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

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. In cancer many gene variants may contribute to disease etiology, but the impact of a given gene variant may have varied effect size. Here, the authors analyse summary statistics of genome-wide association studies from fourteen cancers, and show the utility of polygenic risk scores may vary depending on cancer type.

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

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