Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers
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Published:2020-07-03
Issue:1
Volume:11
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Zhang Yan DoraORCID, Hurson Amber N.ORCID, Zhang Haoyu, Choudhury Parichoy Pal, Easton Douglas F.ORCID, Milne Roger L.ORCID, Simard JacquesORCID, Hall Per, Michailidou KyriakiORCID, Dennis JoeORCID, Schmidt Marjanka K.ORCID, Chang-Claude Jenny, Gharahkhani PuyaORCID, Whiteman DavidORCID, Campbell Peter T., Hoffmeister Michael, Jenkins MarkORCID, Peters UlrikeORCID, Hsu Li, Gruber Stephen B., Casey Graham, Schmit Stephanie L.ORCID, O’Mara Tracy A.ORCID, Spurdle Amanda B.ORCID, Thompson Deborah J.ORCID, Tomlinson IanORCID, De Vivo Immaculata, Landi Maria TeresaORCID, Law Matthew H.ORCID, Iles Mark M.ORCID, Demenais FlorenceORCID, Kumar RajivORCID, MacGregor StuartORCID, Bishop D. TimothyORCID, Ward Sarah V., Bondy Melissa L., Houlston RichardORCID, Wiencke John K., Melin Beatrice, Barnholtz-Sloan JillORCID, Kinnersley BenORCID, Wrensch Margaret R., Amos Christopher I.ORCID, Hung Rayjean J.ORCID, Brennan PaulORCID, McKay James, Caporaso Neil E., Berndt Sonja I., Birmann Brenda M.ORCID, Camp Nicola J.ORCID, Kraft PeterORCID, Rothman Nathaniel, Slager Susan L., Berchuck Andrew, Pharoah Paul D. P.ORCID, Sellers Thomas A., Gayther Simon A.ORCID, Pearce Celeste L., Goode Ellen L., Schildkraut Joellen M., Moysich Kirsten B., Amundadottir Laufey T.ORCID, Jacobs Eric J.ORCID, Klein Alison P.ORCID, Petersen Gloria M., Risch Harvey A., Stolzenberg-Solomon Rachel Z., Wolpin Brian M., Li Donghui, Eeles Rosalind A.ORCID, Haiman Christopher A., Kote-Jarai Zsofia, Schumacher Fredrick R.ORCID, Al Olama Ali Amin, Purdue Mark P., Scelo Ghislaine, Dalgaard Marlene D., Greene Mark H.ORCID, Grotmol Tom, Kanetsky Peter A.ORCID, McGlynn Katherine A., Nathanson Katherine L.ORCID, Turnbull Clare, Wiklund FredrikORCID, 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., 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, Campbell Peter T., Hoffmeister Michael, Jenkins Mark, Peters Ulrike, Hsu Li, Gruber Stephen B., Casey Graham, Schmit Stephanie L., Landi Maria Teresa, Law Matthew H., Iles Mark M., Demenais Florence, Kumar Rajiv, MacGregor Stuart, Bishop David T., 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., 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., Amos Christopher I., Brennan Paul, McKay James, Amundadottir Laufey T., Jacobs Eric J., Klein Alison P., Petersen Gloria M., Risch Harvey A., Stolzenberg-Solomon Rachel Z., Wolpin Brian M., Li Donghui, 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., Al Olama Ali Amin, 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.ORCID, Chatterjee Nilanjan, Garcia-Closas MontserratORCID, , , , , , , , , , , , , , , , , ,
Abstract
AbstractGenome-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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
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