thomas A.; Gayther, Simon A.; Pearce, Celeste L.; Goode, Ellen L.; Schildkraut, Joellen M.; Moysich, Kirsten B.; Amundadottir, Laufey T.; Jacobs, Eric J.; Klein, Alison P.; Petersen, Gloria M.; Risch, Harvey A.; Stolzenberg-Solomon, Rachel Z.; Wolpin, Brian M.; Li, Donghui; Eeles, Rosalind A.; Haiman, Christopher A.; Kote-Jarai, Zsofia; Schumacher, Fredrick R.; Olama, Ali Amin Al; Purdue, Mark P.; Scelo, Ghislaine; Dalgaard, Marlene D.; Greene, Mark H.; Grotmol, Tom; Kanetsky, Peter A.; McGlynn, Katherine A.; Nathanson, Katherine L.; Turnbull, Clare; Wiklund, Fredrik; Chanock, Stephen J.; Chatterjee, Nilanjan; Garcia-Closas, Montserrat

Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers

Yan Dora Zhang, Amber N. Hurson, Haoyu Zhang, Parichoy Pal Choudhury, Douglas F. Easton, Roger L. Milne, Jacques Simard, Per Hall, Kyriaki Michailidou, Joe Dennis, Marjanka K. Schmidt, Jenny Chang-Claude, Puya Gharahkhani, David Whiteman, Peter T. Campbell, Michael Hoffmeister, Mark Jenkins, Ulrike Peters, Li Hsu, Stephen B. Gruber, Graham Casey, Stephanie L. Schmit, Tracy A. O’Mara, Amanda B. Spurdle, Deborah J. Thompson, Ian Tomlinson, Immaculata De Vivo, Maria Teresa Landi, Matthew H. Law, Mark M. Iles, Florence Demenais, Rajiv Kumar, Stuart MacGregor, D. Timothy Bishop, Sarah V. Ward, Melissa L. Bondy, Richard Houlston, John K. Wiencke, Beatrice Melin, Jill Barnholtz-Sloan, Ben Kinnersley, Margaret R. Wrensch, Christopher I. Amos, Rayjean J. Hung, Paul Brennan, James McKay, Neil E. Caporaso, Sonja I. Berndt, Brenda M. Birmann, Nicola J. Camp, Peter Kraft, Nathaniel Rothman, Susan L. Slager, Andrew Berchuck, Paul D. P. Pharoah, Thomas A. Sellers, Simon A. Gayther, Celeste L. Pearce, Ellen L. Goode, Joellen M. Schildkraut, Kirsten B. Moysich, Laufey T. Amundadottir, Eric J. Jacobs, Alison P. Klein, Gloria M. Petersen, Harvey A. Risch, Rachel Z. Stolzenberg-Solomon, Brian M. Wolpin, Donghui Li, Rosalind A. Eeles, Christopher A. Haiman, Zsofia Kote-Jarai, Fredrick R. Schumacher, Ali Amin Al Olama, Mark P. Purdue, Ghislaine Scelo, Marlene D. Dalgaard, Mark H. Greene, Tom Grotmol, Peter A. Kanetsky, Katherine A. McGlynn, Katherine L. Nathanson, Clare Turnbull, Fredrik Wiklund, Stephen J. Chanock, Nilanjan Chatterjee () and Montserrat Garcia-Closas
Additional contact information
Yan Dora Zhang: The University of Hong Kong
Amber N. Hurson: National Cancer Institute
Haoyu Zhang: National Cancer Institute
Parichoy Pal Choudhury: National Cancer Institute
Douglas F. Easton: University of Cambridge
Roger L. Milne: Cancer Council Victoria
Jacques Simard: Centre Hospitalier Universitaire de Québec–Université Laval Research Center
Per Hall: Karolinska Institutet
Kyriaki Michailidou: University of Cambridge
Joe Dennis: University of Cambridge
Marjanka K. Schmidt: The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
Jenny Chang-Claude: German Cancer Research Center (DKFZ)
Puya Gharahkhani: QIMR Berghofer Medical Research Institute
David Whiteman: QIMR Berghofer Medical Research Institute
Peter T. Campbell: American Cancer Society
Michael Hoffmeister: German Cancer Research Center (DKFZ)
Mark Jenkins: The University of Melbourne
Ulrike Peters: Fred Hutchinson Cancer Research Center
Li Hsu: Fred Hutchinson Cancer Research Center
Stephen B. Gruber: University of Southern California
Graham Casey: University of Virginia
Stephanie L. Schmit: H. Lee Moffitt Cancer Center and Research Institution
Tracy A. O’Mara: QIMR Berghofer Medical Research Institute
