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Assessment of Polygenic Architecture and Risk Prediction based on Common Variants Across Fourteen Cancers

By Yan Zhang, Amber N. Wilcox, 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 Berndt, Brenda M. Birmann, Nicola J. Camp, Peter Kraft, Nathaniel Rothman, Susan L. Slager, Andrew Berchuck, Paul DP. 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, BCAC, BEACON, CCFR, CORECT, ECAC, GECCO, GenoMEL, GICC, ILCCO, Integral, InterLymph, OCAC, Oral Cancer GWAS, PANC4, PanScan, PRACTICAL, Renal Cancer GWAS, TECAC, Stephen J. Chanock, Nilanjan Chatterjee, Montserrat Garcia-Closas

Posted 09 Aug 2019
bioRxiv DOI: 10.1101/723825 (published DOI: 10.1038/s41467-020-16483-3)

We analyzed summary-level data from genome-wide association studies (GWAS) of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) contributing to risk, as well as the distribution of their associated effect sizes. All cancers evaluated showed polygenicity, involving at a minimum thousands of independent susceptibility variants. For some malignancies, particularly chronic lymphoid leukemia (CLL) and testicular cancer, susceptibility variants have a larger proportion of variants with larger effect sizes than those for other cancers. In contrast, most variants for lung and breast cancers have very small associated effect sizes. We estimate a wide range of GWAS sample sizes for different cancer sites required to explain 80% of GWAS heritability, varying from 60,000 cases for CLL 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, compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that polygenic risk scores have substantial potential for risk stratification for relatively common cancers such as breast, prostate and colon, but limited potential for other cancer sites because of modest heritability and lower disease incidence.

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