Stroke genetics informs drug discovery and risk prediction across ancestries

Aniket Mishra, Rainer Malik, COMPASS Consortium, INVENT Consortium, Estonian Biobank, PRECISEQ Consortium, FinnGen Consortium, MEGASTROKE Consortium, SIREN Consortium, Biobank Japan, CHARGE Consortium, GIGASTROKE Consortium, Regeneron Genetics Ctr, ODYSSEY Study, SICFAIL Study, Generacion Study, SMART Study, Helsinki Stroke Project, EPIC, Tsuyoshi HachiyaTuuli Jurgenson, Shinichi Namba, Daniel C. Posner, Frederick K. Kamanu, Masaru Koido, Quentin Le Grand, Mingyang Shi, Yunye He, Marios K. Georgakis, Ilana Caro, Kristi Krebs, Yi-Ching Liaw, Felix C. Vaura, Kuang Lin, Bendik Slagsvold Winsvold, Vinodh Srinivasasainagendra, Livia Parodi, Hee-Joon Bae, Ganesh Chauhan, Michael R. Chong, Liisa Tomppo, Rufus Akinyemi, Gennady V. Roshchupkin, Naomi Habib, Yon Ho Jee, Jesper Qvist Thomassen, Maria J. Knol, Peter J. Koudstaal, Cornelia M. van Duijn, Andre G. Uitterlinden, Hieab Adams, Arfan Ikram, Martin Dichgans, Stéphanie Debette

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)115-123
Number of pages34
JournalNature
Volume611
Issue number7934
DOIs
Publication statusE-pub ahead of print - 30 Sep 2022

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