Stroke genetics informs drug discovery and risk prediction across ancestries.
Creators: name: Mishra, Aniket
name: Malik, Rainer
name: Hachiya, Tsuyoshi
name: Jürgenson, Tuuli
name: Namba, Shinichi
name: Posner, Daniel C
name: Kamanu, Frederick K
name: Koido, Masaru
name: Le Grand, Quentin
name: Shi, Mingyang
name: He, Yunye
name: Georgakis, Marios K
name: Caro, Ilana
name: Krebs, Kristi
name: Liaw, Yi-Ching
name: Vaura, Felix C
name: Lin, Kuang
name: Winsvold, Bendik Slagsvold
name: Srinivasasainagendra, Vinodh
name: Parodi, Livia
name: Bae, Hee-Joon
name: Chauhan, Ganesh
name: Chong, Michael R
name: Tomppo, Liisa
name: Akinyemi, Rufus
name: Roshchupkin, Gennady V
name: Habib, Naomi
name: Jee, Yon Ho
name: Thomassen, Jesper Qvist
name: Abedi, Vida
name: Cárcel-Márquez, Jara
name: Nygaard, Marianne
name: Leonard, Hampton L
name: Yang, Chaojie
name: Yonova-Doing, Ekaterina
name: Knol, Maria J
name: Lewis, Adam J
name: Judy, Renae L
name: Ago, Tetsuro
name: Amouyel, Philippe
name: Armstrong, Nicole D
name: Bakker, Mark K
name: Bartz, Traci M
name: Bennett, David A
name: Bis, Joshua C
name: Bordes, Constance
name: Børte, Sigrid
name: Cain, Anael
name: Ridker, Paul M
name: Cho, Kelly
name: Chen, Zhengming
name: Cruchaga, Carlos
name: Cole, John W
name: De Jager, Phil L
name: De Cid, Rafael
name: Endres, Matthias
name: Ferreira, Leslie E
name: Geerlings, Mirjam I
name: Gasca, Natalie C
name: Gudnason, Vilmundur
name: Hata, Jun
name: He, Jing
name: Heath, Alicia K
name: Ho, Yuk-Lam
name: Havulinna, Aki S
name: Hopewell, Jemma C
name: Hyacinth, Hyacinth I
name: Inouye, Michael
name: Jacob, Mina A
name: Jeon, Christina E
name: Jern, Christina
name: Kamouchi, Masahiro
name: Keene, Keith L
name: Kitazono, Takanari
name: Kittner, Steven J
name: Konuma, Takahiro
name: Kumar, Amit
name: Lacaze, Paul
name: Launer, Lenore J
name: Lee, Keon-Joo
name: Lepik, Kaido
name: Li, Jiang
name: Li, Liming
name: Manichaikul, Ani
name: Markus, Hugh S
name: Marston, Nicholas A
name: Meitinger, Thomas
name: Mitchell, Braxton D
name: Montellano, Felipe A
name: Morisaki, Takayuki
name: Mosley, Thomas H
name: Nalls, Mike A
name: Nordestgaard, Børge G
name: O'Donnell, Martin J
name: Okada, Yukinori
name: Onland-Moret, N Charlotte
name: Ovbiagele, Bruce
name: Peters, Annette
name: Psaty, Bruce M
name: Rich, Stephen S
name: Rosand, Jonathan
name: Sabatine, Marc S
name: Sacco, Ralph L
name: Saleheen, Danish
name: Sandset, Else Charlotte
name: Salomaa, Veikko
name: Sargurupremraj, Muralidharan
name: Sasaki, Makoto
name: Satizabal, Claudia L
name: Schmidt, Carsten O
name: Shimizu, Atsushi
name: Smith, Nicholas L
name: Sloane, Kelly L
name: Sutoh, Yoichi
name: Sun, Yan V
name: Tanno, Kozo
name: Tiedt, Steffen
name: Tatlisumak, Turgut
name: Torres-Aguila, Nuria P
name: Tiwari, Hemant K
name: Trégouët, David-Alexandre
name: Trompet, Stella
name: Tuladhar, Anil Man
name: Tybjærg-Hansen, Anne
name: Van Vugt, Marion
name: Vibo, Riina
name: Verma, Shefali S
name: Wiggins, Kerri L
name: Wennberg, Patrik
name: Woo, Daniel
name: Wilson, Peter W F
name: Xu, Huichun
name: Yang, Qiong
name: Yoon, Kyungheon
name: Millwood, Iona Y
name: Gieger, Christian
name: Ninomiya, Toshiharu
name: Grabe, Hans J
name: Jukema, J Wouter
name: Rissanen, Ina L
name: Strbian, Daniel
name: Kim, Young Jin
name: Chen, Pei-Hsin
name: Mayerhofer, Ernst
name: Howson, Joanna M M
name: Irvin, Marguerite R
name: Adams, Hieab
name: Wassertheil-Smoller, Sylvia
name: Christensen, Kaare
name: Ikram, Mohammad A
name: Rundek, Tatjana
name: Worrall, Bradford B
name: Lathrop, G Mark
name: Riaz, Moeen
name: Simonsick, Eleanor M
name: Kõrv, Janika
name: França, Paulo H C
name: Zand, Ramin
name: Prasad, Kameshwar
name: Frikke-Schmidt, Ruth
name: De Leeuw, Frank-Erik
name: Liman, Thomas
name: Haeusler, Karl Georg
name: Ruigrok, Ynte M
name: Heuschmann, Peter Ulrich
name: Longstreth, W T
name: Jung, Keum Ji
name: Bastarache, Lisa
name: Paré, Guillaume
name: Damrauer, Scott M
name: Chasman, Daniel I
name: Rotter, Jerome I
name: Anderson, Christopher D
name: Zwart, John-Anker
name: Niiranen, Teemu J
name: Fornage, Myriam
name: Liaw, Yung-Po
name: Seshadri, Sudha
name: Fernández-Cadenas, Israel
name: Walters, Robin G
name: Ruff, Christian T
name: Owolabi, Mayowa O
name: Huffman, Jennifer E
name: Milani, Lili
name: Kamatani, Yoichiro
name: Dichgans, Martin
name: Debette, Stephanie
Publisher: name: Apollo - University of Cambridge Repository
Year: 2022

description: Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry<sup>1,2</sup>. 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 &lt; 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis<sup>3</sup>, 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<sup>4</sup>, 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<sup>5</sup>. 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.