Pulse lineResearch With Heart Logo

Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies.

TitleGenetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies.
Publication TypeJournal Article
Year of Publication2012
AuthorsTraylor M, Farrall M, Holliday EG, Sudlow C, Hopewell JC, Cheng Y-C, Fornage M, M Ikram A, Malik R, Bevan S, Thorsteinsdottir U, Nalls MA, Longstreth W, Wiggins KL, Yadav S, Parati EA, DeStefano AL, Worrall BB, Kittner SJ, Khan MSaleem, Reiner AP, Helgadottir A, Achterberg S, Fernandez-Cadenas I, Abboud S, Schmidt R, Walters M, Chen W-M, E Ringelstein B, O'Donnell M, Ho WKee, Pera J, Lemmens R, Norrving B, Higgins P, Benn M, Sale M, Kuhlenbäumer G, Doney ASF, Vicente AM, Delavaran H, Algra A, Davies G, Oliveira SA, Palmer CNA, Deary I, Schmidt H, Pandolfo M, Montaner J, Carty C, de Bakker PIW, Kostulas K, Ferro JM, van Zuydam NR, Valdimarsson E, Nordestgaard BG, Lindgren A, Thijs V, Slowik A, Saleheen D, Paré G, Berger K, Thorleifsson G, Hofman A, Mosley TH, Mitchell BD, Furie K, Clarke R, Levi C, Seshadri S, Gschwendtner A, Boncoraglio GB, Sharma P, Bis JC, Gretarsdottir S, Psaty BM, Rothwell PM, Rosand J, Meschia JF, Stefansson K, Dichgans M
Secondary AuthorsMarkus HS
Corporate AuthorsAustralian Stroke Genetics Collaborative, Wellcome Trust Case Control Consortium 2(WTCCC2), International Stroke Genetics Consortium
JournalLancet Neurol
Volume11
Issue11
Pagination951-62
Date Published2012 Nov
ISSN1474-4465
KeywordsBrain Ischemia, Databases, Genetic, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Risk Factors, Stroke
Abstract

BACKGROUND: Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes.

METHODS: We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls.

FINDINGS: We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10(-16)) and ZFHX3 (p=2·28×10(-8)), and for large-vessel stroke at a 9p21 locus (p=3·32×10(-5)) and HDAC9 (p=2·03×10(-12)). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p

INTERPRETATION: Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes.

FUNDING: Wellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS).

DOI10.1016/S1474-4422(12)70234-X
Alternate JournalLancet Neurol
PubMed ID23041239
PubMed Central IDPMC3490334
Grant ListHHSN268201100009I / HL / NHLBI NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
R01 HL080295 / HL / NHLBI NIH HHS / United States
U01 HG005157 / HG / NHGRI NIH HHS / United States
BB/F019394/1 / / Biotechnology and Biological Sciences Research Council / United Kingdom
U54 RR020278 / RR / NCRR NIH HHS / United States
N01HC55020 / HL / NHLBI NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
U01 HG005160 / HG / NHGRI NIH HHS / United States
R01 NS045012 / NS / NINDS NIH HHS / United States
R01 NS017950 / NS / NINDS NIH HHS / United States
R01 NS042733 / 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
Z01 AG000015 / / Intramural NIH HHS / United States
R01 AG015928 / AG / NIA NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
R01 HL087676 / HL / NHLBI NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
U01 HL096917 / HL / NHLBI NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
N01 HC015103 / HC / NHLBI NIH HHS / United States
R01 HL085251 / HL / NHLBI NIH HHS / United States
R56 AG020098 / AG / NIA NIH HHS / United States
HHSN268201100011I / HL / NHLBI 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
UL1 TR000124 / TR / NCATS NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
Z01 AG000954 / / Intramural NIH HHS / United States
U01 HG004424 / HG / NHGRI NIH HHS / United States
N01HC55022 / HL / NHLBI NIH HHS / United States
MR/K026992/1 / / Medical Research Council / United Kingdom
MC_U137686857 / / Medical Research Council / United Kingdom
N01HC55015 / HL / NHLBI NIH HHS / United States
R01 HL093029 / HL / NHLBI NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
G0601325 / / Medical Research Council / United Kingdom
P30 DK063491 / DK / NIDDK NIH HHS / United States
HHSN268200782096C / HG / NHGRI NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
R01 AG008122 / AG / NIA NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
P30 DK072488 / DK / NIDDK NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States
U01 NS069208 / NS / NINDS NIH HHS / United States
R01 NS039987 / NS / NINDS NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
RP-PG-0606-1146 / / Department of Health / United Kingdom
090532 / / Wellcome Trust / United Kingdom
N01HC55016 / HL / NHLBI NIH HHS / United States
R01 AG020098 / AG / NIA NIH HHS / United States
R01 NS034447 / NS / NINDS NIH HHS / United States
N01HC55019 / HL / NHLBI NIH HHS / United States
U01 HG004436 / HG / NHGRI NIH HHS / United States
N01HC75150 / HL / NHLBI 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
N01HC25195 / HL / NHLBI NIH HHS / United States
G0700704 / / Medical Research Council / United Kingdom
HHSN268201100007I / HL / NHLBI NIH HHS / United States
/ / Wellcome Trust / United Kingdom
N01HC85079 / HL / NHLBI NIH HHS / United States
N01HC55021 / HL / NHLBI NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
R01 HL073410 / HL / NHLBI NIH HHS / United States
U01 HG005152 / HG / NHGRI NIH HHS / United States
R01 AG027058 / AG / NIA NIH HHS / United States
N01 HC045133 / HC / NHLBI NIH HHS / United States
N01 HC035129 / HC / NHLBI NIH HHS / United States
R56 AG023629 / AG / NIA NIH HHS / United States