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Common NOTCH3 Variants and Cerebral Small-Vessel Disease
Loes C A Rutten-Jacobs1, Matthew Traylor2, Poneh Adib-Samii2
1From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (L.C.A.R.-J., M.T., S.B., H.S.M.); Stroke and Dementia Research Center, Department of Clinical Neuroscience, St George's University of London, London, United Kingdom (P.A.-S.); Department of Experimental Neurology, KULeuven and Leuven Research Institute for Neuroscience and Disease, University of Leuven, Leuven, Belgium (V.T.); Laboratory of Neurobiology, Vesalius Research Center, VIB, Leuven, Belgium (V.T.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, Oxford, United Kingdom (P.M.R.); Department of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milano, Italy (G.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich, Germany (M.D.); Department of Neurology, Mayo Clinic, Jacksonville, FL (J.M.); Center for Clinical Epidemiology and Biostatistics, Department of Neurology, Hunter Medical Research Institute and School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia (C.L.); Department of Neurology, Center for Human Genetic Research and Massachusetts General Hospital, Boston (N.S.R., J.R.); and Department of Neurology, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom (A.H.). LR406@medschl.cam.ac.uk.
Background And Purpose:
The most common monogenic cause of cerebral small-vessel disease is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, caused by NOTCH3 gene mutations. It has been hypothesized that more common variants in NOTCH3 may also contribute to the risk of sporadic small-vessel disease. Previously, 4 common variants (rs10404382, rs1043994, rs10423702, and rs1043997) were found to be associated with the presence of white matter hyperintensity in hypertensive community-dwelling elderly.
Methods:
We investigated the association of common single nucleotide polymorphisms (SNPs) in NOTCH3 in 1350 patients with MRI-confirmed lacunar stroke and 7397 controls, by meta-analysis of genome-wide association study data sets. In addition, we investigated the association of common SNPs in NOTCH3 with MRI white matter hyperintensity volumes in 3670 white patients with ischemic stroke. In each analysis, we considered all SNPs within the NOTCH3 gene, and within 50-kb upstream and downstream of the coding region. A total of 381 SNPs from the 1000 genome population with a mean allele frequency>0.01 were included in the analysis. A significance level of P<0.0015 was used, adjusted for the effective number of independent SNPs in the region using the Galwey method.
Results:
We found no association of any common variants in NOTCH3 (including rs10404382, rs1043994, rs10423702, and rs1043997) with lacunar stroke or white matter hyperintensity volume. We repeated our analysis stratified for hypertension but again found no association.
Conclusions:
Our study does not support a role for common NOTCH3 variation in the risk of sporadic small-vessel disease.
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