: Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
Stroke genetics informs drug discovery and risk prediction across ancestries / Aniket, Mishra; Rainer, Malik; Tsuyoshi, Hachiya; Tuuli, Jürgenson; Shinichi, Namba; Daniel C., Posner; Frederick K., Kamanu; Masaru, Koido; Quentin, Le Grand; Mingyang, Shi; Yunye, He; Marios K., Georgakis; Ilana, Caro; Kristi, Krebs; Yi-Ching, Liaw; Felix C., Vaura; Kuang, Lin; Bendik Slagsvold, Winsvold; Vinodh, Srinivasasainagendra; Livia, Parodi; Hee-Joon, Bae; Ganesh, Chauhan; Michael R., Chong; Liisa, Tomppo; Rufus, Akinyemi; Gennady V., Roshchupkin; Naomi, Habib; Yon Ho, Jee; Jesper Qvist, Thomassen; Vida, Abedi; Jara, Cárcel-Márquez; Marianne, Nygaard; Hampton L., Leonard; Chaojie, Yang; Ekaterina, Yonova-Doing; Maria J., Knol; Adam J., Lewis; Renae L., Judy; Tetsuro, Ago; Philippe, Amouyel; Nicole D., Armstrong; Mark K., Bakker; Traci M., Bartz; David A., Bennett; Joshua C., Bis; Constance, Bordes; Sigrid, Børte; Anael, Cain; Paul M., Ridker; Kelly, Cho; Zhengming, Chen; Carlos, Cruchaga; John W., Cole; Phil L., de Jager; Rafael, de Cid; Matthias, Endres; Leslie E., Ferreira; Mirjam I., Geerlings; Natalie C., Gasca; Vilmundur, Gudnason; Jun, Hata; Jing, He; Alicia K., Heath; Yuk-Lam, Ho; Aki S., Havulinna; Jemma C., Hopewell; Hyacinth I., Hyacinth; Michael, Inouye; Mina A., Jacob; Christina E., Jeon; Christina, Jern; Masahiro, Kamouchi; Keith L., Keene; Takanari, Kitazono; Steven J., Kittner; Takahiro, Konuma; Amit, Kumar; Paul, Lacaze; Lenore J., Launer; Keon-Joo, Lee; Kaido, Lepik; Jiang, Li; Liming, Li; Ani, Manichaikul; Hugh S., Markus; Nicholas A., Marston; Thomas, Meitinger; Braxton D., Mitchell; Felipe A., Montellano; Takayuki, Morisaki; Thomas H., Mosley; Mike A., Nalls; Børge G., Nordestgaard; Martin J., O'Donnell; Yukinori, Okada; N. Charlotte, Onland-Moret; Bruce, Ovbiagele; Annette, Peters; Bruce M., Psaty; Stephen S., Rich; Jonathan, Rosand; Marc S., Sabatine; Ralph L., Sacco; Danish, Saleheen; Else Charlotte, Sandset; Veikko, Salomaa; Muralidharan, Sargurupremraj; Makoto, Sasaki; Claudia L., Satizabal; Carsten O., Schmidt; Atsushi, Shimizu; Nicholas L., Smith; Kelly L., Sloane; Yoichi, Sutoh; Yan V., Sun; Kozo, Tanno; Steffen, Tiedt; Turgut, Tatlisumak; Nuria P., Torres-Aguila; Hemant K., Tiwari; David-Alexandre, Trégouët; Stella, Trompet; Anil Man, Tuladhar; Anne, Tybjærg-Hansen; Marion, van Vugt; Riina, Vibo; Shefali S., Verma; Kerri L., Wiggins; Patrik, Wennberg; Daniel, Woo; Peter W. F., Wilson; Huichun, Xu; Qiong, Yang; Kyungheon, Yoon; Null, Null; Joshua C., Bis; Jin-Moo, Lee; Yu-Ching, Cheng; James F., Meschia; Wei Min, Chen; Michèle M., Sale; Alan B., Zonderman; Michele K., Evans; James G., Wilson; Adolfo, Correa; Matthew, Traylor; Cathryn M., Lewis; Cara L., Carty; Alexander, Reiner; Jeffrey, Haessler; Carl