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

Christian Opherk, Mariya Gonik, Marco Duering, Rainer Malik, Eric Jouvent, Dominique Hervé, Poneh Adib-Samii, Steve Bevan, Luigi Pianese, Serena Silvestri, Maria Teresa Dotti, Nicola De Stefano, Michael Liem, Elles M.J. Boon, Francesca Pescini, Chahin Pachai, Luc Bracoud, Bertram Müller-Myhsok, Thomas Meitinger, Natalia RostLeonardo Pantoni, Saskia Lesnik Oberstein, Antonio Federico, Michele Ragno, Hugh S. Markus, Elisabeth Tournier-Lasserve, Jonathan Rosand, Hugues Chabriat, Martin Dichgans

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


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.

Original languageEnglish
Pages (from-to)968-972
Number of pages5
Issue number4
StatePublished - Apr 2014
Externally publishedYes


  • Cerebral small vessel diseases
  • Genetics


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