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Common variants at 6p21.1 are associated with large artery atherosclerotic stroke.

TitleCommon variants at 6p21.1 are associated with large artery atherosclerotic stroke.
Publication TypeJournal Article
Year of Publication2012
AuthorsHolliday 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, Gretarsdottir S, Gschwendtner A, M Ikram A, 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
Secondary AuthorsAttia J
Corporate AuthorsAustralian Stroke Genetics Collaborative, International Stroke Genetics Consortium, Wellcome Trust Case Control Consortium 2
JournalNat Genet
Volume44
Issue10
Pagination1147-51
Date Published2012 Oct
ISSN1546-1718
KeywordsCase-Control Studies, Cerebral Infarction, Chromosomes, Human, Pair 6, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Intracranial Arteriosclerosis, Linkage Disequilibrium, Odds Ratio, Polymorphism, Single Nucleotide
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.

DOI10.1038/ng.2397
Alternate JournalNat Genet
PubMed ID22941190
PubMed Central IDPMC3651583
Grant ListN01HC55020 / HL / NHLBI NIH HHS / United States
090532/Z/09/Z / / Wellcome Trust / United Kingdom
HHSN268201100012C / HL / NHLBI NIH HHS / United States
R01 NS045012 / NS / NINDS NIH HHS / United States
U01 HG004446 / HG / NHGRI NIH HHS / United States
N01HC55018 / HL / NHLBI NIH HHS / United States
095626 / / Wellcome Trust / United Kingdom
HHSN268201100010C / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
R01 HL087676 / HL / NHLBI NIH HHS / United States
U01 HL096917 / HL / NHLBI NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
R01 HL085251 / HL / NHLBI NIH HHS / United States
Z01 AG000015-50 / / Intramural NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
G0500987 / / Medical Research Council / United Kingdom
U01 HG004402 / HG / NHGRI NIH HHS / United States
N01HC55022 / HL / NHLBI NIH HHS / United States
K23 NS042720 / NS / NINDS NIH HHS / United States
N01HC55015 / HL / NHLBI NIH HHS / United States
R01 HL093029 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
P50 NS051343 / NS / NINDS NIH HHS / United States
P30 DK072488 / DK / NIDDK NIH HHS / United States
U01 NS069208 / NS / NINDS NIH HHS / United States
RP-PG-0606-1146 / / Department of Health / United Kingdom
090532 / / Wellcome Trust / United Kingdom
WT084724MA / / Wellcome Trust / United Kingdom
N01HC55016 / HL / NHLBI NIH HHS / United States
085475/B/08/Z / / Wellcome Trust / United Kingdom
N01HC55019 / HL / NHLBI NIH HHS / United States
U01 HG004436 / HG / NHGRI NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
OSRP2/1006 / / The Dunhill Medical Trust / United Kingdom
HHSN268201100005C / HL / NHLBI NIH HHS / United States
N01HC55021 / HL / NHLBI NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
Z01 AG000954-06 / / Intramural NIH HHS / United States
R01 HL073410 / HL / NHLBI NIH HHS / United States
U01NS069208 / NS / NINDS NIH HHS / United States
085475/Z/08/Z / / Wellcome Trust / United Kingdom