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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?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 PrCa1.

SUBMITTER: Schumacher FR 

PROVIDER: S-EPMC6568012 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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

Schumacher Fredrick R FR   Al Olama Ali Amin AA   Berndt Sonja I SI   Benlloch Sara S   Ahmed Mahbubl M   Saunders Edward J EJ   Dadaev Tokhir T   Leongamornlert Daniel D   Anokian Ezequiel E   Cieza-Borrella Clara C   Goh Chee C   Brook Mark N MN   Sheng Xin X   Fachal Laura L   Dennis Joe J   Tyrer Jonathan J   Muir Kenneth K   Lophatananon Artitaya A   Stevens Victoria L VL   Gapstur Susan M SM   Carter Brian D BD   Tangen Catherine M CM   Goodman Phyllis J PJ   Thompson Ian M IM   Batra Jyotsna J   Chambers Suzanne S   Moya Leire L   Clements Judith J   Horvath Lisa L   Tilley Wayne W   Risbridger Gail P GP   Gronberg Henrik H   Aly Markus M   Nordström Tobias T   Pharoah Paul P   Pashayan Nora N   Schleutker Johanna J   Tammela Teuvo L J TLJ   Sipeky Csilla C   Auvinen Anssi A   Albanes Demetrius D   Weinstein Stephanie S   Wolk Alicja A   Håkansson Niclas N   West Catharine M L CML   Dunning Alison M AM   Burnet Neil N   Mucci Lorelei A LA   Giovannucci Edward E   Andriole Gerald L GL   Cussenot Olivier O   Cancel-Tassin Géraldine G   Koutros Stella S   Beane Freeman Laura E LE   Sorensen Karina Dalsgaard KD   Orntoft Torben Falck TF   Borre Michael M   Maehle Lovise L   Grindedal Eli Marie EM   Neal David E DE   Donovan Jenny L JL   Hamdy Freddie C FC   Martin Richard M RM   Travis Ruth C RC   Key Tim J TJ   Hamilton Robert J RJ   Fleshner Neil E NE   Finelli Antonio A   Ingles Sue Ann SA   Stern Mariana C MC   Rosenstein Barry S BS   Kerns Sarah L SL   Ostrer Harry H   Lu Yong-Jie YJ   Zhang Hong-Wei HW   Feng Ninghan N   Mao Xueying X   Guo Xin X   Wang Guomin G   Sun Zan Z   Giles Graham G GG   Southey Melissa C MC   MacInnis Robert J RJ   FitzGerald Liesel M LM   Kibel Adam S AS   Drake Bettina F BF   Vega Ana A   Gómez-Caamaño Antonio A   Szulkin Robert R   Eklund Martin M   Kogevinas Manolis M   Llorca Javier J   Castaño-Vinyals Gemma G   Penney Kathryn L KL   Stampfer Meir M   Park Jong Y JY   Sellers Thomas A TA   Lin Hui-Yi HY   Stanford Janet L JL   Cybulski Cezary C   Wokolorczyk Dominika D   Lubinski Jan J   Ostrander Elaine A EA   Geybels Milan S MS   Nordestgaard Børge G BG   Nielsen Sune F SF   Weischer Maren M   Bisbjerg Rasmus R   Røder Martin Andreas MA   Iversen Peter P   Brenner Hermann H   Cuk Katarina K   Holleczek Bernd B   Maier Christiane C   Luedeke Manuel M   Schnoeller Thomas T   Kim Jeri J   Logothetis Christopher J CJ   John Esther M EM   Teixeira Manuel R MR   Paulo Paula P   Cardoso Marta M   Neuhausen Susan L SL   Steele Linda L   Ding Yuan Chun YC   De Ruyck Kim K   De Meerleer Gert G   Ost Piet P   Razack Azad A   Lim Jasmine J   Teo Soo-Hwang SH   Lin Daniel W DW   Newcomb Lisa F LF   Lessel Davor D   Gamulin Marija M   Kulis Tomislav T   Kaneva Radka R   Usmani Nawaid N   Singhal Sandeep S   Slavov Chavdar C   Mitev Vanio V   Parliament Matthew M   Claessens Frank F   Joniau Steven S   Van den Broeck Thomas T   Larkin Samantha S   Townsend Paul A PA   Aukim-Hastie Claire C   Gago-Dominguez Manuela M   Castelao Jose Esteban JE   Martinez Maria Elena ME   Roobol Monique J MJ   Jenster Guido G   van Schaik Ron H N RHN   Menegaux Florence F   Truong Thérèse T   Koudou Yves Akoli YA   Xu Jianfeng J   Khaw Kay-Tee KT   Cannon-Albright Lisa L   Pandha Hardev H   Michael Agnieszka A   Thibodeau Stephen N SN   McDonnell Shannon K SK   Schaid Daniel J DJ   Lindstrom Sara S   Turman Constance C   Ma Jing J   Hunter David J DJ   Riboli Elio E   Siddiq Afshan A   Canzian Federico F   Kolonel Laurence N LN   Le Marchand Loic L   Hoover Robert N RN   Machiela Mitchell J MJ   Cui Zuxi Z   Kraft Peter P   Amos Christopher I CI   Conti David V DV   Easton Douglas F DF   Wiklund Fredrik F   Chanock Stephen J SJ   Henderson Brian E BE   Kote-Jarai Zsofia Z   Haiman Christopher A CA   Eeles Rosalind A RA  

Nature genetics 20180611 7


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<sup>-8</sup>) with PrCa and one locus significantly associated with ear  ...[more]

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