Stroke genetics informs drug discovery and risk prediction across ancestries.

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Anglais

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doi: 10.1038/s41586-022-05165-3
issn: 0028-0836

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Serveur académique Lausannois

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info:eu-repo/semantics/altIdentifier/doi/10.1038/s41586-022-05165-3

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info:eu-repo/semantics/altIdentifier/pmid/36180795

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info:eu-repo/semantics/altIdentifier/eissn/1476-4687

Ce document est lié à :
info:eu-repo/semantics/altIdentifier/urn/urn:nbn:ch:serval-BIB_AC35CD14FB1F6

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Serveur Académique Lausannois

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Université de Lausanne et CHUV

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info:eu-repo/semantics/openAccess , CC BY 4.0 , https://creativecommons.org/licenses/by/4.0/

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Humans; Brain Ischemia/genetics; Drug Discovery; Genetic Predisposition to Disease/genetics; Genome-Wide Association Study; Ischemic Stroke/genetics; Molecular Targeted Therapy; Multifactorial Inheritance; Europe/ethnology; Asia, Eastern/ethnology; Africa/ethnology

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Apoplexy Cerebrovascular disorders Cerebrovascular syndrome Brain--Blood-vessels--Diseases Cerebral circulation disorders Stroke CVA (Disease) Cerebral vascular accident Cerebrovascular accident

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A. Mishra et al., « Stroke genetics informs drug discovery and risk prediction across ancestries. », Serveur académique Lausannois, ID : 10.1038/s41586-022-05165-3

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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.

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