Stroke genetics informs drug discovery and risk prediction across ancestries
Salomaa Veikko; Akinyemi Rufus; Kissela BM; Jousilahti P; Williams SR; Heath Alicia K.; Magnusson PK; Delgado-Mederos R; Hopewell Jemma C.; Luijckx GJ; Pozarickij A; McKnight B; Walters M; Delavaran H; Armasu SM; Lindgren AG; Gretarsdottir S; Pattee JW; Heuch I; Holliday EG; Gurpreet WS; Amouyel Philippe; Pankratz N; Deleuze JF; Cotlarciuc I; Braekkan SK; Strbian Daniel; Kamouchi Masahiro; Cho Kelly; van Setten J; Furie KL; Cushman M; Lee Keon-Joo; Wahab K; Vaura Felix C.; Soriano-Tarraga C; Launer Lenore J.; Haeusler Karl Georg; Yamaji T; Schmidt Carsten O.; Stine OC; Paré Guillaume; Lathrop G. Mark; Debette Stephanie; Berr C; Bastarache Lisa; Wakai K; Haessler J; Suchon P; Riaz Moeen; Lewis CM; Schmidt D; Aparicio HJ; Anderson Christopher D.; Kristoffersen ES; McArdle PF; Uitterlinden AG; Tomppo Liisa; Uvere E; Rissanen Ina L.; Gieger Christian; Ago Tetsuro; Lledos M; Morisaki Takayuki; Hveem K; Sandset Else Charlotte; Kappelle LJ; Niiranen Teemu J.; Yoon Kyungheon; Ingelsson E; Brown RD; Alvarez-Sabin J; Dartigues JF; Weir D; Fairhurst-Hunter Z; Bartz Traci M.; Tsugane S; Obach V; Ninomiya Toshiharu; van Vugt Marion; Pulit SL; Onland-Moret N. Charlotte; Lv J; Giulianini F; Hsu FC; Kinnunen J; Adams Hieab; Montellano Felipe A.; Parodi Livia; Chen YP; Ikram MK; Hachiya Tsuyoshi; Geerlings MI; Yang Qiong; Millan M; Akpalu A; Rexrode KM; Manichaikul Ani; Delgado P; Wassertheil-Smoller Sylvia; Rothwell PM; Mitchell Braxton D.; Jensen GB; Leys D; Dichgans Martin; Sutoh Yoichi; Jood K; Koudstaal PJ; Zhou W; Ridker Paul M.; Arenillas JF; Duan Q; Sigurdsson A; Kumar Amit; Howard G; Chowhan A; Sargurupremraj Muralidharan; Kabrhel C; Gallego-Fabrega C; Attia J; MacDonald J; Tang WH; Lorentzen E; Kleindorfer DO; Kamanu Frederick K.; Ungethum K; Sarnowski C; Rich Stephen S.; Lemmons R; Norrving B; Muino E; Chauhan Ganesh; Marti-Fabregas J; Heit JA; Agunloye A; Owolabi Mayowa O.; Trompet Stella; Frikke-Schmidt Ruth; Sarfo FS; Lopez OL; Campos F; Chen WM; Fongang B; Sapkota BR; Sale MM; Adeoye AM; Konuma Takahiro; Bis Joshua C.; Yang CR; Minegishi N; Maguire J; Lee TH; Romero JR; Cain Anael; Touze E; Smith Nicholas L.; Abedi Vida; Mayerhofer Ernst; Fornage Myriam; Cárcel-Márquez Jara; Akinyemi J; Bae Hee-Joon; Vibo Riina; Srinivasasainagendra Vinodh; Rost NS; Li Liming; Llucia-Carol L; Chasman Daniel I.; Segura T; de Bakker PIW; Kanai M; Melander O; Onland-Moret NC; Wareham NJ; Posner Daniel C.; van Rooij FGW; Woo Daniel; de Leeuw Frank-Erik; Lewis Adam J.; Koido Masaru; Ingelsson M; Peddareddygari