The prevalence and penetrance of monogenic small vessel stroke variants in 450,000 UK Biobank participants

Abstract:

Background and Aims: NOTCH3, HTRA1 and COL4A1/2 variants identical to those causing monogenic forms of stroke appear more common than expected in the general population. This study aims to examine their association with disease, and factors that may modify their penetrance in the community. Methods: HTRA1 and COL4A1/2 variants, reported in familial cerebral small vessel disease (SVD) cases, were examined for pathogenicity using the ACMG guidelines. The variants, along with the established pathogenic cysteine-altering variants in NOTCH3, were identified in UK Biobank whole-exome sequencing data. Frequency of stroke, dementia and other clinical manifestations of familial stroke, and MRI features were compared between variant carriers and non-carriers. Statistical tests for interaction were performed for Framingham cardiovascular risk score, ischaemic stroke polygenic risk score and variant status. Results: Of 454,787 participants, 973 carried NOTCH3 variants, 546 carried HTRA1 variants, and 336 carried COL4A1/2 variants. After adjustment for covariates, variant carriers were at least 66% more likely to have a history of stroke. Additionally, NOTCH3 carriers had increased risk of vascular dementia (OR=5.41, 95% CI=3.10-8.72), HTRA1 carriers an increased risk of all-cause dementia (OR=2.15, 95% CI=1.27-3.39), and COL4A1/2 carriers an increased risk of intracerebral haemorrhage (OR=3.55, 95% CI=1.33-7.50). NOTCH3 and HTRA1 carriers had MRI features consistent with monogenic SVD. Cardiovascular risk factors and variant location affected the penetrance of these associations. Conclusions: Pathogenic variants in NOTCH3, HTRA1 and COL4A1/2 are risk factors for apparently “sporadic” stroke and dementia in the community. Intensive cardiovascular risk factor modification is likely to reduce stroke and dementia risk in individuals with these variants.