Stroke genetics informs drug discovery and risk prediction across ancestries
Authors: Debette Stéphanie , Mishra Aniket , Malik Rainer , Hachiya Tsuyoshi , Jürgenson Tuuli , Namba Shinichi , Koido Masaru , Grand Quentin Le , Kamanu Frederick , Shi Mingyang , He Yunye , Georgakis Marios , Caro Ilana , Krebs Kristi , Vaura Felix , Habib Naomi , Winsvold Bendik , Jee Yon Ho , Thomassen Jesper Qvist , Abedi Vida , Cárcel-Márquez Jara , Lin Kuang , Nygaard Marianne , Chauhan Ganesh , Leonard Hampton , Yang Chaojie , Yonova-Doing Ekaterina , Knol Maria , Ago Tetsuro , Amouyel Philippe , Anderson Christopher , Armstrong Nicole , Bakker Mark , Bartz Traci , Bis Joshua , Bordes Constance , Borte Sigrid , Cain Anael , Ridker Paul , Chen Zhengming , Chong Michael , Cole John , de Cid Rafael , Endres Matthias , Ferreira Leslie , Gasca Natalie , Gudnason Vilmundur , Hata Jun , Havulinna Aki , Hopewell Jemma , Hyacinth Hyacinth , Inouye Michael , Jacob Mina , Jeon Christina  , Jern Christina , Kamouchi Masahiro , Keene Keith , Kitazono Takanari , Kittner Steven , Konuma Takahiro , Kumar Amit , Lacaze Paul , Launer Lenore , Lepik Kaido , Li Jiang , Li Liming , Manichaikul Ani , Markus Hugh , Marston Nicholas , Meitinger Thomas , Mitchell Braxton , Montellano Felipe , Morisaki Takayuki , Mosley Thomas , Nalls Mike , Nordestgaard Børge , O'Donnell Martin , Okada Yukinori , Pare Guillaume , Peters Annette , Psaty Bruce , Rich Stephen , Rosand Jonathan , Sabatine Marc , Sacco Ralph , Saleheen Danish , Sandset Else Charlotte , Sargurupremraj Muralidharan , Sasaki Makoto , Satizabal Claudia , Schmidt Carsten , Shimizu Atsushi , Smith Nicholas , Strbian Daniel , Sutoh Yoichi , Tanno Kozo , Tiedt Steffen , Torres-Aguila Nuria , Trégouët David-Alexandre , Trompet Stella , Tuladhar Anil , Tybjærg-Hansen Anne , Vugt Marion van , Vibo Riina , Wiggins Kerri , Woo Daniel , Xu Huichun , Yang Qiong , Lathrop Mark , Millwood Iona , Gieger Christian , Ninomiya Toshiharu , Grabe Hans , Jukema J Wouter , Rissanen Ina , Seshadri Sudha , Longstreth William , Chasman Daniel , Howson Joanna , Irvin Marguerite , Adams Hieab , Wasssertheil-Smoller Sylvia , Christensen Kaare , Ikram M. Arfan , Rundek Tatjana , Rotter Jerome , Riaz Moeen , Simonsick Eleanor , Kõrv Janika , França Paulo , Fornage Myriam , Zand Ramin , Prasad Kameshwar , Frikke-Schmidt Ruth , de Leeuw Frank-Erik , Liman Thomas , Haeusler Karl Georg , Ruigrok Ynte , Heuschmann Peter , Jung Keum , Zwart John-Anker , Niiranen Teemu , Ruff Christian , Fernández-Cadenas Israel , Walters Robin , Milani Lili , Kamatani Yoichiro , Dichgans Martin 
Published: January 2022

Abstract
Previous genome-wide association studies (GWAS) of stroke, the second leading cause of death, have been conducted in populations of predominantly European ancestry.1,2 We undertook cross-ancestry GWAS meta-analyses of stroke and its subtypes in 110,182 stroke patients (33% non-European) and 1,503,898 control individuals of five ancestries from population- and clinic-based studies, nearly doubling the number of cases in previous stroke GWAS. We identified association signals at 89 independent loci, of which 61 were novel. Effect sizes were overall highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis using a novel machine-learning approach,3 transcriptome and proteome-wide association analyses revealed putative causal genes (e.g. SH3PXD2A and FURIN) and variants (e.g. at GRK5 and NOS3). Using a novel three-pronged approach,4 we provided genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, 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 GWAS with vascular risk factor GWAS (iPGS) showed strong prediction of ischemic stroke risk in European and, for the first time, East-Asian populations.5,6 The iPGS performed better than stroke PGS alone and better than previous best iPGS, in Europeans and East-Asians. Transferability of European-specific iPGS to East-Asians was limited. Stroke genetic risk scores were predictive of ischemic stroke independent of clinical risk factors in 52,600 clinical trial participants with cardiometabolic disease and performed considerably better than previous scores, both in Europeans and East-Asians. Altogether our results provide critical insight to inform biology, reveal potential drug targets for intervention, and provide genetic risk prediction tools across ancestries for targeted prevention.