Amanda B. Spurdle: QIMR Berghofer Medical Research Institute
Deborah J. Thompson: University of Cambridge
Ian Tomlinson: University of Birmingham
Immaculata De Vivo: Brigham and Women’s Hospital and Harvard Medical School
Maria Teresa Landi: National Cancer Institute
Matthew H. Law: QIMR Berghofer Medical Research Institute
Mark M. Iles: University of Leeds
Florence Demenais: Université de Paris, UMRS-1124, Institut National de la Santé et de la Recherche Médicale (INSERM)
Rajiv Kumar: German Cancer Research Center (DKFZ)
Stuart MacGregor: QIMR Berghofer Medical Research Institute
D. Timothy Bishop: University of Leeds
Sarah V. Ward: The University of Western Australia
Melissa L. Bondy: Baylor College of Medicine
Richard Houlston: The Institute of Cancer Research
John K. Wiencke: University of California, San Francisco
Beatrice Melin: Umeå University
Jill Barnholtz-Sloan: Case Western Reserve University School of Medicine
Ben Kinnersley: The Institute of Cancer Research
Margaret R. Wrensch: University of California, San Francisco
Christopher I. Amos: Baylor College of Medicine
Rayjean J. Hung: Sinai Health System
Paul Brennan: World Health Organization
James McKay: World Health Organization
Neil E. Caporaso: National Cancer Institute
Sonja I. Berndt: National Cancer Institute
Brenda M. Birmann: Brigham and Women’s Hospital and Harvard Medical School
Nicola J. Camp: University of Utah School of Medicine
Peter Kraft: Harvard T.H. Chan School of Public Health
Nathaniel Rothman: National Cancer Institute
Susan L. Slager: Mayo Clinic
Andrew Berchuck: Duke University Medical Center
Paul D. P. Pharoah: University of Cambridge
Thomas A. Sellers: H. Lee Moffitt Cancer Center and Research Institution
Simon A. Gayther: Cedars-Sinai Medical Center
Celeste L. Pearce: University of Southern California
Ellen L. Goode: Mayo Clinic
Joellen M. Schildkraut: Emory University
Kirsten B. Moysich: Roswell Park Cancer Institute
Laufey T. Amundadottir: National Cancer Institute, National Institutes of Health
Eric J. Jacobs: American Cancer Society
Alison P. Klein: Johns Hopkins School of Medicine
Gloria M. Petersen: Mayo Clinic
Harvey A. Risch: Yale School of Medicine
Rachel Z. Stolzenberg-Solomon: National Cancer Institute
Brian M. Wolpin: Dana-Farber Cancer Institute
Donghui Li: The University of Texas MD Anderson Cancer Center
Rosalind A. Eeles: Division of Genetics and Epidemiology, The Institute of Cancer Research
Christopher A. Haiman: University of Southern California
Zsofia Kote-Jarai: Division of Genetics and Epidemiology, The Institute of Cancer Research
Fredrick R. Schumacher: Case Western Reserve University School of Medicine
Ali Amin Al Olama: University of Cambridge
Mark P. Purdue: National Cancer Institute
Ghislaine Scelo: World Health Organization
Marlene D. Dalgaard: Copenhagen University Hospital (Rigshospitalet)
Mark H. Greene: National Cancer Institute
Tom Grotmol: Cancer Registry of Norway
Peter A. Kanetsky: H. Lee Moffitt Cancer Center and Research Institution
Katherine A. McGlynn: National Cancer Institute
Katherine L. Nathanson: University of Pennsylvania
Clare Turnbull: The Institute of Cancer Research
Fredrik Wiklund: Karolinska Institutet
Stephen J. Chanock: National Cancer Institute
Nilanjan Chatterjee: Johns Hopkins University
Montserrat Garcia-Closas: National Cancer Institute

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.

Date: 2020
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DOI: 10.1038/s41467-020-16483-3

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