Stroke genetics informs drug discovery and risk prediction across ancestries.

Mishra, A.; Malik, R.; Hachiya, T.; Jürgenson, T.; Namba, S.; Posner, D.C.; Kamanu, F.K.; Koido, M.; Le Grand, Q.; Shi, M.; He, Y.; Georgakis, M.K.; Caro, I.; Krebs, K.; Liaw, Y.C.; Vaura, F.C.; Lin, K.; Winsvold, B.S.; Srinivasasainagendra, V.; Parodi, L.; Bae, H.J.; Chauhan, G.; Chong, M.R.; Tomppo, L.; Akinyemi, R.; Roshchupkin, G.V.; Habib, N.; Jee, Y.H.; Thomassen, J.Q.; Abedi, V.; Cárcel-Márquez, J.; Nygaard, M.; Leonard, H.L.; Yang, C.; Yonova-Doing, E.; Knol, M.J.; Lewis, A.J.; Judy, R.L.; Ago, T.; Amouyel, P.; Armstrong, N.D.; Bakker, M.K.; Bartz, T.M.; Bennett, D.A.; Bis, J.C.; Bordes, C.; Børte, S.; Cain, A.; Ridker, P.M.; Cho, K.; Chen, Z.; Cruchaga, C.; Cole, J.W.; de Jager, P.L.; de Cid, R.; Endres, M.; Ferreira, L.E.; Geerlings, M.I.; Gasca, N.C.; Gudnason, V.; Hata, J.; He, J.; Heath, A.K.; Ho, Y.L.; Havulinna, A.S.; Hopewell, J.C.; Hyacinth, H.I.; Inouye, M.; Jacob, M.A.; Jeon, C.E.; Jern, C.; Kamouchi, M.; Keene, K.L.; Kitazono, T.; Kittner, S.J.; Konuma, T.; Kumar, A.; Lacaze, P.; Launer, L.J.; Lee, K.J.; Lepik, K.; Li, J.; Li, L.; Manichaikul, A.; Markus, H.S.; Marston, N.A.; Meitinger, T.; Mitchell, B.D.; Montellano, F.A.; Morisaki, T.; Mosley, T.H.; Nalls, M.A.; Nordestgaard, B.G.; O'Donnell, M.J.; Okada, Y.; Onland-Moret, N.C.; Ovbiagele, B.; Peters, A.; Psaty, B.M.; Rich, S.S.; Rosand, J.; Sabatine, M.S.; Sacco, R.L.; Saleheen, D.; Sandset, E.C.; Salomaa, V.; Sargurupremraj, M.; Sasaki, M.; Satizabal, C.L.; Schmidt, C.O.; Shimizu, A.; Smith, N.L.; Sloane, K.L.; Sutoh, Y.; Sun, Y.V.; Tanno, K.; Tiedt, S.; Tatlisumak, T.; Torres-Aguila, N.P.; Tiwari, H.K.; Trégouët, D.A.; Trompet, S.; Tuladhar, A.M.; Tybjærg-Hansen, A.; van Vugt, M.; Vibo, R.; Verma, S.S.; Wiggins, K.L.; Wennberg, P.; Woo, D.; Wilson, PWF; Xu, H.; Yang, Q.; Yoon, K.; Millwood, I.Y.; Gieger, C.; Ninomiya, T.; Grabe, H.J.; Jukema, J.W.; Rissanen, I.L.; Strbian, D.; Kim, Y.J.; Chen, P.H.; Mayerhofer, E.; Howson, JMM; Irvin, M.R.; Adams, H.; Wassertheil-Smoller, S.; Christensen, K.; Ikram, M.A.; Rundek, T.; Worrall, B.B.; Lathrop, G.M.; Riaz, M.; Simonsick, E.M.; Kõrv, J.; França, PHC; Zand, R.; Prasad, K.; Frikke-Schmidt, R.; de Leeuw, F.E.; Liman, T.; Haeusler, K.G.; Ruigrok, Y.M.; Heuschmann, P.U.; Longstreth, W.T.; Jung, K.J.; Bastarache, L.; Paré, G.; Damrauer, S.M.; Chasman, D.I.; Rotter, J.I.; Anderson, C.D.; Zwart, J.A.; Niiranen, T.J.; Fornage, M.; Liaw, Y.P.; Seshadri, S.; Fernández-Cadenas, I.; Walters, R.G.; Ruff, C.T.; Owolabi, M.O.; Huffman, J.E.; Milani, L.; Kamatani, Y.; Dichgans, M.; Debette, S.

doi:10.1038/s41586-022-05165-3

Stroke genetics informs drug discovery and risk prediction across ancestries.

