Common variants at 6p21.1 are associated with large artery atherosclerotic stroke.
Holliday EG., Maguire JM., Evans T-J., Koblar SA., Jannes J., Sturm JW., Hankey GJ., Baker R., Golledge J., Parsons MW., Malik R., McEvoy M., Biros E., Lewis MD., Lincz LF., Peel R., Oldmeadow C., Smith W., Moscato P., Barlera S., Bevan S., Bis JC., Boerwinkle E., Boncoraglio GB., Brott TG., Brown RD., Cheng Y-C., Cole JW., Cotlarciuc I., Devan WJ., Fornage M., Furie KL., Grétarsdóttir S., Gschwendtner A., Ikram MA., Longstreth WT., Meschia JF., Mitchell BD., Mosley TH., Nalls MA., Parati EA., Psaty BM., Sharma P., Stefansson K., Thorleifsson G., Thorsteinsdottir U., Traylor M., Verhaaren BFJ., Wiggins KL., Worrall BB., Sudlow C., Rothwell PM., Farrall M., Dichgans M., Rosand J., Markus HS., Scott RJ., Levi C., Attia J., Australian Stroke Genetics Collaborative None., International Stroke Genetics Consortium None., Wellcome Trust Case Control Consortium 2 None.
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.