Christian Opherk1, Mariya Gonik1, Marco Duering1, Rainer Malik1, Éric Jouvent1, Dominique Hervé1, Poneh Adib‐Samii1, Steve Bevan1, Luigi Pianese1, Serena Silvestri1, Maria Teresa Dotti1, Nicola De Stefano1, Michael Liem1, Elles M. J. Boon1, Francesca Pescini1, Chahin Pachaï1, Luc Bracoud1, Bertram Müller‐Myhsok1, Thomas Meitinger1, Natalia S. Rost1, Leonardo Pantoni1, Saskia A.J. Lesnik Oberstein1, Antonio Federico1, Michele Ragno1, Hugh S. Markus1, Elisabeth Tournier‐Lasserve1, Jonathan Rosand1, Hugues Chabriat1, Martin Dichgans1
1From 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...
Tóm tắt
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.