D., Langefeld; Rebecca F., Gottesman; Kristine, Yaffe; Yong Mei, Liu; Charles, Kooperberg; Leslie A., Lange; Karen L., Furie; Donna K., Arnett; Oscar R., Benavente; Raji P., Grewal; Leema Reddy, Peddareddygari; Null, Null; Charles, Kooperberg; Kristian, Hveem; Sara, Lindstrom; Lu, Wang; Erin N., Smith; William, Gordon; Astrid, van Hylckama Vlieg; Mariza, de Andrade; Jennifer A., Brody; Jack W., Pattee; Jeffrey, Haessler; Ben M., Brumpton; Pierre, Suchon; Ming-Huei, Chen; Kelly A., Frazer; Constance, Turman; Marine, Germain; James, Macdonald; Sigrid K., Braekkan; Sebastian M., Armasu; Nathan, Pankratz; Rebecca D., Jackson; Jonas B., Nielsen; Franco, Giulianini; Marja K., Puurunen; Manal, Ibrahim; Susan R., Heckbert; Theo K., Bammler; Bryan M., Mccauley; Kent D., Taylor; James S., Pankow; Alexander P., Reiner; Maiken E., Gabrielsen; Jean-François, Deleuze; Chris J., O'Donnell; Jihye, Kim; Barbara, Mcknight; Peter, Kraft; John-Bjarne, Hansen; Frits R., Rosendaal; John A., Heit; Weihong, Tang; Pierre-Emmanuel, Morange; Andrew D., Johnson; Christopher, Kabrhel; Null, Null; Ewoud J., van Dijk; Peter J., Koudstaal; Gert-Jan, Luijckx; Paul J., Nederkoorn; Robert J., van Oostenbrugge; Marieke C., Visser; Marieke J. H., Wermer; L. Jaap, Kappelle; Null, Null; Tõnu, Esko; Andres, Metspalu; Reedik, Mägi; Mari, Nelis; Null, Null; Null, Null; Null, Null; Marguerite R., Irvin; Frank-Erik, de Leeuw; Christopher R., Levi; Jane, Maguire; Jordi, Jiménez-Conde; Pankaj, Sharma; Cathie L. M., Sudlow; Kristiina, Rannikmäe; Reinhold, Schmidt; Agnieszka, Slowik; Joanna, Pera; Vincent N. S., Thijs; Arne G., Lindgren; Andreea, Ilinca; Olle, Melander; Gunnar, Engström; Kathryn M., Rexrode; Peter M., Rothwell; Tara M., Stanne; Julie A., Johnson; John, Danesh; Adam S., Butterworth; Laura, Heitsch; Giorgio B., Boncoraglio; Michiaki, Kubo; Alessandro, Pezzini; Arndt, Rolfs; Anne-Katrin, Giese; David, Weir; Rebecca D., Jackson; Owen A., Ross; Robin, Lemmons; Martin, Soderholm; Mary, Cushman; Katarina, Jood; Caitrin W., Mcdonough; Steven, Bell; Birgit, Linkohr; Tsong-Hai, Lee; Jukka, Putaala; Null, Null; Christopher D., Anderson; Oscar L., Lopez; Xueqiu, Jian; Ulf, Schminke; Natalia, Cullell; Pilar, Delgado; Laura, Ibañez; Jerzy, Krupinski; Vasileios, Lioutas; Koichi, Matsuda; Joan, Montaner; Elena, Muiño; Jaume, Roquer; Chloe, Sarnowski; Naveed, Sattar; Gerli, Sibolt; Alexander, Teumer; Loes, Rutten-Jacobs; Masahiro, Kanai; Anne-Katrin, Giese; Solveig, Gretarsdottir; Natalia S., Rost; Salim, Yusuf; Peter, Almgren; Hakan, Ay; Steve, Bevan; Robert D., Brown; Caty, Carrera; Julie E., Buring; Wei-Min, Chen; Ioana, Cotlarciuc; Paul I. W., de Bakker; Anita L., Destefano; Marcel, den Hoed; Qing, Duan; Stefan T., Engelter; Guido J., Falcone; Rebecca F., Gottesman; Stefan, Gustafsson; Ahamad, Hassan; Elizabeth