Genome-wide genotyping demonstrates a polygenic risk score associated with white matter hyperintensity volume in CADASIL.
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.
['Opherk|Christian|C|', 'Gonik|Mariya|M|', 'Duering|Marco|M|', 'Malik|Rainer|R|', 'Jouvent|Eric|E|', 'Hervé|Dominique|D|', 'Adib-Samii|Poneh|P|', 'Bevan|Steve|S|', 'Pianese|Luigi|L|', 'Silvestri|Serena|S|', 'Dotti|Maria Teresa|MT|', 'De Stefano|Nicola|N|', 'Liem|Michael|M|', 'Boon|Elles M J|EM|', 'Pescini|Francesca|F|', 'Pachai|Chahin|C|', 'Bracoud|Luc|L|', 'Müller-Myhsok|Bertram|B|', 'Meitinger|Thomas|T|', 'Rost|Natalia|N|', 'Pantoni|Leonardo|L|', 'Lesnik Oberstein|Saskia|S|', 'Federico|Antonio|A|', 'Ragno|Michele|M|', 'Markus|Hugh S|HS|', 'Tournier-Lasserve|Elisabeth|E|', 'Rosand|Jonathan|J|', 'Chabriat|Hugues|H|', 'Dichgans|Martin|M|']
D000328:Adult D000368:Aged D046589:CADASIL D005260:Female D020022:Genetic Predisposition to Disease D055106:Genome-Wide Association Study D006801:Humans D006973:Hypertension D056784:Leukoencephalopathies D008279:Magnetic Resonance Imaging D008297:Male D008875:Middle Aged D008957:Models, Genetic D040641:Quantitative Trait Loci D012307:Risk Factors
CADASIL cerebral small vessel diseases genetics genome-wide association study leukoaraiosis