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Stroke genetics inf...
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Mishra, A.University of Bordeaux
(author)
Stroke genetics informs drug discovery and risk prediction across ancestries
- Article/chapterEnglish2022
Publisher, publication year, extent ...
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2022-09-30
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Springer Science and Business Media LLC,2022
Numbers
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LIBRIS-ID:oai:gup.ub.gu.se/322231
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https://gup.ub.gu.se/publication/322231URI
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https://doi.org/10.1038/s41586-022-05165-3DOI
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https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-200734URI
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https://lup.lub.lu.se/record/5e54bbd2-c610-458b-81bb-15f6b27f8a9eURI
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http://kipublications.ki.se/Default.aspx?queryparsed=id:150831010URI
Supplementary language notes
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Classification
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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Publisher correction: Mishra, A., Malik, R., Hachiya, T. et al. Publisher Correction: Stroke genetics informs drug discovery and risk prediction across ancestries. Nature 612, E7 (2022). DOI: 10.1038/s41586-022-05492-5
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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.
Subject headings and genre
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Malik, R.
(author)
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Hachiya, T.
(author)
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Jurgenson, T.
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Namba, S.
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Posner, D. C.
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Kamanu, F. K.
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Koido, M.Karolinska Institutet
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Jern, Christina,1962Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Department of Laboratory Medicine(Swepub:gu)xjerch
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Yonova-Doing, E.
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Judy, R. L.Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Department of Laboratory Medicine
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Jern, Christina,1962Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Department of Laboratory Medicine(Swepub:gu)xjerch
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Melander, OlleLund University,Lunds universitet,Kardiovaskulär forskning - hypertoni,Forskargrupper vid Lunds universitet,Cardiovascular Research - Hypertension,Lund University Research Groups(Swepub:lu)endo-ome
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Compass Consorti ...
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FinnGen, Consort ...
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Megastroke Conso ...
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Siren Consortium ...
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Biobank, Japan
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Charge Consortiu ...
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Gigastroke Conso ...
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Regeneron Geneti ...
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Odyssey Study, O ...
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Sicfail Study, S ...
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Generacion, Stud ...
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Smart Study, Sma ...
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Helsinki Stroke, ...
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Epic,, Epic
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- About the subject
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- Articles in the publication
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Nature
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University of Gothenburg
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Umeå University
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Lund University
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Karolinska Institutet