Stroke genetics informs drug discovery and risk prediction across ancestries
Mishra Aniket; Malik Rainer; Hachiya Tsuyoshi; Jürgenson Tuuli; Namba Shinichi; Posner Daniel C.; Kamanu Frederick K.; Koido Masaru; Le Grand Quentin; Shi Mingyang; He Yunye; Georgakis Marios K.; Caro Ilana; Krebs Kristi; Liaw Yi-Ching; Vaura Felix C.; Lin Kuang; Winsvold Bendik Slagsvold; Srinivasasainagendra Vinodh; Parodi Livia; Bae Hee-Joon; Chauhan Ganesh; Chong Michael R.; Tomppo Liisa; Akinyemi Rufus; Roshchupkin Gennady V.; Habib Naomi; Jee Yon Ho; Thomassen Jesper Qvist; Abedi Vida; Cárcel-Márquez Jara; Nygaard Marianne; Leonard Hampton L.; Yang Chaojie; Yonova-Doing Ekaterina; Knol Maria J.; Lewis Adam J.; Judy Renae L.; Ago Tetsuro; Amouyel Philippe; Armstrong Nicole D.; Bakker Mark K.; Bartz Traci M.; Bennett David A.; Bis Joshua C.; Bordes Constance; Børte Sigrid; Cain Anael; Ridker Paul M.; Cho Kelly; Chen Zhengming; Cruchaga Carlos; Cole John W.; de Jager Phil L.; de Cid Rafael; Endres Matthias; Ferreira Leslie E.; Geerlings Mirjam I.; Gasca Natalie C.; Gudnason Vilmundur; Hata Jun; He Jing; Heath Alicia K.; Ho Yuk-Lam; Havulinna Aki S.; Hopewell Jemma C.; Hyacinth Hyacinth I.; Inouye Michael; Jacob Mina A.; Jeon Christina E.; Jern Christina; Kamouchi Masahiro; Keene Keith L.; Kitazono Takanari; Kittner Steven J.; Konuma Takahiro; Kumar Amit; Lacaze Paul; Launer Lenore J.; Lee Keon-Joo; Lepik Kaido; Li Jiang; Li Liming; Manichaikul Ani; Markus Hugh S.; Marston Nicholas A.; Meitinger Thomas; Mitchell Braxton D.; Montellano Felipe A.; Morisaki Takayuki; Mosley Thomas H.; Nalls Mike A.; Nordestgaard Børge G.; O'Donnell Martin J.; Okada Yukinori; Onland-Moret N. 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F.; Xu Huichun; Yang Qiong; Yoon Kyungheon; Bis JC; Bis JC; Lee JM; Cheng YC; Meschia JF; Chen WM; Sale MM; Zonderman AB; Evans MK; Wilson JG; Correa A; Traylor M; Lewis CM; Carty CL; Reiner A; Haessler J; Langefeld CD; Gottesman RF; Yaffe K; Liu YM; Kooperberg C; Lange LA; Furie KL; Arnett DK; Benavente OR; Grewal RP; Peddareddygari LR; Kooperberg C; Kooperberg C; Hveem K; Lindstrom S; Wang L; Smith EN; Gordon W; Vlieg AV; de Andrade M; Brody JA; Pattee JW; Haessler J; Brumpton BM; Suchon P; Chen MH; Frazer KA; Turman C; Germain M; MacDonald J; Braekkan SK; Armasu SM; Pankratz N; Jackson RD; Nielsen JB; Giulianini F; Puurunen MK; Ibrahim M; Heckbert SR; Bammler TK; McCauley BM; Taylor KD; Pankow JS; Reiner AP; Gabrielsen ME; Deleuze JF; O'Donnell CJ; Kim J; McKnight B; Kraft P; Hansen JB; Rosendaal FR; Heit JA; Tang WH; Morange PE; Johnson AD; Kabrhel C; van Dijk EJ; van Dijk EJ; Koudstaal PJ; Luijckx GJ; Nederkoorn PJ; van Oostenbrugge RJ; Visser MC; Wermer