G., Holliday; George, Howard; Fang-Chi, Hsu; Erik, Ingelsson; Tamara B., Harris; Brett M., Kissela; Dawn O., Kleindorfer; Claudia, Langenberg; Robin, Lemmens; Didier, Leys; Wei-Yu, Lin; Erik, Lorentzen; Patrik K., Magnusson; Patrick F., Mcardle; Sara L., Pulit; Kenneth, Rice; Saori, Sakaue; Bishwa R., Sapkota; Christian, Tanislav; Gudmar, Thorleifsson; Unnur, Thorsteinsdottir; Christophe, Tzourio; Cornelia M., van Duijn; Matthew, Walters; Nicholas J., Wareham; Najaf, Amin; Hugo J., Aparicio; John, Attia; Alexa S., Beiser; Claudine, Berr; Mariana, Bustamante; Valeria, Caso; Seung Hoan, Choi; Ayesha, Chowhan; Jean-François, Dartigues; Hossein, Delavaran; Marcus, Dörr; Ian, Ford; Wander S., Gurpreet; Anders, Hamsten; Atsushi, Hozawa; Martin, Ingelsson; Motoki, Iwasaki; Sara, Kaffashian; Lalit, Kalra; Olafur, Kjartansson; Manja, Kloss; Daniel L., Labovitz; Cathy C., Laurie; Linxin, Li; Lars, Lind; Cecilia M., Lindgren; Hirata, Makoto; Naoko, Minegishi; Andrew P., Morris; Martina, Müller-Nurasyid; Bo, Norrving; Soichi, Ogishima; Eugenio A., Parati; Nancy L., Pedersen; Markus, Perola; Pekka, Jousilahti; Silvana, Pileggi; Raquel, Rabionet; Iolanda, Riba-Llena; Marta, Ribasés; Jose R., Romero; Anthony G., Rudd; Antti-Pekka, Sarin; Ralhan, Sarju; Mamoru, Satoh; Norie, Sawada; Ásgeir, Sigurdsson; Albert, Smith; O. Colin, Stine; David J., Stott; Konstantin, Strauch; Takako, Takai; Hideo, Tanaka; Emmanuel, Touze; Shoichiro, Tsugane; Andre G., Uitterlinden; Einar M., Valdimarsson; Sven J., van der Lee; Kenji, Wakai; Stephen R., Williams; Charles D. A., Wolfe; Quenna, Wong; Taiki, Yamaji; Dharambir K., Sanghera; Kari, Stefansson; Kent D., Taylor; Nicolas, Martinez-Majander; Kenji, Sobue; Carolina, Soriano-Tárraga; Henry, Völzke; Null, Null; Onoja, Akpa; Fred S., Sarfo; Albert, Akpalu; Reginald, Obiako; Kolawole, Wahab; Godwin, Osaigbovo; Lukman, Owolabi; Morenikeji, Komolafe; Carolyn, Jenkins; Oyedunni, Arulogun; Godwin, Ogbole; Abiodun M., Adeoye; Joshua, Akinyemi; Atinuke, Agunloye; Adekunle G., Fakunle; Ezinne, Uvere; Abimbola, Olalere; Olayinka J., Adebajo; Null, Null; Junshi, Chen; Robert, Clarke; Rory, Collins; Yu, Guo; Chen, Wang; Jun, Lv; Richard, Peto; Yiping, Chen; Zammy, Fairhurst-Hunter; Michael, Hill; Alfred, Pozarickij; Dan, Schmidt; Becky, Stevens; Iain, Turnbull; Canqing, Yu; Null, Null; Null, Null; Quentin, Le Grand; Leslie E., Ferreira; Null, Null; Akiko, Nagai; Yoishinori, Murakami; Null, Null; Mirjam I., Geerlings; Natalie C., Gasca; Vilmundur, Gudnason; Marion, van Vugt; Rebecca F., Gottesman; Eric J., Shiroma; Sigurdur, Sigurdsson; Mohsen, Ghanbari; Eric, Boerwinkle; Alexa S., Beiser; Bernard, Fongang; Ruiqi, Wang; Mohammad K., Ikram; Uwe, Völker; Null, Null; Phil L., de Jager; Rafael, de Cid; Børge G., Nordestgaard; Muralidharan, Sargurupremraj; Shefali S., Verma; Null, Null; Null, Null; Karlijn F., de Laat; Anouk G. W., van Norden; Paul L., de Kort; Sarah E., Vermeer; Paul J. A. M., Brouwers; Rob A. R., Gons; Paul J., Nederkoorn; Tom, den Heijer; Gert W., van Dijk; Frank G. W., van Rooij; Null, Null; Anne H., Aamodt; Anne H., Skogholt; Ben M., Brumpton; Cristen J., Willer; Ingrid, Heuch; Knut, Hagen; Lars G., Fritsche; Linda M., Pedersen; Maiken E., Gabrielsen; Hanne, Ellekjær; Wei, Zhou; Amy E., Martinsen; Espen S., Kristoffersen; Jonas B., Nielsen; Kristian, Hveem; Laurent F., Thomas; Null, Null; Christoph, Kleinschnitz; Stefan, Frantz; Kathrin, Ungethüm; Null, Null; Cristina, Gallego-Fabrega; Miquel, Lledós; Laia, Llucià-Carol; Tomas, Sobrino; Francisco, Campos; José, Castillo; Marimar, Freijó; Juan Francisco, Arenillas; Victor, Obach; José, Álvarez-Sabín; Carlos A., Molina; Marc, Ribó; Lucia, Muñoz-Narbona; Elena, Lopez-Cancio; Mònica, Millán; Rosa, Diaz-Navarro; Cristòfol, Vives-Bauza; Gemma, Serrano-Heras; Tomás, Segura; Pilar, Delgado; Rajat, Dhar; Raquel, Delgado-Mederos; Luis, Prats-Sánchez; Pol, Camps-Renom; Natalia, Blay; Lauro, Sumoy; Joan, Martí-Fàbregas; Null, Null; Peter, Schnohr; Gorm B., Jensen; Marianne, Benn; Shoaib, Afzal; Pia R., Kamstrup; Null, Null; Jessica, van Setten; Sander W., van der Laan; Jet M. J., Vonk; Null, Null; Bong-Jo, Kim; Null, Null; Sami, Curtze; Marjaana, Tiainen; Janne, Kinnunen; Null, Null; Vilas, Menon; Yun Ju, Sung; Chengran, Yang; Florence, Saillour-Glenisson; Simon, Gravel; Null, Null; N. Charlotte, Onland-Moret; Alicia K., Heath; Iona Y., Millwood; Christian, Gieger; Toshiharu, Ninomiya; Hans J., Grabe; J. Wouter, Jukema; Ina L., Rissanen; Daniel, Strbian; Young Jin, Kim; Pei-Hsin, Chen; Ernst, Mayerhofer; Joanna M. M., Howson; Marguerite R., Irvin; Hieab, Adams; Sylvia, Wassertheil-Smoller; Kaare, Christensen; Mohammad A., Ikram; Tatjana, Rundek; Bradford B., Worrall; G. Mark, Lathrop; Moeen, Riaz; Eleanor M., Simonsick; Janika, Kõrv; Paulo H. C., França; Ramin, Zand; Kameshwar, Prasad; Ruth, Frikke-Schmidt; Frank-Erik, de Leeuw; Thomas, Liman; Karl Georg, Haeusler; Ynte M., Ruigrok; Peter Ulrich, Heuschmann; W. T., Longstreth; Keum Ji, Jung; Lisa, Bastarache; Guillaume, Paré; Scott M., Damrauer; Daniel I., Chasman; Jerome I., Rotter; Christopher D., Anderson; John-Anker, Zwart; Teemu J., Niiranen; Myriam, Fornage; Yung-Po, Liaw; Sudha, Seshadri; Israel, Fernández-Cadenas; Robin G., Walters; Christian T., Ruff; Mayowa O., Owolabi; Jennifer E., Huffman; Lili, Milani; Yoichiro, Kamatani; Martin, Dichgans; Stephanie, Debette; Jacob88, Mina A.; Man Tuladhar88, Anil; de Leeuw88, Frank-Erik; F de Laat186, Karlijn; GW van Norden187, Anouk; L de Kort188, Paul; E Vermeer189, Sarah; JAM Brouwers190, Paul; AR Gons191, Rob; JAM Nederkoorn192, Paul; Heijer193, Tomden; JAM Oostenbrugge194, Robert; W van Dijk195, Gert; GW