Candidate Genes For Small Vessel Ischemic Stroke: A Gwas Pilot Study

Background: The genetic basis of small vessel stroke (SVS) is poorly understood. Few genetic loci have been identified that may provide insights into SVS pathogenesis. We sought to identify genetic associations with incident SVS. Methods: A GWAS analysis was performed on a prospective cohort of patients enrolled in the American Stroke Association- Bugher Small Vessel Intracranial Disease Whole Genome Association Study which included patients from 4 hospitals in North Carolina recruited between December 2007-August 2012. Patients with SVS in the prior 2 years confirmed clinically and on neuroimaging were compared to a control group who had no previous history of stroke. A logistic regression model with SVS as the outcome and single nucleotide polymorphisms (SNPs) as the main predictor was performed and adjusted for baseline demographics and clinical characteristics, including age, race/ethnicity, sex, tobacco use, history of hypertension, diabetes, hyperlipidemia, atrial fibrillation, history of stroke/TIA, and principal components. Because of the relatively small sample size, SNPs with p-values <1E-4 were considered significant. Results: The cohort included 139 patients who had SVS and 64 controls. Among this cohort, 50% were men and 38% African-American. The mean age of the study group was 63-years. Sixteen SNPs in 9 genes met the statistical cutoff for association with SVS. These were involved in extracellular matrix integrity (CHD23, CLDN14, SPTBN1), neuronal differentiation (DSCAML1), cholesterol transport (GRAMD1B), transcriptional regulation (JARID2, LINC02111, LINC01993) and voltage-gated potassium channel (KCND2). Conclusion: In this pilot GWAS study, several loci variations were associated with SVS. Although this study is hypothesis generating, previous studies have also shown an association of SVS with genes involved in extracellular matrix integrity. In addition, we found it interesting that SNPs in both CLDN14 and CDH23 genes, which have been linked to non-syndromic sensorineural deafness, are also more common in SVS. Some forms of sensorineural deafness have been associated with cognitive impairment and stroke, and if a genetic association is confirmed, it would suggest a common pathophysiology may link the two conditions.