NOTCH3 variants are common in the general population and associated with stroke and vascular dementia: an analysis of 200,000 participants


ABSTRACT Background Cysteine-altering NOTCH3 variants identical to those causing the rare monogenic form of stroke, CADASIL, have been reported more common than expected in the general population, but their clinical significance and contribution to stroke and dementia risk in the community remains unclear. Methods Cysteine-altering NOTCH3 variants were identified in UK Biobank whole-exome sequencing data (N=200,632). Frequency of stroke, dementia and other clinical features of CADASIL, and MRI white matter hyperintensity volume were compared between variant carriers and non-carriers. MRIs from those with variants were visually rated, each matched with three controls. Results Of 200,632 participants with exome sequencing data available, 443 (∼1 in 450) carried 67 different cysteine-altering NOTCH3 variants. After adjusting for age, sex, and ancestry principal components, NOTCH3 variant carriers had increased risk of stroke (OR: 2.33, p=0.0003), and vascular dementia (OR: 5.03, p=0.007), and increased WMH volume (standardised difference: 0.52, p