Abstract 28: Genetic Variants From Lysine-Specific Demethylase 4C (KDM4C) Associated With White Matter Hyperintensity Burden in Ischemic Stroke Patients

Abstract

Introduction: Although white matter hyperintensities (WMH) have been linked to cerebrovascular disease, the exact pathogenesis is not known. The purpose of this study was to identify common variants associated with WMH burden among patients with an acute ischemic stroke (AIS) through a genome-wide association study (GWAS). Methods: A total of 946 AIS patients with validated European ancestry and MRI data were included in this study. WMH volume (WMHv), as a quantitative trait, was calculated by a fully-automated quantification process, which integrates the automated brain extraction, intensity normalization, and WMH segmentation using spatial priors. The GWAS was carried out by a linear mixed regression model (GEMMA), adjusted for covariates, to account for the potential population structure and relatedness. The WMHv ranked in top and bottom quantile were converted to a binary trait which represent high and low WMHv subgroups. Results: The rs10815506 (MAF = 0.043; β=3.89; p=6.66E-09), at an intronic region of KDM4C , which encodes Lysine-specific demethylase 4C , was the top signal associated with WMHv. This SNP is in high linkage disequilibrium (LD) (R 2 = 0.79; D’ = 0.93) with rs35389625, a nonsynonymous variant (Asn>Ser), predicted to be pathogenic by SIFT and Polyphen. The rs35389625 was also associated with WMHv but at a lower significance level (MAF=0.040; β=3.19; p=3.21E-06). Patients with homozygous mutant alleles (GG) of rs35389625 showed significantly increased WMHv (14.93±10.15) than GA (7.94±8.48) and AA (5.09±5.85) carriers. Both rs10815506 and rs35389625 also predicted a subset of high and low WMHv group (OR=2.81, p=0.005; OR=2.42, p=0.016, respectively). No significant interaction between the top SNPs at KDM4C and other risk factors was identified in their association with WMHv. We also conducted a candidate-gene analysis by including several known SNPs, gathered from a reported meta-analysis for WMH. The frequency of MTHFR677 cytosine/thymine (rs1801133) showed difference between lower and upper quantile groups with OR=2.18 for T allele (p=0.030), the direction of which was consistent with previous studies. Conclusion: This study provides the first evidence that genetic variants at KDM4C are associated with WMH in AIS patients.