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Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2.

Cheng Y-C., Stanne TM., Giese A-K., Ho WK., Traylor M., Amouyel P., Holliday EG., Malik R., Xu H., Kittner SJ., Cole JW., O'Connell JR., Danesh J., Rasheed A., Zhao W., Engelter S., Grond-Ginsbach C., Kamatani Y., Lathrop M., Leys D., Thijs V., Metso TM., Tatlisumak T., Pezzini A., Parati EA., Norrving B., Bevan S., Rothwell PM., Sudlow C., Slowik A., Lindgren A., Walters MR., WTCCC-2 Consortium None., Jannes J., Shen J., Crosslin D., Doheny K., Laurie CC., Kanse SM., Bis JC., Fornage M., Mosley TH., Hopewell JC., Strauch K., Müller-Nurasyid M., Gieger C., Waldenberger M., Peters A., Meisinger C., Ikram MA., Longstreth WT., Meschia JF., Seshadri S., Sharma P., Worrall B., Jern C., Levi C., Dichgans M., Boncoraglio GB., Markus HS., Debette S., Rolfs A., Saleheen D., Mitchell BD.

BACKGROUND AND PURPOSE:Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset <60 years. METHODS:The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10(-6) and performed in silico association analyses in an independent sample of ≤1003 cases and 7745 controls. RESULTS:One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10(-9)). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2. CONCLUSIONS:HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.

Original publication

DOI

10.1161/strokeaha.115.011328

Type

Journal article

Journal

Stroke

Publication Date

02/2016

Volume

47

Pages

307 - 316

Addresses

From the Veterans Affairs Maryland Health Care System, Baltimore, MD (Y.-C.C., S.J.K., J.W.C., B.D.M.); University of Maryland School of Medicine, Baltimore (Y.-C.C., H.X., S.J.K., J.W.C., J.R.O., B.D.M.); The University of Gothenburg, Gothenburg, Sweden (T.M.S., C.J.); University of Rostock, Rostock, Germany (A.-K.G., A. Rolfs); University of Nottingham Malaysia Campus, Selangor Darul Ehsa, Malaysia (W.K.H.); University of Cambridge, Cambridge, UK (M.T., J.D., S.B., H.S.M., S.D., D.S.); Institut Pasteur de Lille, F-59000 Lille, France (P.A.); University of Newcastle, Australia (E.G.H.); Ludwig-Maximilians-Universität, Munich, Germany (R.M., K.S., M.D.); Wellcome Trust Sanger Institute, Cambridge, UK (J.D.); Center for Non-Communicable Diseases, Karachi, Pakistan (A. Rasheed, D.S.); University of Pennsylvania (W.Z., D.S.); Basel University Hospital, Switzerland (S.E.); Heidelberg University Hospital, Germany (C.G.-G.); Centre d'Étude du Polymorphisme Humain, Paris, France (Y.K.); RIKEN Center for Integrative Medical Sciences, Yokohama, Japan (Y.K.); National Genotyping Center, Evry, France (M.L.); Genome Quebec, McGill University, Montreal, Canada (M.L.); Lille University Hospital, France (D.L., S.D.); KU Leuven - University of Leuven, Leuven, Belgium (V.T.); Vesalius Research Center, VIB, Leuven, Belgium (V.T.); University Hospitals Leuven, Leuven, Belgium (V.T.); Helsinki University Central Hospital, Helsinki, Finland (T.M.M., T.T.); Università degli Studi di Brescia, Brescia, Italy (A. Pezzini); Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy (E.A.P., G.B.B.); University of Lund, Sweden (B.N.); University of Oxford, John Radcliffe Hospital (P.M.R.); University of Edinburgh, Edinburgh, UK (C.S.); Jagiellonian University Medical College, Krakow, Poland (A.S.); Lund University, Lund, Sweden (A.L.); Skåne University Hospital, Lund, Sweden (A.L.); University of Glasgow, Glasgow, UK (M.R.W.); University of Adelaide, Australia (J.J.); Mount Sinai Hos

Keywords

WTCCC-2 Consortium, Chromosomes, Human, Pair 10, Humans, Brain Ischemia, Genetic Predisposition to Disease, Serine Endopeptidases, DNA, Intergenic, Odds Ratio, Age of Onset, Polymorphism, Single Nucleotide, Computer Simulation, Adult, Aged, Middle Aged, African Continental Ancestry Group, Asian Continental Ancestry Group, European Continental Ancestry Group, Female, Male, Stroke, Genome-Wide Association Study