Stroke genetics informs drug discovery and risk prediction across ancestries
Aniket Mishra, Rainer Malik, Tsuyoshi Hachiya, Tuuli Jürgenson, Shinichi Namba, Daniel Posner, Frederick Kamanu, Masaru Koido, Quentin Le Grand, Mingyang Shi, Yunye He, Marios K. Georgakis, Ilana Caro, Kristi Krebs, Yi‐Ching Liaw, Felix Vaura, Kuang Lin, Bendik S. Winsvold, Vinodh Srinivasasainagendra, Livia Parodi, Hee‐Joon Bae, Ganesh Chauhan, Michael Chong, Liisa Tomppo, Rufus Akinyemi, Gennady V. Roshchupkin, Naomi Habib, Yon Ho Jee, Jesper Qvist Thomassen, Vida Abedi, Jara Cárcel‐Márquez, Marianne Nygaard, Hampton L. Leonard, Chaojie Yang, Ekaterina Yonova-Doing, Maria J. Knol, Adam Lewis, Renae Judy, Tetsuro Ago, Philippe Amouyel, Nicole D. Armstrong, Mark K. Bakker, Traci M. Bartz, David A. Bennett, Joshua C. Bis, Constance Bordes, Sigrid Børte, Anael Cain, Paul M. Ridker, Kelly Cho, Zhengming Chen, Carlos Cruchaga, John W. Cole, Phil L. de Jager, Rafael de Cid, Matthias Endres, Leslie Ecker Ferreira, Mirjam I. Geerlings, Natalie C. Gasca, Vilmundur Guðnason, Jun Hata, Jing He, Alicia K. Heath, Yuk‐Lam Ho, Aki S. Havulinna, Jemma C. Hopewell, Hyacinth I. Hyacinth, Michael Inouye, Mina A. Jacob, Christina Jeon, Christina Jern, Masahiro Kamouchi, Keith L. Keene, Takanari Kitazono, Steven J. Kittner, Takahiro Konuma, Amit Kumar, Paul Lacaze, Lenore J. Launer, Keon‐Joo Lee, Kaido Lepik, Jiang Li, Liming Li, Ani Manichaikul, Hugh S. Markus, Nicholas A. Marston, Thomas Meitinger, Braxton D. Mitchell, Felipe A. Montellano, Takayuki Morisaki, Thomas H. Mosley, Mike A. Nalls, Børge G. Nordestgaard, Martin O’Donnell, Yukinori Okada, N. Charlotte Onland-Moret, Bruce Ovbiagele, Annette Peters, Bruce M. Psaty, Stephen S. Rich
Abstract
Abstract Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry 1,2 . 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 < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis 3 , 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 4 , 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 5 . 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.