MJH; Kappelle LJ; Esko T; Esko T; Metspalu A; Magi R; Nelis M; Irvin MR; Irvin MR; de Leeuw FE; Levi CR; Maguire J; Jimenez-Conde J; Sharma P; Sudlow CLM; Rannikmae K; Schmidt R; Slowik A; Pera J; Thijs VNS; Lindgren AG; Ilinca A; Melander O; Engstrom G; Rexrode KM; Rothwell PM; Stanne TM; Johnson JA; Danesh J; Butterworth AS; Heitsch L; Boncoraglio GB; Kubo M; Pezzini A; Rolfs A; Giese AK; Weir D; Jackson RD; Ross OA; Lemmons R; Soderholm M; Cushman M; Jood K; McDonough CW; Bell S; Linkohr B; Lee TH; Putaala J; Anderson CD; Anderson CD; Lopez OL; Jian XQ; Schminke U; Cullell N; Delgado P; Ibanez L; Krupinski J; Lioutas V; Matsuda K; Montaner J; Muino E; Roquer J; Sarnowski C; Sattar N; Sibolt G; Teumer A; Rutten-Jacobs L; Kanai M; Giese AK; Gretarsdottir S; Rost NS; Yusuf S; Almgren P; Ay H; Bevan S; Brown RD; Carrera C; Buring JE; Chen WM; Cotlarciuc I; de Bakker PIW; DeStefano AL; den Hoed M; Duan Q; Engelter ST; Falcone GJ; Gottesman RF; Gustafsson S; Hassan A; Holliday EG; Howard G; Hsu FC; Ingelsson E; Harris TB; Kissela BM; Kleindorfer DO; Langenberg C; Lemmens R; Leys D; Lin WY; Lorentzen E; Magnusson PK; McArdle PF; Pulit SL; Rice K; Sakaue S; Sapkota BR; Tanislav C; Thorleifsson G; Thorsteinsdottir U; Tzourio C; van Duijn CM; Walters M; Wareham NJ; Amin N; Aparicio HJ; Attia J; Beiser AS; Berr C; Bustamante M; Caso V; Choi SH; Chowhan A; Dartigues JF; Delavaran H; Dorr M; Ford I; Gurpreet WS; Hamsten A; Hozawa A; Ingelsson M; Iwasaki M; Kaffashian S; Kalra L; Kjartansson O; Kloss M; Labovitz DL; Laurie CC; Li LN; Lind L; Lindgren CM; Makoto H; Minegishi N; Morris AP; Muller-Nurasyid M; Norrving B; Ogishima S; Parati EA; Pedersen NL; Perola M; Jousilahti P; Pileggi S; Rabionet R; Riba-Llena I; Ribases M; Romero JR; Rudd AG; Sarin AP; Sarju R; Satoh M; Sawada N; Sigurdsson A; Smith A; Stine OC; Stott DJ; Strauch K; Takai T; Tanaka H; Touze E; Tsugane S; Uitterlinden AG; Valdimarsson EM; van der Lee SJ; Wakai K; Williams SR; Wolfe CDA; Wong QN; Yamaji T; Sanghera DK; Stefansson K; Taylor KD; Martinez-Majander N; Sobue K; Soriano-Tarraga C; Volzke H; Akpa O; Akpa O; Sarfo FS; Akpalu A; Obiako R; Wahab K; Osaigbovo G; Owolabi L; Komolafe M; Jenkins C; Arulogun O; Ogbole G; Adeoye AM; Akinyemi J; Agunloye A; Fakunle AG; Uvere E; Olalere A; Adebajo OJ; Chen JS; Chen JS; Clarke R; Collins R; Guo Y; Wang C; Lv J; Peto R; Chen YP; Fairhurst-Hunter Z; Hill M; Pozarickij A; Schmidt D; Stevens B; Turnbull I; Yu CQ; Le Grand Q; Le Grand Q; Ferreira LE; Nagai A; Nagai A; Murakami Y; Geerlings MI; Geerlings MI; Gasca NC; Gudnason V; van Vugt M; Gottesman RF; Shiroma EJ; Sigurdsson S; Ghanbari M; Boerwinkle E; Beiser AS; Fongang B; Wang RQ; Ikram MK; Volker U; de Jager