Both vascular risk factors and common genetic variants influence penetrance of variants causing monogenic stroke

ABSTRACT Monogenic forms of stroke have been thought to be rare with high penetrance. However, recent studies have reported typical monogenic stroke pathogenic variants are much commoner than expected in the general population. Whether such variants are associated with disease, and why the phenotype of these variants varies so widely remain unclear. In 454,787 individuals in UK Biobank, we identified typical pathogenic variants in NOTCH3, HTRA1 and COL4A1/2 genes in 1 in 467, 1 in 832 and 1 in 1353 subjects, respectively. Variants in all three genes were associated with stroke risk, and NOTCH3 and HTRA1 with dementia risk. Cardiovascular risk (assessed by Framingham cardiovascular risk score), polygenic risk (assessed by a polygenic stroke risk score), and variant location within each gene, were all associated with penetrance of NOTCH3 and HTRA1 variants. Our results suggest intensive cardiovascular risk factor modification may reduce stroke and dementia risk in individuals with such variants.