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Open Access Green as soon as Postprint is submitted to ZB.
Genome-wide genotyping demonstrates a polygenic risk score associated with white matter hyperintensity volume in CADASIL.
Stroke 45, 968-972 (2014)
BACKGROUND AND PURPOSE: White matter hyperintensities (WMH) on MRI are a quantitative marker for sporadic cerebral small vessel disease and are highly heritable. To date, large-scale genetic studies have identified only a single locus influencing WMH burden. This might in part relate to biological heterogeneity of sporadic WMH. The current study searched for genetic modifiers of WMH volume in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a monogenic small vessel disease. METHODS: We performed a genome-wide association study to identify quantitative trait loci for WMH volume by combining data from 517 CADASIL patients collected through 7 centers across Europe. WMH volumes were centrally analyzed and quantified on fluid attenuated inversion recovery images. Genotyping was performed using the Affymetrix 6.0 platform. Individuals were assigned to 2 distinct genetic clusters (cluster 1 and cluster 2) based on their genetic background. RESULTS: Four hundred sixty-six patients entered the final genome-wide association study analysis. The phenotypic variance of WMH burden in CADASIL explained by all single nucleotide polymorphisms in cluster 1 was 0.85 (SE=0.21), suggesting a substantial genetic contribution. Using cluster 1 as derivation and cluster 2 as a validation sample, a polygenic score was significantly associated with WMH burden (P=0.001) after correction for age, sex, and vascular risk factors. No single nucleotide polymorphism reached genome-wide significance. CONCLUSIONS: We found a polygenic score to be associated with WMH volume in CADASIL subjects. Our findings suggest that multiple variants with small effects influence WMH burden in CADASIL. The identification of these variants and the biological pathways involved will provide insights into the pathophysiology of white matter disease in CADASIL and possibly small vessel disease in general.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Cadasil ; Cerebral Small Vessel Diseases ; Genetics ; Genome-wide Association Study ; Leukoaraiosis
ISSN (print) / ISBN
0039-2499
e-ISSN
1524-4628
Journal
Stroke
Quellenangaben
Volume: 45,
Issue: 4,
Pages: 968-972
Publisher
Lippincott Williams & Wilkins
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Human Genetics (IHG)