COL4A2 is associated with lacunar ischemic stroke and deep ICH: Meta-analyses among 21,500 cases and 40,600 controls

Stroke Genetics Network (SiGN), METASTROKE Collaboration, and International Stroke Genetics Consortium (ISGC), Graeme J. Hankey

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Abstract

OBJECTIVE: To determine whether common variants in familial cerebral small vessel disease (SVD) genes confer risk of sporadic cerebral SVD.

METHODS: We meta-analyzed genotype data from individuals of European ancestry to determine associations of common single nucleotide polymorphisms (SNPs) in 6 familial cerebral SVD genes (COL4A1,COL4A2,NOTCH3,HTRA1,TREX1, andCECR1) with intracerebral hemorrhage (ICH) (deep, lobar, all; 1,878 cases, 2,830 controls) and ischemic stroke (IS) (lacunar, cardioembolic, large vessel disease, all; 19,569 cases, 37,853 controls). We applied data quality filters and set statistical significance thresholds accounting for linkage disequilibrium and multiple testing.

RESULTS: A locus inCOL4A2was associated (significance thresholdp< 3.5 × 10-4) with both lacunar IS (lead SNP rs9515201: odds ratio [OR] 1.17, 95% confidence interval [CI] 1.11-1.24,p= 6.62 × 10-8) and deep ICH (lead SNP rs4771674: OR 1.28, 95% CI 1.13-1.44,p= 5.76 × 10-5). A SNP inHTRA1was associated (significance thresholdp< 5.5 × 10-4) with lacunar IS (rs79043147: OR 1.23, 95% CI 1.10-1.37,p= 1.90 × 10-4) and less robustly with deep ICH. There was no clear evidence for association of common variants in eitherCOL4A2orHTRA1with non-SVD strokes or in any of the other genes with any stroke phenotype.

CONCLUSIONS: These results provide evidence of shared genetic determinants and suggest common pathophysiologic mechanisms of distinct ischemic and hemorrhagic cerebral SVD stroke phenotypes, offering new insights into the causal mechanisms of cerebral SVD.

Original languageEnglish
Pages (from-to)1829-1839
Number of pages11
JournalNeurology
Volume89
Issue number17
DOIs
Publication statusPublished - 24 Oct 2017

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