Abstract | BACKGROUND AND PURPOSE: METHODS: Using genome-wide association study results for 14 coagulation factors from the population-based TwinsUK sample (N≈2000 for each factor), meta-analysis results from the METASTROKE consortium ischemic stroke genome-wide association study (12 389 cases, 62 004 controls), and genotype data for 9520 individuals from the WTCCC2 ischemic stroke study (3548 cases, 5972 controls-the largest METASTROKE subsample), we explored shared genetic risk for coagulation and stroke. We performed three analyses: (1) a test for excess concordance (or discordance) in single nucleotide polymorphism effect direction across coagulation and stroke, (2) an estimation of the joint effect of multiple coagulation-associated single nucleotide polymorphisms in stroke, and (3) an evaluation of common genetic risk between coagulation and stroke. RESULTS: One coagulation factor, factor XIII subunit B (FXIIIB), showed consistent effects in the concordance analysis, the estimation of polygenic risk, and the validation with genotype data, with associations specific to the cardioembolic stroke subtype. Effect directions for FXIIIB-associated single nucleotide polymorphisms were significantly discordant with cardioembolic disease (smallest P=5.7×10(-04)); the joint effect of FXIIIB-associated single nucleotide polymorphisms was significantly predictive of ischemic stroke (smallest P=1.8×10(-04)) and the cardioembolic subtype (smallest P=1.7×10(-04)). We found substantial negative genetic covariation between FXIIIB and ischemic stroke (rG=-0.71, P=0.01) and the cardioembolic subtype (rG=-0.80, P=0.03). CONCLUSIONS:
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Authors | Ken B Hanscombe, Matthew Traylor, Pirro G Hysi, Stephen Bevan, Martin Dichgans, Peter M Rothwell, Bradford B Worrall, Sudha Seshadri, Cathie Sudlow, METASTROKE Consortium, Wellcome Trust Case Control Consortium 2, Frances M K Williams, Hugh S Markus, Cathryn M Lewis |
Journal | Stroke
(Stroke)
Vol. 46
Issue 8
Pg. 2069-74
(Aug 2015)
ISSN: 1524-4628 [Electronic] United States |
PMID | 26159793
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2015 The Authors. |
Chemical References |
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Topics |
- Brain Ischemia
(diagnosis, epidemiology, genetics)
- Case-Control Studies
- Cohort Studies
- Diseases in Twins
(diagnosis, epidemiology, genetics)
- Factor XIII
(genetics)
- Female
- Genetic Predisposition to Disease
(epidemiology, genetics)
- Genome-Wide Association Study
(methods)
- Humans
- Male
- Meta-Analysis as Topic
- Polymorphism, Single Nucleotide
(genetics)
- Risk Factors
- Stroke
(diagnosis, epidemiology, genetics)
- Twin Studies as Topic
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