Stroke genetics informs drug discovery and risk prediction across ancestries

The COMPASS Consortium, The INVENT Consortium, The Dutch Parelsnoer Initiative (PSI) Cerebrovascular Disease Study Group, The Estonian Biobank, The PRECISEQ Consortium, The FinnGen Consortium, The NINDS Stroke Genetics Network (SiGN), The MEGASTROKE Consortium, The SIREN Consortium, The China Kadoorie Biobank Collaborative Group, The VA Million Veteran Program, The International Stroke Genetics Consortium (ISGC), The Biobank Japan, The CHARGE Consortium, The GIGASTROKE Consortium, Regeneron Genetics Center, The ODYSSEY Study, HUNT All-In Stroke, The SICFAIL Study, The Generacion StudyThe Copenhagen City Heart Study, The SMART Study, Clinical Research Collaboration for Stroke in Korea (CRCS-K) and Korea Biobank Array (KBA) Project, Helsinki Stroke Project, Follow-up Studies, EPIC-CVD

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103 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 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 < 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.

Original languageEnglish
Pages (from-to)115-123
Number of pages9
JournalNature
Volume611
Issue number7934
DOIs
Publication statusPublished - Nov 3 2022
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General

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