Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes / R. Malik, G. Chauhan, M. Traylor, M. Sargurupremraj, Y. Okada, A. Mishra, L. Rutten-Jacobs, A.-. Giese, S.W. Van Der Laan, S. Gretarsdottir, C.D. Anderson, M. Chong, H.H.H. Adams, T. Ago, P. Almgren, P. Amouyel, H. Ay, T.M. Bartz, O.R. Benavente, S. Bevan, G.B. Boncoraglio, R.D. Brown, A.S. Butterworth, C. Carrera, C.L. Carty, D.I. Chasman, W.-. Chen, J.W. Cole, A. Correa, I. Cotlarciuc, C. Cruchaga, J. Danesh, P.I.W. De Bakker, A.L. Destefano, M. Den Hoed, Q. Duan, S.T. Engelter, G.J. Falcone, R.F. Gottesman, R.P. Grewal, V. Gudnason, S. Gustafsson, J. Haessler, T.B. Harris, A. Hassan, A.S. Havulinna, S.R. Heckbert, E.G. Holliday, G. Howard, F.-. Hsu, H.I. Hyacinth, M.A. Ikram, E. Ingelsson, M.R. Irvin, X. Jian, J. Jimenez-Conde, J.A. Johnson, J.W. Jukema, M. Kanai, K.L. Keene, B.M. Kissela, D.O. Kleindorfer, C. Kooperberg, M. Kubo, L.A. Lange, C.D. Langefeld, C. Langenberg, L.J. Launer, J.-. Lee, R. Lemmens, D. Leys, C.M. Lewis, W.-. Lin, A.G. Lindgren, E. Lorentzen, P.K. Magnusson, J. Maguire, A. Manichaikul, P.F. McArdle, J.F. Meschia, B.D. Mitchell, T.H. Mosley, M.A. Nalls, T. Ninomiya, M.J. O'Donnell, B.M. Psaty, S.L. Pulit, K. Rannikmae, A.P. Reiner, K.M. Rexrode, K. Rice, S.S. Rich, P.M. Ridker, N.S. Rost, P.M. Rothwell, J.I. Rotter, T. Rundek, R.L. Sacco, S. Sakaue, M.M. Sale, V. Salomaa, B.R. Sapkota, R. Schmidt, C.O. Schmidt, U. Schminke, P. Sharma, A. Slowik, C.L.M. Sudlow, C. Tanislav, T. Tatlisumak, K.D. Taylor, V.N.S. Thijs, G. Thorleifsson, U. Thorsteinsdottir, S. Tiedt, S. Trompet, C. Tzourio, C.M. Van Duijn, M. Walters, N.J. Wareham, S. Wassertheil-Smoller, J.G. Wilson, K.L. Wiggins, Q. Yang, S. Yusuf, J.C. Bis, T. Pastinen, A. Ruusalepp, E.E. Schadt, S. Koplev, J.L.M. Bjorkegren, V. Codoni, M. Civelek, N.L. Smith, D.A. Tregouet, I.E. Christophersen, C. Roselli, S.A. Lubitz, P.T. Ellinor, E.S. Tai, J.S. Kooner, N. Kato, J. He, P. Van Der Harst, P. Elliott, J.C. Chambers, F. Takeuchi, A.D. Johnson, D.K. Sanghera, O. Melander, C. Jern, D. Strbian, I. Fernandez-Cadenas, W.T. Longstreth, A. Rolfs, J. Hata, D. Woo, J. Rosand, G. Pare, J.C. Hopewell, D. Saleheen, K. Stefansson, B.B. Worrall, S.J. Kittner, S. Seshadri, M. Fornage, H.S. Markus, J.M.M. Howson, Y. Kamatani, S. Debette, M. Dichgans, N. Amin, H.S. Aparicio, D.K. Arnett, J. Attia, A.S. Beiser, C. Berr, J.E. Buring, M. Bustamante, V. Caso, Y.-. Cheng, S.H. Choi, A. Chowhan, N. Cullell, J.-. Dartigues, H. Delavaran, P. Delgado, M. Dorr, G. Engstrom, I. Ford, W.S. Gurpreet, A. Hamsten, L. Heitsch, A. Hozawa, L. Ibanez, A. Ilinca, M. Ingelsson, M. Iwasaki, R.D. Jackson, K. Jood, P. Jousilahti, S. Kaffashian, L. Kalra, M. Kamouchi, T. Kitazono, O. Kjartansson, M. Kloss, P.J. Koudstaal, J. Krupinski, D.L. Labovitz, C.C. Laurie, C.R. Levi, L. Li, L. Lind, C.M. Lindgren, V. Lioutas, Y.M. Liu, O.L. Lopez, H. Makoto, N. Martinez-Majander, K. Matsuda, N. Minegishi, J. Montaner, A.P. Morris, E. Muino, M. Muller-Nurasyid, B. Norrving, S. Ogishima, E.A. Parati, L.R. Peddareddygari, N.L. Pedersen, J. Pera, M. Perola, A. Pezzini, S. Pileggi, R. Rabionet, I. Riba-Llena, M. Ribases, J.R. Romero, J. Roquer, A.G. Rudd, A.-. Sarin, R. Sarju, C. Sarnowski, M. Sasaki, C.L. Satizabal, M. Satoh, N. Sattar, N. Sawada, G. Sibolt, A. Sigurdsson, A. Smith, K. Sobue, C. Soriano-Tarraga, T. Stanne, O.C. Stine, D.J. Stott, K. Strauch, T. Takai, H. Tanaka, K. Tanno, A. Teumer, L. Tomppo, N.P. Torres-Aguila, E. Touze, S. Tsugane, A.G. Uitterlinden, E.M. Valdimarsson, S.J. Van Der Lee, H. Volzke, K. Wakai, D. Weir, S.R. Williams, C.D.A. Wolfe, Q. Wong, H. Xu, T. Yamaji. - In: NATURE GENETICS. - ISSN 1061-4036. - 50:4(2018 Apr), pp. 524-537. [10.1038/s41588-018-0058-3]

Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

S. Pileggi;
2018-04

Abstract

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.
Computational Biology; Databases, Genetic; Epigenesis, Genetic; Female; Gene Regulatory Networks; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; INDEL Mutation; Linkage Disequilibrium; Male; Models, Genetic; Polymorphism, Single Nucleotide; Risk Factors; Stroke
Settore BIO/11 - Biologia Molecolare
Settore MED/03 - Genetica Medica
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/726055
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