LR; Wang RQ; Gabrielsen ME; de Laat KF; Wang C; Lacaze Paul; Brody JA; Schminke U; Keene Keith L.; Clarke R; Akpa O; Boerwinkle E; Shiroma EJ; Obiako R; Puurunen MK; Nygaard Marianne; Bis JC; Roshchupkin Gennady V.; Wang L; Munoz-Narbona L; Okada Yukinori; Reiner A; Muller-Nurasyid M; Chen Zhengming; Nederkoorn PJ; Bustamante M; Kitazono Takanari; Bordes Constance; Matsuda K; Rotter Jerome I.; Gasca Natalie C.; de Leeuw FE; de Cid Rafael; Gasca NC; Stott DJ; Murakami Y; Thomassen Jesper Qvist; Olalere A; Gons RAR; Lin Kuang; Shi Mingyang; Sung YJ; Jimenez-Conde J; Saillour-Glenisson F; Lindstrom S; Liaw Yung-Po; Ford I; Sakaue S; Heitsch L; Tzourio C; Traylor M; Gordon W; Tanno Kozo; Metspalu A; Rabionet R; Chong Michael R.; Turnbull I; Grabe Hans J.; Jenkins C; Chen JS; Stevens B; Kaffashian S; Hata Jun; Frantz S; Volzke H; He Jing; Nielsen JB; Heath AK; Afzal S; van Dijk GW; Pezzini A; Lind L; Buring JE; Gudnason Vilmundur; Teumer A; Sabatine Marc S.; Strauch K; Blay N; Hansen JB; Ferreira Leslie E.; Cole John W.; Ellekjaer H; DeStefano AL; Nelis M; Knol Maria J.; Seshadri Sudha; Slowik A; Frazer KA; Zonderman AB; Winsvold Bendik Slagsvold; Volker U; Morange PE; Ovbiagele Bruce; Wilson Peter W. F.; Jürgenson Tuuli; Satoh M; Sigurdsson S; Hill M; Choi SH; Judy Renae L.; McDonough CW; Willer CJ; Krupinski J; Wolfe CDA; Sumoy L; Arulogun O; Adebajo OJ; Esko T; Correa A; Gottesman RF; Ogbole G; Yang Chaojie; Georgakis Marios K.; Zwart John-Anker; Worrall Bradford B.; Zand Ramin; Lin WY; Carrera C; Lioutas V; Liman Thomas; Heckbert SR; Carty CL; Aamodt AH; Irvin Marguerite R.; Ross OA; Inouye Michael; Owolabi L; Diaz-Navarro R; Leonard Hampton L.; Sharma P; Gustafsson S; Levi CR; Turman C; Labovitz DL; Kõrv Janika; Verma Stefali S.; Simonsick Eleanor M.; van Oostenbrugge RJ; Parati EA; Habib Naomi; Ghanbari M; O'Donnell CJ; Krebs Kristi; Benavente OR; Laurie CC; Danesh J; Visser MC; Marston Nicholas A.; Børte Sigrid; Kloss M; Thorleifsson G; Hyacinth Hyacinth I.; Montaner J; Curtze S; Hamsten A; Pedersen LM; Nagai A; Jern Christina; Gudnason V; Hassan A; Jackson RD; Thomas LF; Saleheen Danish; Vives-Bauza C; Anderson CD; Heuschmann Peter Ulrich; Malik Rainer; Xu Huichun; Harris TB; Boncoraglio GB; Jeon Christina E.; de Kort PL; Falcone GJ; Rannikmae K; Kooperberg C; Pera J; Le Grand Q; Liaw Yi-Ching; Nordestgaard Børge G.; Dorr M; Collins R; Freijo M; Chen MH; Tanislav C; Perola M; Sanghera DK; Fritsche LG; van Duijn CM; Ho Yuk-Lam; Martinsen AE; van der Laan SW; Tiainen M; Yusuf S; Hagen K; Armstrong Nicole D.; Kalra L; Iwasaki M; Ruigrok Ynte M.; Wiggins Kerri L.; Ribases