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, W. T. 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

Research output: Contribution to journalArticle

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 21968 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 (US)
Pages (from-to)307-316
Number of pages10
JournalStroke
Volume47
Issue number2
DOIs
StatePublished - Feb 1 2016

Keywords

  • Factor VII
  • Genetics
  • Genome-wide analysis
  • Ischemic stroke
  • Stroke

ASJC Scopus subject areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialized Nursing

Fingerprint Dive into the research topics of 'Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2'. Together they form a unique fingerprint.

  • Cite this

    Cheng, Y. C., Stanne, T. M., Giese, A. K., Ho, W. K., Traylor, M., Amouyel, P., Holliday, E. G., Malik, R., Xu, H., Kittner, S. J., Cole, J. W., O'Connell, J. R., Danesh, J., Rasheed, A., Zhao, W., Engelter, S., Grond-Ginsbach, C., Kamatani, Y., Lathrop, M., ... Mitchell, B. D. (2016). Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2. Stroke, 47(2), 307-316. https://doi.org/10.1161/STROKEAHA.115.011328