Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2. / Cheng, Yu-Ching; Stanne, Tara M. ; Giese, Anne-Katrin ; Ho, Weang Kee ; Traylor, Matthew ; Amouyel, Philippe ; Holliday, Elizabeth G; Malik, Rainer ; Xu, Huichun; Kittner, Steven J ; Cole, John W; O’Connell, Jeffrey R ; Danesh, John ; Rasheed, Asif ; Zhao, Wei ; Engelter, Stefan; Grond-Ginsbach, Caspar; Kamatani, Yoichiro; Lathrop, Mark ; Leys, Didier; Thijs, Vincent ; Metso, Tiina M; Tatlisumak, Turgut ; Pezzini, Alessandro ; Parati, Eugenio A; Norrving, Bo; Bevan, Steve ; Rothwell, Peter M ; Sudlow, Cathie ; Slowik, Agnieszka ; Lindgren, Arne ; Walters, Matthew R ; Jannes, Jim; Shen, Jess ; Crosslin, David; Doheny, Kimberly ; Laurie, Cathy C; Kanse, Sandip M; Bis, Joshua C; Fornage, Myriam; Mosley, Thomas H; Hopewell, Jemma C; Strauch, Konstantin ; Müller-Nurasyid, Martina ; Gieger, Christian ; Waldenberger, Melanie ; Peters, Annette ; Meisinger, Christine ; Ikram, M Arfan ; Longstreth, WT ; Meschia, James F; Seshadri, Sudha ; Sharma, Pankaj; Worrall, Bradford ; Jern, Christina ; Levi, Christopher; Dichgans, Martin ; Boncoraglio, Giorgio B; Markus, Hugh S; Debette, Stephanie ; Rolfs, Arndt ; Saleheen, Danish ; Mitchell, Braxton D.

In: Stroke, Vol. 47, No. 2, 05.01.2016, p. 307-316.

Research output: Contribution to journalArticlepeer-review

E-pub ahead of print

Documents

  • 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 Leys
  • Vincent 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
  • Bradford Worrall
  • Christina Jern
  • Christopher Levi
  • Martin Dichgans
  • Giorgio B Boncoraglio
  • Hugh S Markus
  • Stephanie Debette
  • Arndt Rolfs
  • Danish Saleheen
  • Braxton D Mitchell

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.
Original languageEnglish
Pages (from-to)307-316
Number of pages10
JournalStroke
Volume47
Issue number2
Early online date5 Jan 2016
DOIs
Publication statusE-pub ahead of print - 5 Jan 2016
This open access research output is licenced under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.

ID: 25720597