Replication of Top Loci from COL4A1/2 Associated with White Matter Hyperintensity Burden in Patients with Ischemic Stroke

Background and Purpose: The purpose of this study was to replicate the top loci associated with white matter hyperintensity (WMH) phenotypes identified by large genome-wide association studies and the loci identified from the previous candidate gene studies. Methods: A total of 946 Geisinger MyCode patients with acute ischemic stroke with validated European ancestry and magnetic resonance imaging data were included in this study. Log-transformed WMH volume, as a quantitative trait, was calculated by a fully automated quantification process. The genome-wide association studies was carried out by a linear mixed regression model (GEMMA). A candidate-single nucleotide polymorphism analysis by including known single nucleotide polymorphisms, reported from a meta-analysis and several large GWAS for WMH, was conducted in all cases and binary converted extreme cases. Results: No genome-wide significantly associated variants were identified. In a candidate-single nucleotide polymorphism study, rs9515201 (COL4A2) and rs3744028 (TRIM65), 2 known genetic loci, showed nominal or trend of association with the WMH volume (β=0.13 and P=0.001 for rs9515201; β=0.094 and P=0.094 for rs3744028), and replicated in a subset of extreme cases versus controls (odds ratio=1.78, P=7.74×10^-4for rs9515201; odds ratio=1.53, P=0.047 for rs3744028, respectively). MTHFR677 cytosine/thymine (rs1801133) also showed an association with the binary WMH with odds ratio=1.47 for T allele (P=0.019). Conclusions: Replication of COL4A1/2 associated with WMH reassures that the genetic risk factors for monogenic and polygenic ischemic stroke are shared at gene level.