van Rooij196, Frank; Slagsvold Winsvold19, Bendik; 21, 20; Børte20, Sigrid; 61, 60; Charlotte Sandset129, Else; 130, ; Zwart19, John-Anker; 60, 20; H Aamodt21, Anne; H Skogholt20, Anne; M Brumpton20, Ben; J Willer197, Cristen; Heuch19, Ingrid; Hagen198, Knut; G Fritsche199, Lars; M Pedersen19, Linda; E Gabrielsen20, Maiken; Ellekjær198, Hanne; 200, ; Zhou201, Wei; 202, ; E Martinsen19, Amy; 60, 20; S Kristoffersen19, Espen; 204, 203; B Nielsen20, Jonas; 205, 197; Hveem20, Kristian; 207, 206; F Thomas20, Laurent; 209, 208; 210, ; Montellano108, Felipe A.; 109, ; Georg Haeusler109, Karl; Ulrich Heuschmann108, Peter; 169, 168; Kleinschnitz211, Christoph; Frantz167, Stefan; 212, ; Ungethüm108, Kathrin; Cárcel-Márquez37, Jara; 38, ; Cruchaga65, Carlos; 66, ; de Cid70, Rafael; Torres-Aguila37, Nuria P.; Muiño37, Elena; Gallego-Fabrega37, Cristina; 213, ; Cullell37, Natalia; 214, ; Lledós37, Miquel; 215, ; Llucià-Carol37, Laia; Sobrino216, Tomas; Campos217, Francisco; Castillo217, José; Freijó218, Marimar; Francisco Arenillas219, Juan; Obach220, Victor; Álvarez-Sabín221, José; A Molina221, Carlos; Ribó221, Marc; Jiménez-Conde222, Jordi; Roquer222, Jaume; Muñoz-Narbona223, Lucia; Lopez-Cancio224, Elena; Millán223, Mònica; Diaz-Navarro225, Rosa; Vives-Bauza225, Cristòfol; Serrano-Heras226, Gemma; Segura226, Tomás; Ibañez440, Laura; Heitsch227, Laura; 228, ; Delgado229, Pilar; Dhar228, Rajat; Krupinski230, Jerzy; Delgado-Mederos213, Raquel; Prats-Sánchez213, Luis; Camps-Renom213, Pol; Blay70, Natalia; Sumoy231, Lauro; Montaner232, Joan; Lee228, Jin-Moo; Martí-Fàbregas213, Joan; Fernández-Cadenas37, Israel; Qvist Thomassen34, Jesper; Nordestgaard111, Børge G.; 112, ; Tybjærg-Hansen34, Anne; 112, ; Frikke-Schmidt34, Ruth; 112, ; Schnohr233, Peter; B Jensen234, Gorm; Benn34, Marianne; 112, ; Afzal111, Shoaib; 112, ; R Kamstrup111, Pia; van Vugt141, Marion; Rissanen75, Ina L.; Geerlings75, Mirjam I.; van Setten141, Jessica; W van der Laan234, Sander; Vonk75, Jet M. J.; 235, ; Bae23, Hee-Joon; Lee98, Keon-Joo; Yoon149, Kyungheon; Jin Kim149, Young; Kim149, Bong-Jo; Tomppo27, Liisa; Salomaa131, Veikko; Tatlisumak140, Turgut; Sibolt27, Gerli; Curtze27, Sami; Tiainen27, Marjaana; Kinnunen27, Janne; Menon236, Vilas; Ju Sung65, Yun; 66, ; Yang65, Chengran; 66, ; Saillour-Glenisson1, Florence; 185, ; Gravel237, Simon; Mishra1, Aniket; Le Grand1, Quentin; Caro1, Ilana; Roshchupkin30, Gennady V.; 31, ; Leonard41, Hampton L.; 43, 42; Yang44, Chaojie; 45, ; Knol30, Maria J.; Bartz57, Traci M.; 58, ; Bis57, Joshua C.; Bordes1, Constance; Ridker62, Paul M.; 63, ; Geerlings75, Mirjam I.; Gasca58, Natalie C.; Gudnason76, Vilmundur; 77, ; Lacaze96, Paul; Launer97, Lenore J.; Manichaikul44, Ani; Mosley110, Thomas H.; Nalls41, Mike A.; 43, 42; Rich44, Stephen S.; Sargurupremraj132, Muralidharan; Satizabal132, Claudia