Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants.
Wang A., Shen J., Rodriguez AA., Saunders EJ., Chen F., Janivara R., Darst BF., Sheng X., Xu Y., Chou AJ., Benlloch S., Dadaev T., Brook MN., Plym A., Sahimi A., Hoffman TJ., Takahashi A., Matsuda K., Momozawa Y., Fujita M., Laisk T., Figuerêdo J., Muir K., Ito S., Liu X., Biobank Japan Project None., Uchio Y., Kubo M., Kamatani Y., Lophatananon A., Wan P., Andrews C., Lori A., Choudhury PP., Schleutker J., Tammela TLJ., Sipeky C., Auvinen A., Giles GG., Southey MC., MacInnis RJ., Cybulski C., Wokolorczyk D., Lubinski J., Rentsch CT., Cho K., Mcmahon BH., Neal DE., Donovan JL., Hamdy FC., Martin RM., Nordestgaard BG., Nielsen SF., Weischer M., Bojesen SE., Røder A., Stroomberg HV., Batra J., Chambers S., Horvath L., Clements JA., Tilly W., Risbridger GP., Gronberg H., Aly M., Szulkin R., Eklund M., Nordstrom T., Pashayan N., Dunning AM., Ghoussaini M., Travis RC., Key TJ., Riboli E., Park JY., Sellers TA., Lin H-Y., Albanes D., Weinstein S., Cook MB., Mucci LA., Giovannucci E., Lindstrom S., Kraft P., Hunter DJ., Penney KL., Turman C., Tangen CM., Goodman PJ., Thompson IM., Hamilton RJ., Fleshner NE., Finelli A., Parent M-É., Stanford JL., Ostrander EA., Koutros S., Beane Freeman LE., Stampfer M., Wolk A., Håkansson N., Andriole GL., Hoover RN., Machiela MJ., Sørensen KD., Borre M., Blot WJ., Zheng W., Yeboah ED., Mensah JE., Lu Y-J., Zhang H-W., Feng N., Mao X., Wu Y., Zhao S-C., Sun Z., Thibodeau SN., McDonnell SK., Schaid DJ., West CML., Barnett G., Maier C., Schnoeller T., Luedeke M., Kibel AS., Drake BF., Cussenot O., Cancel-Tassin G., Menegaux F., Truong T., Koudou YA., John EM., Grindedal EM., Maehle L., Khaw K-T., Ingles SA., Stern MC., Vega A., Gómez-Caamaño A., Fachal L., Rosenstein BS., Kerns SL., Ostrer H., Teixeira MR., Paulo P., Brandão A., Watya S., Lubwama A., Bensen JT., Butler EN., Mohler JL., Taylor JA., Kogevinas M., Dierssen-Sotos T., Castaño-Vinyals G., Cannon-Albright L., Teerlink CC., Huff CD., Pilie P., Yu Y., Bohlender RJ., Gu J., Strom SS., Multigner L., Blanchet P., Brureau L., Kaneva R., Slavov C., Mitev V., Leach RJ., Brenner H., Chen X., Holleczek B., Schöttker B., Klein EA., Hsing AW., Kittles RA., Murphy AB., Logothetis CJ., Kim J., Neuhausen SL., Steele L., Ding YC., Isaacs WB., Nemesure B., Hennis AJM., Carpten J., Pandha H., Michael A., De Ruyck K., De Meerleer G., Ost P., Xu J., Razack A., Lim J., Teo S-H., Newcomb LF., Lin DW., Fowke JH., Neslund-Dudas CM., Rybicki BA., Gamulin M., Lessel D., Kulis T., Usmani N., Abraham A., Singhal S., Parliament M., Claessens F., Joniau S., Van den Broeck T., Gago-Dominguez M., Castelao JE., Martinez ME., Larkin S., Townsend PA., Aukim-Hastie C., Bush WS., Aldrich MC., Crawford DC., Srivastava S., Cullen J., Petrovics G., Casey G., Wang Y., Tettey Y., Lachance J., Tang W., Biritwum RB., Adjei AA., Tay E., Truelove A., Niwa S., Yamoah K., Govindasami K., Chokkalingam AP., Keaton JM., Hellwege JN., Clark PE., Jalloh M., Gueye SM., Niang L., Ogunbiyi O., Shittu O., Amodu O., Adebiyi AO., Aisuodionoe-Shadrach OI., Ajibola HO., Jamda MA., Oluwole OP., Nwegbu M., Adusei B., Mante S., Darkwa-Abrahams A., Diop H., Gundell SM., Roobol MJ., Jenster G., van Schaik RHN., Hu JJ., Sanderson M., Kachuri L., Varma R., McKean-Cowdin R., Torres M., Preuss MH., Loos RJF., Zawistowski M., Zöllner S., Lu Z., Van Den Eeden SK., Easton DF., Ambs S., Edwards TL., Mägi R., Rebbeck TR., Fritsche L., Chanock SJ., Berndt SI., Wiklund F., Nakagawa H., Witte JS., Gaziano JM., Justice AC., Mancuso N., Terao C., Eeles RA., Kote-Jarai Z., Madduri RK., Conti DV., Haiman CA.
The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.