Whole Exome Sequencing Analyses Support a Role of Vitamin D Metabolism in Ischemic Stroke

Ischemic stroke (IS) is a highly heritable trait. Genome-wide association studies have identified several commonly occurring susceptibility risk loci for this condition. However, there are limited data on the contribution of rare genetic variation to IS. We conducted a whole-exome association study of IS in 152,058 UK Biobank participants (mean age 57, 6.8 [SD 8.0], 83,131 [54.7%] were females), including 1,777 IS cases (mean age 61.4 [SD 6.6], 666 [37.5%] were females). We performed single-variant analyses for all variants and gene-based analyses for loss of function and deleterious missense rare variants. In the gene-based analysis, rare genetic variation at CYP2R1 was significantly associated with IS risk (P=2.6x10-6), exceeding the Bonferroni-corrected threshold for 16,074 tests (P<3.1 x 10-6). We first replicated these findings using summary statistics from a genome-wide association study that included 67,162 IS cases and 454,450 controls (gene-based test for CYP2R1, P=0.003). We pursued a second replication focused on IS recurrence using individual-level data from 1,706 IS survivors, including 142 cases of recurrent IS, enrolled in the VISP trial (gene-based test for CYP2R1, P=0.001). We also found that common genetic variation at CYP2R1 was associated with white matter hyperintensity volume (42,310 participants) and both mean diffusivity and fractional anisotropy (17,663 participants) in the subcohort of UK Biobank (all gene-based tests P<0.05). Because CYP2R1 plays an important role in vitamin D metabolism, our results support a role of this pathway in the occurrence of ischemic cerebrovascular disease.