 and structural integrity of small arteries by regulating vascular smooth muscle cell differentiation, maturation and phenotypic behaviour ([@awr252-B4]; [@awr252-B16]; [@awr252-B53]). We hypothesized that Notch3 not only plays a role in CADASIL but is also involved in the development of age-related cerebral small vessel disease, with both common and rare single nucleotide polymorphisms (SNPs) of the *NOTCH3* gene contributing to the risk of this multi-factorial disorder. We took a two step approach to evaluate this hypothesis in the setting of the Austrian Stroke Prevention Study. First, we screened the promoter, the coding and the 3' untranslated region of the *NOTCH3* gene for the presence of mutations in all individuals with either coalescent white matter lesions or lacunes and compared the frequency of genetic variants to a random subset of participants from the Austrian Stroke Prevention Study who were free from focal lesions on MRI. We then genotyped the whole cohort (*n = *888) for the observed common SNPs (minor allele frequency ≥ 5%) and assessed their association with the presence of white matter lesions and lacunes as a primary phenotype and white matter lesion progression as a secondary phenotype. We sought to replicate our finding in an independent sample of 8545 stroke-free individuals of European descent in the Cohorts for Heart and Ageing Research in Genomic Epidemiology (CHARGE) Consortium including six community-based cohorts with brain MRI scans and genome-wide genotype data ([@awr252-B19]). We further elucidated the effects of the rare (minor allele frequency \<5%) non-synonymous SNPs in the *NOTCH3* gene by studying their association with CADASIL-specific clinical and MRI characteristics and by analysing the possible functionality of non-synonymous SNPs using bioinformatical tools.

Materials and methods
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Study population
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The Austrian Stroke Prevention Study is a prospective cohort study on the effects of vascular risk factors on brain struct