NOTCH3 variants are more common than expected 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 (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), 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 remain unclear.

Methods: Cysteine-altering NOTCH3 variants were identified in UK Biobank whole-exome sequencing data (N=200 632). Frequency of stroke, vascular 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 adjustment for various covariates, NOTCH3 variant carriers had increased risk of stroke (OR: 2.33, p=0.0004) and vascular dementia (OR: 5.00, p=0.007), and increased white matter hyperintensity volume (standardised difference: 0.52, p<0.001) and white matter ultrastructural damage on diffusion MRI (standardised difference: 0.72, p<0.001). On visual analysis of MRIs from 47 carriers and 148 matched controls, variants were associated with presence of lacunes (OR: 5.97, p<0.001) and cerebral microbleeds (OR: 4.38, p<0.001). White matter hyperintensity prevalence was most increased in the anterior temporal lobes (OR: 7.65, p<0.001) and external capsule (OR: 13.32, p<0.001).

Conclusions: Cysteine-changing NOTCH3 variants are more common in the general population than expected from CADASIL prevalence and are risk factors for apparently 'sporadic' stroke and vascular dementia. They are associated with MRI changes of small vessel disease, in a distribution similar to that seen in CADASIL.

Figure 1

Lolliplot showing the distribution of distinct pathogenic variants in UK Biobank across the reverse strand of the NOTCH3 gene. Lighter circles represent variants without rsID; darker circles represent variants with rsID; lighter rectangular boxes represent exons that encode EGFRs 7–34; darker rectangular boxes represent exons that encode EGFRs 1–6. EGFR, epidermal growth factor-like repeat.

Figure 2

Forest plot showing the association of NOTCH3 variant with different diagnoses. Family history and prevalence of disease cases were analysed with the presence of NOTCH3 variant through logistic regression. Firth’s correction was applied to all the regression models. N=200 632. *Significance at p<0.05.

Figure 3

Forest plot showing the effect of NOTCH3 variant location on the odds of stroke or vascular dementia. The location of variant was stratified by EGFRs 7–34 and EGFRs 1–6; their effect on disease risk was relative to that without the variant. Firth’s correction was applied to all the regression models. N=200 632. *Significance at p<0.05. EGFR, epidermal growth factor-like repeat.

Figure 4

Axial T2 FLAIR brain MRI of two subjects with a pathogenic NOTCH3 variant in UK Biobank. (A) A woman in her 50s, carrying a p.Arg1231Cys variant that affects EGFR domain 31, with WMH involving the right anterior temporal lobe (arrow). (B) A man in his 60s, carrying a p.Arg578Cys variant that affects EGFR domain 14, with WMH involving the external capsule bilaterally (arrows). EGFR, epidermal growth factor-like repeat; FLAIR, fluid attenuated inversion recovery; WMH, white matter hyperintensity.

Figure 5

Forest plot showing the severity of WMH in different brain regions. Inversely transformed measures of the Schelten’s scale were analysed with the presence of NOTCH3 variant through linear regression. A total of 193 participants were included in the regression analyses, of which 45 were variant carriers and 148 were non-carriers. *Significance p<0.05. WM, white matter; WMH, white matter hyperintensity.

Figure 6

Estimated polygenic risk equivalent for the association of NOTCH3 status with ischaemic stroke. Average=ratio of the log-OR of models of NOTCH3 status and a 1 SD increase in polygenic risk score (PRS) for ischaemic stroke; conservative NOTCH3=ratio of the lower 95% CI of the log-OR for NOTCH3 status and the log-OR for a 1 SD increase in PRS for ischaemic stroke; most conservative=ratio of the lower 95% CI of the log-OR for NOTCH3 status and the upper 95% CI of the log-OR for a 1 SD increase in PRS for ischaemic stroke. Population percentages calculated using a 1-sided z-score.