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 WF
name: Xu, Huichun
name: Yang, Qiong
name: Yoon, Kyungheon
name: COMPASS Consortium
name: INVENT Consortium
name: Dutch Parelsnoer Initiative (PSI) Cerebrovascular Disease Study Group
name: Estonian Biobank
name: PRECISEQ Consortium
name: FinnGen Consortium
name: NINDS Stroke Genetics Network (SiGN)
name: MEGASTROKE Consortium
name: SIREN Consortium
name: China Kadoorie Biobank Collaborative Group
name: VA Million Veteran Program
name: International Stroke Genetics Consortium (ISGC)
name: Biobank Japan
name: CHARGE Consortium
name: GIGASTROKE Consortium
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 MM
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 HC
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, WT
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
Subjects: Article
/692/617/375/534
/631/208/205/2138
/631/378/1689/534
/692/53/2423
/631/208/721
/45/43
article

description: 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 &lt; 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.