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Stroke. 2014 Apr;45(4):968-72. doi: 10.1161/STROKEAHA.113.004461. Epub 2014 Feb 27.

Genome-wide genotyping demonstrates a polygenic risk score associated with white matter hyperintensity volume in CADASIL.

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From Institute for Stroke and Dementia Research (C.O., M.G., M. Duering, R.M., M. Dichgans), and Department of Neurology (C.O.), Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany; Department of Neurology, DHU NeuroVasc, Hopital Lariboisiere, APHP, Paris, France (E.J., H.C.); Université Paris Diderot, Sorbonne Paris Cité, Génétique des Maladies Vasculaires, INSERM UMR-S740, Paris, France (D.H., E.T.-L.); Stroke and Dementia Research Centre, St George's University of London, London, United Kingdom (P.A.-S., S.B.); Neurology Division and Molecular Medicine Section, Mazzoni Hospital, Ascoli Piceno, Italy (L.P., S.S., M.R.); Department of Medicine, Surgery and Neurosciences, University of Siena, Italy (M.T.D., N.D.S., A.F.); Departments of Radiology (M.L.) and Clinical Genetics (E.M.J.B., S.L.O.), Leiden University Medical Center, Leiden, the Netherlands; Stroke Unit and Neurology, Azienda Ospedaliero Universitaria Careggi, Florence, Italy (F.P., L.P.); BioClinica Inc, Lyon, France (C.P., L.B.); Max-Planck Institute of Psychiatry, Munich, Germany (B.M.-M.); Institute of Human Genetics, Helmholtz Center, Munich, Germany (T.M.); Center for Human Genetic Research and Department of Neurology, Massachusetts General Hospital, Boston, MA (N.R., J.R.); Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (H.S.M.); Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (J.R.); and Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M. Dichgans).



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.


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.


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.


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.


CADASIL; cerebral small vessel diseases; genetics; genome-wide association study; leukoaraiosis

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