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


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.

SUBMITTER: Cheng YC 

PROVIDER: S-EPMC4729659 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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

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

Stroke 20160105 2


<h4>Background and purpose</h4>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.<h4>Methods</h4>The discovery stage of our genome-wide association studies i  ...[more]

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