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Serval ID

serval:BIB_AC35CD14FB1F

Type

Article: article from journal or magazin.

Collection

Publications

Institution

UNIL/CHUV

Title

Stroke genetics informs drug discovery and risk prediction across ancestries.

Journal

Nature

Author(s)

Mishra A., Malik R., Hachiya T., Jürgenson T., Namba S., Posner D.C., Kamanu F.K., Koido M., Le Grand Q., Shi M., He Y., Georgakis M.K., Caro I., Krebs K., Liaw Y.C., Vaura F.C., Lin K., Winsvold B.S., Srinivasasainagendra V., Parodi L., Bae H.J., Chauhan G., Chong M.R., Tomppo L., Akinyemi R., Roshchupkin G.V., Habib N., Jee Y.H., Thomassen J.Q., Abedi V., Cárcel-Márquez J., Nygaard M., Leonard H.L., Yang C., Yonova-Doing E., Knol M.J., Lewis A.J., Judy R.L., Ago T., Amouyel P., Armstrong N.D., Bakker M.K., Bartz T.M., Bennett D.A., Bis J.C., Bordes C., Børte S., Cain A., Ridker P.M., Cho K., Chen Z., Cruchaga C., Cole J.W., de Jager P.L., de Cid R., Endres M., Ferreira L.E., Geerlings M.I., Gasca N.C., Gudnason V., Hata J., He J., Heath A.K., Ho Y.L., Havulinna A.S., Hopewell J.C., Hyacinth H.I., Inouye M., Jacob M.A., Jeon C.E., Jern C., Kamouchi M., Keene K.L., Kitazono T., Kittner S.J., Konuma T., Kumar A., Lacaze P., Launer L.J., Lee K.J., Lepik K., Li J., Li L., Manichaikul A., Markus H.S., Marston N.A., Meitinger T., Mitchell B.D., Montellano F.A., Morisaki T., Mosley T.H., Nalls M.A., Nordestgaard B.G., O'Donnell M.J., Okada Y., Onland-Moret N.C., Ovbiagele B., Peters A., Psaty B.M., Rich S.S., Rosand J., Sabatine M.S., Sacco R.L., Saleheen D., Sandset E.C., Salomaa V., Sargurupremraj M., Sasaki M., Satizabal C.L., Schmidt C.O., Shimizu A., Smith N.L., Sloane K.L., Sutoh Y., Sun Y.V., Tanno K., Tiedt S., Tatlisumak T., Torres-Aguila N.P., Tiwari H.K., Trégouët D.A., Trompet S., Tuladhar A.M., Tybjærg-Hansen A., van Vugt M., Vibo R., Verma S.S., Wiggins K.L., Wennberg P., Woo D., Wilson PWF, Xu H., Yang Q., Yoon K., Millwood I.Y., Gieger C., Ninomiya T., Grabe H.J., Jukema J.W., Rissanen I.L., Strbian D., Kim Y.J., Chen P.H., Mayerhofer E., Howson JMM, Irvin M.R., Adams H., Wassertheil-Smoller S., Christensen K., Ikram M.A., Rundek T., Worrall B.B., Lathrop G.M., Riaz M., Simonsick E.M., Kõrv J., França PHC, Zand R., Prasad K., Frikke-Schmidt R., de Leeuw F.E., Liman T., Haeusler K.G., Ruigrok Y.M., Heuschmann P.U., Longstreth W.T., Jung K.J., Bastarache L., Paré G., Damrauer S.M., Chasman D.I., Rotter J.I., Anderson C.D., Zwart J.A., Niiranen T.J., Fornage M., Liaw Y.P., Seshadri S., Fernández-Cadenas I., Walters R.G., Ruff C.T., Owolabi M.O., Huffman J.E., Milani L., Kamatani Y., Dichgans M., Debette S.