L.; 133, ; Schmidt134, Carsten O.; Trompet141, Stella; 142, ; van Vugt143, Marion; Yang133, Qiong; 148, ; Grabe151, Hans J.; 152, ; Wouter Jukema142, J; 154, 153; Rissanen75, Ina L.; Adams155, Hieab; 156, ; Wassertheil-Smoller157, Sylvia; Ikram30, Mohammad A.; Riaz96, Moeen; Simonsick162, Eleanor M.; Longstreth123, W T.; 170, ; Chasman62, Daniel I.; 63, ; Rotter175, Jerome I.; Fornage178, Myriam; 179, ; Seshadri132, Sudha; 181, 133; Debette1, Stephanie; F Gottesman238, 185 Rebecca; Sattar239, Naveed; J Stott240, David; J Shiroma241, Eric; L Lopez242, Oscar; Sigurdsion76, Sigurdur; Ghanbari30, Mohsen; Schminke243, Ulf; Boerwinkle179, Eric; 244, ; J Aparicio133, Hugo; 181, ; S Beiser133, Alexa; 148, ; R Romero133, Jose; 181, ; Lioutas133, Vasileios; 245, ; Jian132, Xuequi; 133, ; Fongang132, Bernard; 133, ; Wang133, Ruiqi; 148, ; L Sarnowski133, Chloe; 246, ; K Ikram30, Mohammad; 247, ; Teumer134, Alexander; 248, ; Völker248, Uwe; Koido10, Masaru; 11, ; Morisaki10, Takayuki; Kamatani11, Yoichiro; Nagai250, Akiko; Murakami10, Yoishinori; Matsuda14, Koichi; Lin18, Kuang; Chen18, Zhengming; 64, ; Li102, Liming; Millwood18, Iona Y.; 64, ; Walters18, Robin G.; 64, ; Chen4, Junshi; Clarke18, Robert; Collins18, Rory; Guo5, Yu; Wang6, Chen; 7, ; Lv8, Jun; Peto18, Richard; Chen18, Yiping; 64, ; Fairhurst-Hunter18, Zammy; Hill18, Mike; Pozarickij18, Alfred; Schmidt18, Dan; Stevens18, Becky; Turnbull18, Iain; Yu8, Canqing; Srinivasasainagendra22, Vinodh; Akinyemi28, Rufus; 29, ; Ovbiagele119, Bruce; Tiwari22, Hemant K.; Owolabi28, Mayowa O.; 182, ; Akpa255, Onoja; 256, ; Sarfo257, Fred S.; Akpalu258, Albert; Obiako259, Reginald; Wahab260, Kolawole; Osaigbovo261, Godwin; Owolabi262, Lukman; Komolafe263, Morenikeji; Jenkins264, Carolyn; Arulogun265, Oyedunni; Ogbole266, Godwin; Adeoye182, Abiodun M.; Akinyemi1, Joshua; Agunloye182, Atinuke; Fakunle182, Adekunle G.; Uvere182, Ezinne; Olalere182, Abimbola; Adebajo182, Olayinka J.; Jürgenson4, Tuuli; 5, ; Krebs4, Kristi; Lepik4, Kaido; 100, 99; 101, ; Milani4, Lili; Esko4, Tõnu; Metspalu4, Andres; Mägi4, Reedik; Nelis4, Mari; Milani4, Lili; Bakker56, Mark K.; Ruigrok56, Ynte M.; J van Dijk267, Ewoud; J Koudstaal247, Peter; Luijckx268, Gert-Jan; J Nederkoorn269, Paul; J van Oostenbrugge268, Robert; C Visser271, Marieke; Wermer272, Marieke J. H.; Jaap Kappelle56, L; Keene93, Keith L.; Hyacinth83, Hyacinth I.; Bis57, Joshua C.; Kittner68, Steven J.; 94, ; Mitchell106, Braxton D.; 107, ; Paré25, Guillaume; 172, 26; Chong25, Michael R.; 26, ; Rich44, Stephen S.; Nalls41, Mike A.; 43, 42; Markus103, Hugh S.; Mosley110, Thomas H.; Woo83, Daniel; Longstreth123, W T.; 170, ; Psaty57, Bruce M.; 124, 123; Sacco126, Ralph L.; 127, ; Rundek126, Tatjana; 127, ; Lee228, Jin-Moo; Cruchaga65, Carlos; 66, ; Dichgans2, Martin; 184, 183; Malik2, Rainer; Worrall159, Bradford