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

Abstract

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 PrCa(1).

Type Journal
ISBN 1061-4036
Authors Schumacher, F. R.; Al Olama, A. A.; Berndt, S. I.; Benlloch, S.; Ahmed, M.; Saunders, E. J.; Dadaev, T.; Leongamornlert, D.; Anokian, E.; Cieza-Borrella, C.; Goh, C.; Brook, M. N.; Sheng, X.; Fachal, L.; Dennis, J.; Tyrer, J.; Muir, K.; Lophatananon, A.; Stevens, V. L.; Gapstur, S. M.; Carter, B. D.; Tangen, C. M.; Goodman, P. J.; Thompson, I. M., Jr.; Batra, J.; Chambers, S.; Moya, L.; Clements, J.; Horvath, L.; Tilley, W.; Risbridger, G. P.; Gronberg, H.; Aly, M.; Nordstrom, T.; Pharoah, P.; Pashayan, N.; Schleutker, J.; Tammela, T. L. J.; Sipeky, C.; Auvinen, A.; Albanes, D.; Weinstein, S.; Wolk, A.; Hakansson, N.; West, C. M. L.; Dunning, A. M.; Burnet, N.; Mucci, L. A.; Giovannucci, E.; Andriole, G. L.; Cussenot, O.; Cancel-Tassin, G.; Koutros, S.; Beane Freeman, L. E.; Sorensen, K. D.; Orntoft, T. F.; Borre, M.; Maehle, L.; Grindedal, E. M.; Neal, D. E.; Donovan, J. L.; Hamdy, F. C.; Martin, R. M.; Travis, R. C.; Key, T. J.; Hamilton, R. J.; Fleshner, N. E.; Finelli, A.; Ingles, S. A.; Stern, M. C.; Rosenstein, B. S.; Kerns, S. L.; Ostrer, H.; Lu, Y. J.; Zhang, H. W.; Feng, N.; Mao, X.; Guo, X.; Wang, G.; Sun, Z.; Giles, G. G.; Southey, M. C.; MacInnis, R. J.; FitzGerald, L. M.; Kibel, A. S.; Drake, B. F.; Vega, A.; Gomez-Caamano, A.; Szulkin, R.; Eklund, M.; Kogevinas, M.; Llorca, J.; Castano-Vinyals, G.; Penney, K. L.; Stampfer, M.; Park, J. Y.; Sellers, T. A.; Lin, H. Y.; Stanford, J. L.; Cybulski, C., et al.
Responsible Garvan Author Prof Lisa Horvath
Publisher Name NATURE GENETICS
Published Date 2018-07-01
Published Volume 50
Published Issue 7
Published Pages 928-936
Status Published in-print
DOI 10.1038/s41588-018-0142-8
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/29892016