Working group(s)

COMPASS Consortium, INVENT Consortium, Dutch Parelsnoer Initiative (PSI) Cerebrovascular Disease Study Group, Estonian Biobank, PRECISE4Q Consortium, FinnGen Consortium, NINDS Stroke Genetics Network (SiGN), MEGASTROKE Consortium, SIREN Consortium, China Kadoorie Biobank Collaborative Group, VA Million Veteran Program, International Stroke Genetics Consortium (ISGC), Biobank Japan, CHARGE Consortium, GIGASTROKE Consortium

Contributor(s)

Bis J.C., Lee J.M., Cheng Y.C., Meschia J.F., Chen W.M., Sale M.M., Zonderman A.B., Evans M.K., Wilson J.G., Correa A., Traylor M., Lewis C.M., Carty C.L., Reiner A., Haessler J., Langefeld C.D., Gottesman R.F., Yaffe K., Liu Y.M., Kooperberg C., Lange L.A., Furie K.L., Arnett D.K., Benavente O.R., Grewal R.P., Peddareddygari L.R., Kooperberg C., Hveem K., Lindstrom S., Wang L., Smith E.N., Gordon W., van Hylckama Vlieg A., de Andrade M., Brody J.A., Pattee J.W., Haessler J., Brumpton B.M., Suchon P., Chen M.H., Frazer K.A., Turman C., Germain M., MacDonald J., Braekkan S.K., Armasu S.M., Pankratz N., Jackson R.D., Nielsen J.B., Giulianini F., Puurunen M.K., Ibrahim M., Heckbert S.R., Bammler T.K., McCauley B.M., Taylor K.D., Pankow J.S., Reiner A.P., Gabrielsen M.E., Deleuze J.F., O'Donnell C.J., Kim J., McKnight B., Kraft P., Hansen J.B., Rosendaal F.R., Heit J.A., Tang W., Morange P.E., Johnson A.D., Kabrhel C., van Dijk E.J., Koudstaal P.J., Luijckx G.J., Nederkoorn P.J., van Oostenbrugge R.J., Visser M.C., Wermer MJH, Kappelle L.J., Esko T., Metspalu A., Mägi R., Nelis M., Irvin M.R., de Leeuw F.E., Levi C.R., Maguire J., Jiménez-Conde J., Sharma P., Sudlow CLM, Rannikmäe K., Schmidt R., Slowik A., Pera J., Thijs VNS, Lindgren A.G., Ilinca A., Melander O., Engström G., Rexrode K.M., Rothwell P.M., Stanne T.M., Johnson J.A., Danesh J., Butterworth A.S., Heitsch L., Boncoraglio G.B., Kubo M., Pezzini A., Rolfs A., Giese A.K., Weir D., Jackson R.D., Ross O.A., Lemmons R., Soderholm M., Cushman M., Jood K., McDonough C.W., Bell S., Linkohr B., Lee T.H., Putaala J., Anderson C.D., Lopez O.L., Jian X., Schminke U., Cullell N., Delgado P., Ibañez L., Krupinski J., Lioutas V., Matsuda K., Montaner J., Muiño E., Roquer J., Sarnowski C., Sattar N., Sibolt G., Teumer A., Rutten-Jacobs L., Kanai M., Giese A.K., Gretarsdottir S., Rost N.S., Yusuf S., Almgren P., Ay H., Bevan S., Brown R.D., Carrera C., Buring J.E., Chen W.M., Cotlarciuc I., de Bakker PIW, DeStefano A.L., den Hoed M., Duan Q., Engelter S.T., Falcone G.J., Gottesman R.F., Gustafsson S., Hassan A., Holliday E.G., Howard G., Hsu F.C., Ingelsson E., Harris T.B., Kissela B.M., Kleindorfer D.O., Langenberg C., Lemmens R., Leys D., Lin W.Y., Lorentzen E., Magnusson P.K., McArdle P.F., Pulit S.L., Rice K., Sakaue S., Sapkota B.R., Tanislav C., Thorleifsson G., Thorsteinsdottir U., Tzourio C., van Duijn C.M., Walters M., Wareham N.J., Amin N., Aparicio H.J., Attia J., Beiser A.S., Berr C., Bustamante M., Caso V., Choi S.H., Chowhan A., Dartigues J.F., Delavaran H., Dörr M., Ford I., Gurpreet W.S., Hamsten A., Hozawa A., Ingelsson M., Iwasaki M., Kaffashian S., Kalra L., Kjartansson O., Kloss