title: Common variants at 6p21.1 are associated with large artery atherosclerotic stroke.
abstract: Genome-wide association studies (GWAS) have not consistently detected replicable genetic risk factors for ischemic stroke, potentially due to etiological heterogeneity of this trait. We performed GWAS of ischemic stroke and a major ischemic stroke subtype (large artery atherosclerosis, LAA) using 1,162 ischemic stroke cases (including 421 LAA cases) and 1,244 population controls from Australia. Evidence for a genetic influence on ischemic stroke risk was detected, but this influence was higher and more significant for the LAA subtype. We identified a new LAA susceptibility locus on chromosome 6p21.1 (rs556621: odds ratio (OR)=1.62, P=3.9×10(-8)) and replicated this association in 1,715 LAA cases and 52,695 population controls from 10 independent population cohorts (meta-analysis replication OR=1.15, P=3.9×10(-4); discovery and replication combined OR=1.21, P=4.7×10(-8)). This study identifies a genetic risk locus for LAA and shows how analyzing etiological subtypes may better identify genetic risk alleles for ischemic stroke.
authors.affiliation: Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia. liz.holliday@newcastle.edu.au
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Holliday
authors.forename: Jane M
authors.initials: JM
authors.lastname: Maguire
authors.forename: Tiffany-Jane
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authors.lastname: Koblar
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authors.lastname: Cheng
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authors.lastname: Meschia
authors.forename: Braxton D
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authors.lastname: Mitchell
authors.forename: Thomas H
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authors.lastname: Mosley
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authors.lastname: Nalls
authors.forename: Eugenio A
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authors.lastname: Parati
authors.forename: Bruce M
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authors.lastname: Psaty
authors.forename: Pankaj
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authors.lastname: Sharma
authors.forename: Kari
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authors.lastname: Stefansson
authors.forename: Gudmar
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authors.lastname: Thorleifsson
authors.forename: Unnur
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authors.lastname: Thorsteinsdottir
authors.forename: Matthew
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authors.lastname: Traylor
authors.forename: Benjamin F J
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authors.lastname: Verhaaren
authors.forename: Kerri L
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authors.forename: Bradford B
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authors.lastname: Worrall
authors.forename: Cathie
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authors.lastname: Sudlow
authors.forename: Peter M
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authors.lastname: Rothwell
authors.forename: Martin
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authors.lastname: Farrall
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authors.lastname: Dichgans
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authors.forename: Hugh S
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authors.lastname: Markus
authors.forename: Rodney J
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mesh_terms: D016022:Case-Control Studies; D002544:Cerebral Infarction / Q000235:genetics*; D002896:Chromosomes, Human, Pair 6; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D002537:Intracranial Arteriosclerosis / Q000235:genetics*; D015810:Linkage Disequilibrium; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide