Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2016 Feb;47(2):307-16.
doi: 10.1161/STROKEAHA.115.011328. Epub 2016 Jan 5.

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

Yu-Ching Cheng  1 , Tara M Stanne  1 , Anne-Katrin Giese  1 , Weang Kee Ho  1 , Matthew Traylor  1 , Philippe Amouyel  1 , Elizabeth G Holliday  1 , Rainer Malik  1 , Huichun Xu  1 , Steven J Kittner  1 , John W Cole  1 , Jeffrey R O'Connell  1 , John Danesh  1 , Asif Rasheed  1 , Wei Zhao  1 , Stefan Engelter  1 , Caspar Grond-Ginsbach  1 , Yoichiro Kamatani  1 , Mark Lathrop  1 , Didier Leys  1 , Vincent Thijs  1 , Tiina M Metso  1 , Turgut Tatlisumak  1 , Alessandro Pezzini  1 , Eugenio A Parati  1 , Bo Norrving  1 , Steve Bevan  1 , Peter M Rothwell  1 , Cathie Sudlow  1 , Agnieszka Slowik  1 , Arne Lindgren  1 , Matthew R Walters  1 ; WTCCC-2 Consortium; Jim Jannes  1 , Jess Shen  1 , David Crosslin  1 , Kimberly Doheny  1 , Cathy C Laurie  1 , Sandip M Kanse  1 , Joshua C Bis  1 , Myriam Fornage  1 , Thomas H Mosley  1 , Jemma C Hopewell  1 , Konstantin Strauch  1 , Martina Müller-Nurasyid  1 , Christian Gieger  1 , Melanie Waldenberger  1 , Annette Peters  1 , Christine Meisinger  1 , M Arfan Ikram  1 , W T Longstreth Jr  1 , James F Meschia  1 , Sudha Seshadri  1 , Pankaj Sharma  1 , Bradford Worrall  1 , Christina Jern  1 , Christopher Levi  1 , Martin Dichgans  1 , Giorgio B Boncoraglio  1 , Hugh S Markus  1 , Stephanie Debette  1 , Arndt Rolfs  1 , Danish Saleheen  1 , Braxton D Mitchell  1
Affiliations
Meta-Analysis

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

Yu-Ching Cheng et al. Stroke. 2016 Feb.

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: factor VII; genetics; genome-wide analysis; ischemic stroke; stroke.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Genome-wide association results of early-onset ischemic stroke based on (A) Trans-ethnic meta-analysis and (B) European-only meta-analysis. Red line: P=5×10−8; grey line: P=5×10−6.
Figure 2
Figure 2
Regional plot of the chr10q25.3 locus from trans-ethnic association analysis in the Discovery stage. Recombination rate was based on 1000 Genomes EUR data. Plot was generated using LocusZoom software.
Figure 3
Figure 3
Forest plot of rs11196288 at 10q25.3, including Discovery and Follow-up studies, in trans-ethnic analysis.
Figure 4
Figure 4
Associations of rs11196288 and rs4918896 at 10q25.3 with risk of stroke in METASTROKE studies, by mean age of stroke cases.
Figure 5
Figure 5
Plasma FSAP levels are associated with rs7906302 and rs1338423 in normolipidemic controls in SAHLSIS. Median and interquartile range (IQR) of FSAP according to genotype in controls. Differences in logFSAPag levels were calculated with Student’s t-test. * P<0.05
See this image and copyright information in PMC

References

    1. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, et al. Heart disease and stroke statistics--2014 update: A report from the American Heart Association. Circulation. 2014;129:e28–e292. - PMC - PubMed
    1. Bevan S, Traylor M, Adib-Samii P, Malik R, Paul NL, Jackson C, et al. Genetic heritability of ischemic stroke and the contribution of previously reported candidate gene and genomewide associations. Stroke. 2012;43:3161–3167. - PubMed
    1. Holliday EG, Maguire JM, Evans TJ, Koblar SA, Jannes J, Sturm JW, et al. Common variants at 6p21.1 are associated with large artery atherosclerotic stroke. Nat Genet. 2012;44:1147–1151. - PMC - PubMed
    1. Cheng YC, Cole JW, Kittner SJ, Mitchell BD. Genetics of ischemic stroke in young adults. Circ Cardiovasc Genet. 2014;7:383–392. - PMC - PubMed
    1. Falcone GJ, Malik R, Dichgans M, Rosand J. Current concepts and clinical applications of stroke genetics. Lancet Neurol. 2014;13:405–418. - PubMed

Publication types

MeSH terms

Associated data

Grants and funding