B.; 160, ; Fornage178, Myriam; 179, ; Cheng272, Yu-Ching; O’Donnell273, Martin; Meschia274, James F.; Chen44, Weimin; Sale44, Michele M.; Zonderman275, Alan B.; Evans275, Michele K.; Wilson276, James G.; Correa276, Adolfo; Traylor277, Matthew; Lewis278, Cathryn M.; Carty279, Cara L.; Reiner280, Alexander; Haessler280, Jeff; Langefeld281, Carl D.; Gottesman282, Rebecca; Yaffe283, Kristine; Liu281, Yongmei; Kooperberg280, Charles; Lange284, Leslie A.; Furie285, Karen L.; Arnett286, Donna K.; Benavente287, Oscar R.; Grewal288, Raji P.; Reddy Peddareddygari288, Leema; Chasman62, Daniel I.; 63, ; Wiggins57, Kerri L.; Rotter175, Jerome I.; Psaty57, Bruce M.; 124, 123; Kooperberg280, Charles; Hveem20, Kristian; 207, 206; Ridker62, Paul M.; 63, ; Trégouët1, David-Alexandre; Smith123, Nicholas L.; 136, 135; Lindstrom123, Sara; 280, ; Wang289, Lu; Smith290, Erin N.; Gordon123, William; van Hylckama Vlieg291, Astrid; de Andrade292, Mariza; Brody57, Jennifer A.; Pattee293, Jack W.; Haessler280, Jeffrey; Brumpton294, Ben M.; Suchon295, Pierre; Chen296, Ming-Huei; Turman304, Constance; Germain1, Marine; Macdonald289, James; Braekkan298, Sigrid K.; Armasu299, Sebastian M.; Pankratz300, Nathan; Jackson301, Rabecca D.; Nielsen302, Jonas B.; Giulianini62, Franco; Puurunen303, Marja K.; Ibrahim295, Manal; Heckbert123, Susan R.; 135, ; Bammler289, Theo K.; Frazer304, Kelly A.; Mccauley299, Bryan M.; Taylor305, Kent; Pankow306, James S.; Reiner123, Alexander P.; 280, ; Gabrielsen298, Maiken E.; Deleuze307, Jean-François; O'Donnell308, Chris J.; Kim297, Jihye; Mcknight58, Barbara; 280, ; Kraft297, Peter; Hansen298, John-Bjarne; Rosendaal291, Frits R.; Heit299, John A.; Tang306, Weihong; Morange309, Pierre-Emmanuel; Johnson296, Andrew D.; Kabrhel310, Christopher; Mishra1, Aniket; Malik2, Rainer; Chauhan24, Ganesh; Chong25, Michael R.; 26, ; Tomppo27, Liisa; Ago50, Tetsuro; Amouyel51, Philippe; 53, 52; Bartz57, Traci M.; 58, ; Ridker62, Paul M.; 63, ; Cruchaga65, Carlos; 66, ; Cole67, John W.; 68, ; Gudnason76, Vilmundur; 77, ; Hata78, Jun; Havulinna, Aki S.; 81, 80; Hopewell82, Jemma C.; Hyacinth83, Hyacinth I.; Jern90, Christina; 91, ; Kamouchi92, Masahiro; Keene93, Keith L.; Kitazono50, Takanari; Kittner68, Steven J.; 94, ; Manichaikul44, Ani; Markus103, Hugh S.; Mitchell106, Braxton D.; 107, ; Mosley110, Thomas H.; Nalls41, Mike A.; 43, 42; O'Donnell113, Martin J.; Okada6, Yukinori; 115, 114; 117, 116; 118, ; Psaty57, Bruce M.; 124, 123; Rich44, Stephen S.; Rosand12, Jonathan; 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Stroke genetics informs drug discovery and risk prediction across ancestries
Alessandro PezziniMembro del Collaboration Group
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2022-01-01
Abstract
: Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
