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

Yu-Ching Cheng, Tara M. Stanne, Anne-Katrin Giese, Weang Kee Ho, Matthew Traylor, Philippe Amouyel, Elizabeth G Holliday, Rainer Malik, Huichun Xu, Steven J Kittner, John W Cole, Jeffrey R O’Connell, John Danesh, Asif Rasheed, Wei Zhao, Stefan Engelter, Caspar Grond-Ginsbach, Yoichiro Kamatani, Mark Lathrop, Didier LeysVincent Thijs, Tiina M Metso, Turgut Tatlisumak, Alessandro Pezzini, Eugenio A Parati, Bo Norrving, Steve Bevan, Peter M Rothwell, Cathie Sudlow, Agnieszka Slowik, Arne Lindgren, Matthew R Walters, Jim Jannes, Jess Shen, David Crosslin, Kimberly Doheny, Cathy C Laurie, Sandip M Kanse, Joshua C Bis, Myriam Fornage, Thomas H Mosley, Jemma C Hopewell, Konstantin Strauch, Martina Müller-Nurasyid, Christian Gieger, Melanie Waldenberger, Annette Peters, Christine Meisinger, M Arfan Ikram, WT Longstreth, James F Meschia, Sudha Seshadri, Pankaj Sharma, Bradford Worrall, Christina Jern, Christopher Levi, Martin Dichgans, Giorgio B Boncoraglio, Hugh S Markus, Stephanie Debette, Arndt Rolfs, Danish Saleheen, Braxton D Mitchell

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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 languageEnglish
Pages (from-to)307-316
Number of pages10
Issue number2
Early online date5 Jan 2016
Publication statusE-pub ahead of print - 5 Jan 2016

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