학술논문
Cerebral small vessel disease genomics and its implications across the lifespan
Document Type
Electronic Resource
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Sargurupremraj , M , Suzuki , H , Jian , X , Sarnowski , C , Evans , T E , Bis , J C , Eiriksdottir , G , Sakaue , S , Terzikhan , N , Habes , M , Zhao , W , Armstrong , N J , Hofer , E , Yanek , L R , Hagenaars , S P , Kumar , R B , van den Akker , E B , McWhirter , R E , Trompet , S , Mishra , A , Saba , Y , Satizabal , C L , Beaudet , G , Petit , L , Tsuchida , A , Zago , L , Schilling , S , Sigurdsson , S , Gottesman , R F , Lewis , C E , Aggarwal , N T , Lopez , O L , Smith , J A , Valdés Hernández , M C , van der Grond , J , Wright , M J , Knol , M J , Dörr , M , Thomson , R J , Bordes , C , Le Grand , Q , Duperron , M G , Smith , A V , Niessen , W J , Pers , T H , Ingason , A , Francke Christensen , A , Folkmann Hansen , T , Werge , T , Olesen , J , International Network against Thrombosis (INVENT) Consortium & International Headache Genomics Consortium (IHGC) 2020 , ' Cerebral small vessel disease genomics and its implications across the lifespan ' , Nature Communications , vol. 11 , no. 1 , 6285 .
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Abstract
White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.