ImportanceIt is uncertain whether typical variants causing monogenic stroke are associated with cerebrovascular disease in the general population and why the phenotype of these variants varies so widely.ObjectiveTo determine the frequency of pathogenic variants in the 3 most common monogenic cerebral small vessel diseases (cSVD) and their associations with prevalent and incident stroke and dementia.Design, Setting, and ParticipantsThis cohort study is a multicenter population-based study of data from UK Biobank participants recruited in 2006 through 2010, with the latest follow-up in September 2021. A total of 9.2 million individuals aged 40 to 69 years who lived in the United Kingdom were invited to join UK Biobank, of whom 5.5% participated in the baseline assessment. Participants eligible for our study (n = 454 756, excluding 48 569 with incomplete data) had whole-exome sequencing and available data pertaining to lacunar stroke-related diseases, namely stroke, dementia, migraine, and epilepsy.ExposuresNOTCH3, HTRA1, and COL4A1/2 pathogenic variants in monogenic stroke; Framingham cardiovascular risk; and ischemic stroke polygenic risk.Main Outcomes and MeasuresPrimary outcomes were prevalent and incident stroke and dementia. Odds ratios (ORs) and hazard ratios (HRs) were adjusted for age, sex, ethnicity, exome sequencing batch, and top 10 genetic principal components.ResultsOf the 454 756 participants (208 027 [45.8%] men; mean [SD] age, 56.5 [8.1] years), 973 participants carried NOTCH3 variants, 546 carried HTRA1 variants, and 336 carried COL4A1/2 variants. Variant carriers were at least 66% more likely to have had stroke. NOTCH3 carriers had increased vascular dementia risk (OR, 5.42; 95% CI, 3.11-8.74), HTRA1 carriers an increased all-cause dementia risk (OR, 2.17; 95% CI, 1.28-3.41), and COL4A1/2 carriers an increased intracerebral hemorrhage risk (OR, 3.56; 95% CI, 1.34-7.53). NOTCH3 variants were associated with incident ischemic stroke and vascular dementia. NOTCH3 and HTRA1 variants were associated with magnetic resonance imaging markers of cSVD. Cardiovascular risk burden was associated with increased stroke risk in NOTCH3 and HTRA1 carriers. Variant location was also associated with risk.Conclusions and RelevanceIn this cohort study, pathogenic variants associated with rare monogenic stroke were more common than expected in the general population and associated with stroke and dementia. Cardiovascular risk burden is associated with the penetrance of such variants. Our results support the hypothesis that cardiovascular risk factor control may improve disease prognosis in individuals with monogenic cSVD variants. This lays the foundation for future studies to evaluate the effect of early identification before symptom onset on mitigating stroke and dementia risk.

Cerebral small vessel disease (SVD) affects the small vessels in the brain and is a leading cause of stroke and dementia. Emerging evidence supports a role of the extracellular matrix (ECM), at the interface between blood and brain, in the progression of SVD pathology but this remains poorly characterized. To address ECM role in SVD, we developed a co-culture model of mural and endothelial cells using human induced pluripotent stem cells from patients with COL4A1/A2 SVD-related mutations. This model revealed that these mutations induce apoptosis, migration defects, ECM remodelling and transcriptome changes in mural cells. Importantly, these mural cell defects exert a detrimental effect on endothelial cells tight junctions through paracrine actions. COL4A1/A2 models also express high levels of matrix metalloproteinases (MMP) and inhibiting MMP activity partially rescues the ECM abnormalities and mural cell phenotypic changes. These data provide a basis for targeting MMP as a therapeutic opportunity in SVD.

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.