Abstract 148: Whole Exome Sequence Analysis of Cerebral White Matter Hyperintensities on MRI

White matter hyperintensities (WMH) detected on MRI are commonly identified abnormalities in the adult brain, and are associated with a greater risk of stroke, dementia, and death. Genetic factors play a significant role in WMH etiology, yet, common genetic variants identified by GWAS explain little of the variance in WMH burden. Rare variants with larger effect on the phenotype may be identified from sequence analysis of the protein-coding region of the genome (exome). We sequenced the protein-coding regions of 16,541 genes in 2510 individuals of European or African ancestry from three NHLBI cohorts, and investigated whether putatively functional exomic variants were associated with WMH burden, either individually or in aggregate within a gene. Within each cohort, we used the SeqMeta R package to compute race-specific score statistics for each variant and genotypic covariance matrices within predefined gene regions. These were then combined by meta-analysis to generate single-variant and gene-based tests...