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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.* ; 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.D.* ; 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.* ; 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.* ; Tregouet, 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, P.W.F.* ; 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, J.M.M.* ; Irvin, M.R.* ; Adams, H.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, P.H.C.* ; 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. Jr.* ; 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.* ; Fernandez-Cadenas, I.* ; Walters, R.G.* ; Ruff, C.T.* ; Owolabi, M.O.* ; Huffman, J.E.* ; Milani, L.* ; Kamatani, Y.* ; Dichgans, M.* ; Debette, S.* ; MEGASTROKE Consortium (Müller-Nurasyid, M. ; Strauch, K.)

Stroke genetics informs drug discovery and risk prediction across ancestries.

Nature 611, 115-123 (2022)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords KORA, Herz-Kreislauf, Genetik, DZHK; Genome-wide Association; Mendelian Randomization; Polygenic Risk; Heritability; Statistics; Expression; Brain; Atlas; Regularization; Metaanalysis
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Journal Nature
Quellenangaben Volume: 611, Issue: 7934, Pages: 115-123 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)
Institute of Epidemiology II (EPI2)
Institute of Genetic Epidemiology (IGE)
Grants