Genome-wide association analysis of young-onset stroke identifies a locus on chromosome 10q25 near HABP2

Cheng, Yu-Ching and Stanne, Tara M. and Giese, Anne-Katrin and Ho, Weang Kee and Traylor, Matthew and Amouyel, Philippe and Holliday, Elizabeth G. and Malik, Rainer and Xu, Huichun and Kittner, Steven J. and Cole, John W. and O'Connell, Jeffrey R. and Danesh, John and Rasheed, Asif and Zhao, Wei and Engelter, Stefan and Grond-Ginsbach, Caspar and Kamatani, Yoichiro and Lathrop, Mark and Leys, Didier and Thijs, Vincent and Metso, Tiina M and Tatlisumak, Turgut and Pezzini, Alessandro and Parati, Eugenio A and Norrving, Bo and Bevan, Steve and Rothwell, Peter M. and Sudlow, Cathie and Slowik, Agnieszka and Lindgren, Arne and Walters, Matthew R. and Jannes, Jim and Shen, Jess and Crosslin, David and Doheny, Kimberly and Laurie, Cathy C. and Kanse, Sandip M. and Bis, Joshua C. and Fornage, Myriam and Mosley, Thomas H. and Hopewell, Jemma C. and Strauch, Konstantin and Müller-Nurasyid, Martina and Gieger, Christian and Waldenberger, Melanie and Peters, Annette and Meisinger, Christine and Ikram, M Arfan and Longstreth, W. T. and Meschia, James F. and Seshadri, Sudha and Sharma, Pankaj and Worrall, Bradford and Jern, Christina and Levi, Christopher and Dichgans, Martin and Boncoraglio, Giorgio B. and Markus, Hugh S. and Debette, Stephanie and Rolfs, Arndt and Saleheen, Danish and Mitchell, Braxton D. (2016) Genome-wide association analysis of young-onset stroke identifies a locus on chromosome 10q25 near HABP2. Stroke: a Journal of Cerebral Circulation, 47 (2). pp. 307-16. ISSN 0039-2499

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Abstract

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.

Keywords:Stroke, NotOAChecked
Subjects:C Biological Sciences > C400 Genetics
Divisions:College of Science > School of Life Sciences
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ID Code:23605
Deposited On:01 Aug 2016 20:47

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