TY - JOUR
T1 - Genome-wide genotyping demonstrates a polygenic risk score associated with white matter hyperintensity volume in CADASIL
AU - Opherk, Christian
AU - Gonik, Mariya
AU - Duering, Marco
AU - Malik, Rainer
AU - Jouvent, Eric
AU - Hervé, Dominique
AU - Adib-Samii, Poneh
AU - Bevan, Steve
AU - Pianese, Luigi
AU - Silvestri, Serena
AU - Dotti, Maria Teresa
AU - De Stefano, Nicola
AU - Liem, Michael
AU - Boon, Elles M.J.
AU - Pescini, Francesca
AU - Pachai, Chahin
AU - Bracoud, Luc
AU - Müller-Myhsok, Bertram
AU - Meitinger, Thomas
AU - Rost, Natalia
AU - Pantoni, Leonardo
AU - Lesnik Oberstein, Saskia
AU - Federico, Antonio
AU - Ragno, Michele
AU - Markus, Hugh S.
AU - Tournier-Lasserve, Elisabeth
AU - Rosand, Jonathan
AU - Chabriat, Hugues
AU - Dichgans, Martin
PY - 2014/4
Y1 - 2014/4
N2 - 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.
AB - 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.
KW - CADASIL
KW - Cerebral small vessel diseases
KW - Genetics
UR - http://www.scopus.com/inward/record.url?scp=84897414534&partnerID=8YFLogxK
U2 - https://doi.org/10.1161/STROKEAHA.113.004461
DO - https://doi.org/10.1161/STROKEAHA.113.004461
M3 - Article
C2 - 24578207
SN - 0039-2499
VL - 45
SP - 968
EP - 972
JO - Stroke
JF - Stroke
IS - 4
ER -