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

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

doi:10.1038/s41588-018-0058-3

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

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

2018

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.

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	Parole chiave
	
			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
		
	Settori scientifico-disciplinari dell'articolo
	
			Settore BIO/11 - Biologia Molecolare
Settore MED/03 - Genetica Medica
		
	Data di pubblicazione
	
			apr-2018
		
	Rivista in ANCE
	
			NATURE GENETICS
		
	DOI
	
			https://dx.doi.org/10.1038/s41588-018-0058-3
		
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			01 - Articolo su periodico

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