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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)

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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 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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