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

Thursday,2016-03-31 14:45 America/Los_Angeles — zdrager
TitleGenome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2.
Publication TypeJournal Article
Year of Publication2016
AuthorsCheng, Y-C, Stanne, TM, Giese, A-K, Ho, WKee, 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, 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, AM, 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
Corporate/Institutional AuthorsWTCCC-2 Consortium
JournalStroke
Volume47
Issue2
Pagination307-16
Date Published2016 Feb
ISSN1524-4628
KeywordsAdult, African Continental Ancestry Group, Age of Onset, Aged, Asian Continental Ancestry Group, Brain Ischemia, Chromosomes, Human, Pair 10, Computer Simulation, DNA, Intergenic, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide, Serine Endopeptidases, Stroke
Abstract<p><b>BACKGROUND AND PURPOSE: </b>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.</p><p><b>METHODS: </b>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.</p><p><b>RESULTS: </b>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.</p><p><b>CONCLUSIONS: </b>HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.</p>
DOI10.1161/STROKEAHA.115.011328
Alternate JournalStroke
PubMed ID26732560
PubMed Central IDPMC4729659
Grant List085475/B/08/Z / / Wellcome Trust / United Kingdom
085475/Z/08/Z / / Wellcome Trust / United Kingdom
095626 / / Wellcome Trust / United Kingdom
104040 / / Wellcome Trust / United Kingdom
FS/14/55/30806 / / British Heart Foundation / United Kingdom
G1001799 / / Wellcome Trust / United Kingdom
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