Journal
NATURE GENETICS
Volume 50, Issue 7, Pages 928-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41588-018-0142-8
Keywords
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Categories
Funding
- US National Institutes of Health (NIH) [U19 CA 148537, X01HG007492, HHSN268201200008I]
- NIH NCI [U01 CA188392]
- European Community's Seventh Framework Programme [223175 (HEALTH-F2-2009-223175)]
- Cancer Research UK [C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565, C5047/A7357, C1287/A16563, C5047/A3354, C16913/A6135]
- NIH [CA128978]
- Post-Cancer GWAS Initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]
- Department of Defense [W81XWH-10-1-0341]
- Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure
- Breast Cancer Research Foundation
- Ovarian Cancer Research Fund
- Canadian Institutes of Health Research
- European Commission's Seventh Framework Programme [223175 (HEALTH-F2-2009-223175)]
- NIH Cancer Post-Cancer GWAS initiative [1 U19 CA 148537-01]
- Institute of Cancer Research
- Everyman Campaign
- Prostate Cancer Research Foundation
- Prostate Research Campaign UK (now Prostate Action)
- Orchid Cancer Appeal
- National Cancer Research Network UK
- National Cancer Research Institute (NCRI) UK
- NIHR
- Royal Marsden NHS Foundation Trust
- National Health and Medical Research Council, Australia [126402, 209057, 251533, 396414, 450104, 504700, 504702, 504715, 623204, 940394, 614296]
- VicHealth
- Cancer Council Victoria
- Prostate Cancer Foundation of Australia
- Whitten Foundation, PricewaterhouseCoopers
- Tattersall's
- Intramural Program of the National Human Genome Research Institute
- NIH
- National Cancer Institute [U01-CA98233, U01-CA98710, U01-CA98216, U01-CA98758]
- Swedish Cancer Foundation [09-0677, 11484, 12-823]
- Cancer Risk Prediction Center (CRisP)
- Linneus Centre grant - Swedish Research Council [ID 70867902]
- wedish Research Council [K2010 70X-20430-04-3, 2014-2269]
- Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH
- Cancer Research UK [15007, 16561, 14136, 17528, 16565, 10118, 19169, 21332, 16491] Funding Source: researchfish
- Medical Research Council [MR/N003284/1, G1000143, G0401527] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10114, NF-SI-0513-10121, NF-SI-0509-10242, NF-SI-0510-10096] Funding Source: researchfish
- The Danish Cancer Society [R130-A8313, R130-A8338] Funding Source: researchfish
- The Francis Crick Institute
- Cancer Research UK [10119] Funding Source: researchfish
- MRC [MR/N003284/1] Funding Source: UKRI
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Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 x 10(-8)) with PrCa and one locus significantly associated with early-onset PrCa (<= 55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 x 10(-9); G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 x 10(-9); T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa1.
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