M., Labovitz D.L., Laurie C.C., Li L., Lind L., Lindgren C.M., Makoto H., Minegishi N., Morris A.P., Müller-Nurasyid M., Norrving B., Ogishima S., Parati E.A., Pedersen N.L., Perola M., Jousilahti P., Pileggi S., Rabionet R., Riba-Llena I., Ribasés M., Romero J.R., Rudd A.G., Sarin A.P., Sarju R., Satoh M., Sawada N., Sigurdsson Á., Smith A., Stine O.C., Stott D.J., Strauch K., Takai T., Tanaka H., Touze E., Tsugane S., Uitterlinden A.G., Valdimarsson E.M., van der Lee S.J., Wakai K., Williams S.R., Wolfe CDA, Wong Q., Yamaji T., Sanghera D.K., Stefansson K., Taylor K.D., Martinez-Majander N., Sobue K., Soriano-Tárraga C., Völzke H., Akpa O., Sarfo F.S., Akpalu A., Obiako R., Wahab K., Osaigbovo G., Owolabi L., Komolafe M., Jenkins C., Arulogun O., Ogbole G., Adeoye A.M., Akinyemi J., Agunloye A., Fakunle A.G., Uvere E., Olalere A., Adebajo O.J., Chen J., Clarke R., Collins R., Guo Y., Wang C., Lv J., Peto R., Chen Y., Fairhurst-Hunter Z., Hill M., Pozarickij A., Schmidt D., Stevens B., Turnbull I., Yu C., Le Grand Q., Ferreira L.E., Nagai A., Murakami Y., Geerlings M.I., Gasca N.C., Gudnason V., van Vugt M., Gottesman R.F., Shiroma E.J., Sigurdsson S., Ghanbari M., Boerwinkle E., Beiser A.S., Fongang B., Wang R., Ikram M.K., Völker U., de Jager P.L., de Cid R., Nordestgaard B.G., Sargurupremraj M., Verma S.S., de Laat K.F., van Norden AGW, de Kort P.L., Vermeer S.E., Brouwers PJAM, Gons RAR, Nederkoorn P.J., den Heijer T., van Dijk G.W., van Rooij FGW, Aamodt A.H., Skogholt A.H., Brumpton B.M., Willer C.J., Heuch I., Hagen K., Fritsche L.G., Pedersen L.M., Gabrielsen M.E., Ellekjær H., Zhou W., Martinsen A.E., Kristoffersen E.S., Nielsen J.B., Hveem K., Thomas L.F., Kleinschnitz C., Frantz S., Ungethüm K., Gallego-Fabrega C., Lledós M., Llucià-Carol L., Sobrino T., Campos F., Castillo J., Freijó M., Arenillas J.F., Obach V., Álvarez-Sabín J., Molina C.A., Ribó M., Muñoz-Narbona L., Lopez-Cancio E., Millán M., Diaz-Navarro R., Vives-Bauza C., Serrano-Heras G., Segura T., Delgado P., Dhar R., Delgado-Mederos R., Prats-Sánchez L., Camps-Renom P., Blay N., Sumoy L., Martí-Fàbregas J., Schnohr P., Jensen G.B., Benn M., Afzal S., Kamstrup P.R., van Setten J., van der Laan S.W., Vonk JMJ, Kim B.J., Curtze S., Tiainen M., Kinnunen J., Menon V., Sung Y.J., Yang C., Saillour-Glenisson F., Gravel S., Onland-Moret N.C., Heath A.K.

ISSN

1476-4687 (Electronic)

ISSN-L

0028-0836

Publication state

Published

Issued date

11/2022

Peer-reviewed

Oui

Volume

611

Number

7934

Pages

115-123

Language

english

Notes

Publication types: Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish

Abstract

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.

Keywords

Humans, Brain Ischemia/genetics, Drug Discovery, Genetic Predisposition to Disease/genetics, Genome-Wide Association Study, Ischemic Stroke/genetics, Molecular Targeted Therapy, Multifactorial Inheritance, Europe/ethnology, Asia, Eastern/ethnology, Africa/ethnology

URN

urn:nbn:ch:serval-BIB_AC35CD14FB1F6

OAI-PMH

oai:serval.unil.ch:BIB_AC35CD14FB1F

DOI

10.1038/s41586-022-05165-3

Pubmed

36180795

Web of science

000862209300001

Open Access

Yes