Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci

TY - JOUR

T1 - Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci

AU - Schumacher, Fredrick R

AU - Al Olama, Ali Amin

AU - Berndt, Sonja I

AU - Sorensen, Karina Dalsgaard

AU - Orntoft, Torben Falck

AU - Borre, Michael

AU - Nordestgaard, Børge G

AU - Røder, Martin Andreas

AU - Iversen, Peter

AU - Australian Prostate Cancer BioResource

AU - The IMPACT Study

AU - Canary PASS Investigators

AU - Breast and Prostate Cancer Cohort Consortium (BPC3)

AU - The PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium

AU - Cancer of the Prostate in Sweden (CAPS)

AU - Prostate Cancer Genome-wide Association Study of Uncommon Susceptibility Loci (PEGASUS)

AU - The Genetic Associations and Mechanisms in Oncology (GAME-ON)/Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) Consortium

AU - Kote-Jarai, Zsofia

AU - Haiman, Christopher A.

AU - Eeles, Rosalind A

PY - 2018/7/1

Y1 - 2018/7/1

N2 - 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 × 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 × 10-9; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 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 PrCa 1 .

AB - 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 × 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 × 10-9; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 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 PrCa 1 .

U2 - 10.1038/s41588-018-0142-8

DO - 10.1038/s41588-018-0142-8

M3 - Letter

C2 - 29892016

SN - 1061-4036

VL - 50

SP - 928

EP - 936

JO - Nature Genetics

JF - Nature Genetics

ER -