Whole genome sequencing identifies rare variants in ANK1, LRRN1, HAS1, and other genes and gene regulatory regions for stroke in type 1 diabetes

Individuals with type 1 diabetes (T1D) carry a markedly increased risk of stroke, with distinct clinical and neuroimaging characteristics as compared to those without diabetes. Therefore, we studied stroke genetics in individuals with T1D using whole-genome sequencing (N=571) and whole-exome sequencing (N=480). We attempted replication of the lead discoveries in our T1D specific cohort using a genome-wide association study (N=3,945) and genotyping (N=3,600), and in the general population from the large-scale population-wide FinnGen project and UK Biobank summary statistics. We analysed the genome comprehensively with single-variant analyses, gene aggregate analyses, and aggregate analyses on genomic windows, enhancers and promoters. We discovered T1D specific stroke loci on 4q33-34.1, SREBF1, and ANK1; and stroke loci that likely generalize to the non-diabetic population on HAS1, LRRN1, UACA, LTB4R, LINC01500 (promoter capture loop to DACT1), and TRPM2-AS promoter. We further validated the promoter with an in vitro cell-based assay.