M; Lemmens R; Wong QN; Bell S; Ilinca A; Endres Matthias; Kamstrup PR; Osaigbovo G; Pankow JS; Meitinger Thomas; Ikram Mohammad A.; Markus Hugh S.; Kraft P; Engstrom G; França Paulo H. C.; de Jager PL; Kittner Steven J.; Giese AK; Jukema J. Wouter; Putaala J; Longstreth W. T.; van Vugt M; Vlieg AV; McCauley BM; Jian XQ; Cullell N; Prats-Sanchez L; Le Grand Quentin; Sarin AP; den Hoed M; Nalls Mike A.; Soderholm M; Rutten-Jacobs L; Menon V; van Dijk EJ; Liu YM; Walters Robin G.; Cheng YC; Komolafe M; Magi R; Li LN; Tatlisumak Turgut; Tybjærg-Hansen Anne; Tuladhar Anil Man; Lindgren CM; Grewal RP; Ogishima S; Jung Keum J.; Smith EN; Camps-Renom P; Johnson AD; Irvin MR; Thijs VNS; Sacco Ralph L.; Evans MK; Lange LA; Smith A; Benn M; Ferreira LE; Johnson JA; Rosendaal FR; van Norden AGW; Meschia JF; Kleinschnitz C; Sobue K; Geerlings Mirjam I.; Sloane Kelly L.; Valdimarsson EM; Rosand Jonathan; Wermer MJH; Hozawa A; Bennett David A.; Engelter ST; Sarju R; Sasaki Makoto; Nordestgaard BG; Reiner AP; Lepik Kaido; Schmidt R; Shimizu Atsushi; Rudd AG; Langefeld CD; Psaty Bruce M.; Wennberg Patrik; Caso V; Tanaka H; Arnett DK; Brumpton BM; Thorsteinsdottir U; Takai T; Damrauer Scott M.; Kim J; Morris AP; Chen Pei-Hsin; Verma SS; Mishra Aniket; Ibrahim M; Vermeer SE; Stanne TM; Sawada N; Howson Joanna M. M.; Lee JM; Christensen Kaare; Fernández-Cadenas Israel; Sibolt G; Kim Young Jin; Ribo M; Amin N; Guo Y; de Jager Phil L.; O'Donnell Martin J.; Yu CQ; Rolfs A; Kamatani Yoichiro; Germain M; Peters Annette; de Andrade M; Sobrino T; Butterworth AS; Taylor KD; Li Jiang; Cruchaga Carlos; Riba-Llena I; Sun Yan V.; Rundek Tatjana; Sudlow CLM; Lopez-Cancio E; Vonk JMJ; Fakunle AG; Torres-Aguila Nuria P.; Brouwers PJAM; Jacob Mina A.; Jee Yon Ho; de Cid R; Sargurupremraj M; Castillo J; Namba Shinichi; Dhar R; Caro Ilana; Milani Lili; Tiwari Hemant K.; Bakker Mark K.; Ay H; Martinez-Majander N; Yaffe K; Pileggi S; Prasad Kameshwar; Bevan S; Peto R; Beiser AS; Yonova-Doing Ekaterina; Kjartansson O; Ruff Christian T.; Tiedt Steffen; Almgren P; Serrano-Heras G; Makoto H; Trégouët David-Alexandre; Langenberg C; Rice K; den Heijer T; Stefansson K; Molina CA; Mosley Thomas H.; Satizabal Claudia L.; Wilson JG; Schnohr P; Huffman Jennifer E.; He Yunye; Millwood Iona Y.; Kim BJ; Kubo M; Pedersen NL; Bammler TK; van der Lee SJ; Roquer J; Ibanez L; Gravel S; Skogholt AH; Sattar N; Linkohr B; Havulinna Aki S.
Stroke genetics informs drug discovery and risk prediction across ancestries
NATURE PORTFOLIO
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.
Kokoelmat
- Rinnakkaistallenteet [19207]