PL; de Jager PL; de Cid R; Nordestgaard BG; Sargurupremraj M; Verma SS; de Laat KF; de Laat KF; van Norden AGW; de Kort PL; Vermeer SE; Brouwers PJAM; Gons RAR; Nederkoorn PJ; den Heijer T; van Dijk GW; van Rooij FGW; Aamodt AH; Aamodt AH; Skogholt AH; Brumpton BM; Willer CJ; Heuch I; Hagen K; Fritsche LG; Pedersen LM; Gabrielsen ME; Ellekjaer H; Zhou W; Martinsen AE; Kristoffersen ES; Nielsen JB; Hveem K; Thomas LF; Kleinschnitz C; Kleinschnitz C; Frantz S; Ungethum K; Gallego-Fabrega C; Gallego-Fabrega C; Lledos M; Llucia-Carol L; Sobrino T; Campos F; Castillo J; Freijo M; Arenillas JF; Obach V; Alvarez-Sabin J; Molina CA; Ribo M; Munoz-Narbona L; Lopez-Cancio E; Millan M; Diaz-Navarro R; Vives-Bauza C; Serrano-Heras G; Segura T; Delgado P; Dhar R; Delgado-Mederos R; Prats-Sanchez L; Camps-Renom P; Blay N; Sumoy L; Marti-Fabregas J; Schnohr P; Schnohr P; Jensen GB; Benn M; Afzal S; Kamstrup PR; van Setten J; van Setten J; van der Laan SW; Vonk JMJ; Kim BJ; Kim BJ; Curtze S; Curtze S; Tiainen M; Kinnunen J; Menon V; Menon V; Sung YJ; Yang CR; Saillour-Glenisson F; Gravel S; Onland-Moret NC; Onland-Moret NC; Heath AK; Millwood Iona Y.; Gieger Christian; Ninomiya Toshiharu; Grabe Hans J.; Jukema J. Wouter; Rissanen Ina L.; Strbian Daniel; Kim Young Jin; Chen Pei-Hsin; Mayerhofer Ernst; Howson Joanna M. M.; Irvin Marguerite R.; Adams Hieab; Wassertheil-Smoller Sylvia; Christensen Kaare; Ikram Mohammad A.; Rundek Tatjana; Worrall Bradford B.; Lathrop G. Mark; Riaz Moeen; Simonsick Eleanor M.; Kõrv Janika; França Paulo H. C.; Zand Ramin; Prasad Kameshwar; Frikke-Schmidt Ruth; de Leeuw Frank-Erik; Liman Thomas; Haeusler Karl Georg; Ruigrok Ynte M.; Heuschmann Peter Ulrich; Longstreth W. T.; Jung Keum J.; Bastarache Lisa; Paré Guillaume; Damrauer Scott M.; Chasman Daniel I.; Rotter Jerome I.; Anderson Christopher D.; Zwart John-Anker; Niiranen Teemu J.; Fornage Myriam; Liaw Yung-Po; Seshadri Sudha; Fernández-Cadenas Israel; Walters Robin G.; Ruff Christian T.; Owolabi Mayowa O.; Huffman Jennifer E.; Milani Lili; Kamatani Yoichiro; Dichgans Martin; Debette Stephanie
Stroke genetics informs drug discovery and risk prediction across ancestries
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Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2022122173006
https://urn.fi/URN:NBN:fi-fe2022122173006
Tiivistelmä
Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). 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 analysis(3), 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 approach(4), 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 ancestry(5). 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.
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