Journal Article

Cerebral small vessel disease genomics and its implications across the lifespan

McWhirter, Rebekah E., Evans, Denis A., Psaty, Bruce M., Schilling, Sabrina, Gudnason, Vilmundur, Schreiner, Pamela J., Jiang, Jiyang, Tzourio, Christophe, Tabara, Yasuharu, Bordes, Constance, Sachdev, Perminder S., Fornage, Myriam, Bülow, Robin, van Buchem, Mark A., Jian, Xueqiu, Bryan, R. Nick, Le Grand, Quentin, Yanek, Lisa R., Gottesman, Rebecca F., Eiriksdottir, Gudny, DeCarli, Charles, Dörr, Marcus, Srikanth, Velandai K., Sidney, Stephen, Hofer, Edith, Okada, Yukinori, Hagenaars, Saskia P., Lathrop, Mark, Beekman, Marian, Knopman, David S., Schofield, Peter R., Miyamoto, Susumu, Schmidt, Helena, Jukema, J. Wouter, Sakaue, Saori, Beiser, Alexa S., Davies, Gail, Boerwinkle, Eric, Adams, Hieab H., Bastin, Mark E., Debette, Stéphanie, Zhao, Wei, Turner, Stephen T., Thomson, Russell J., Kumar, Rajan B., Slagboom, Eline P., Stott, David J., Schmidt, Reinhold, Wright, Margaret J., Nagata, Manabu, Warren, Helen R., Kwok, John B., Wittfeld, Katharina, Smith, Albert V., Yoshida, Kazumichi, Smith, Jennifer A., Armstrong, Nicola J., Nyquist, Paul A., Saba, Yasaman, Matsuda, Fumihiko, Trollor, Julian, Wen, Wei, va

2020

Overview

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. White matter hyperintensities (WMH) are a common brain-imaging feature of cerebral small vessel disease. Here, the authors carry out a GWAS and followup analyses for WMH-volume, implicating several variants with potential for risk stratification and drug targeting.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45/43 / 631/208/205/2138 / 692/617/375/599 / Adult / Aged / Aged, 80 and over / Alzheimer Disease - epidemiology / Alzheimer Disease - genetics / Blood pressure / Blood vessels / Brain / Cerebral Small Vessel Diseases - complications / Cerebral Small Vessel Diseases - diagnosis / Cerebral Small Vessel Diseases - genetics / Clinical trials / Cognitive science / Dementia disorders / Diffusion Tensor Imaging / Female / Gene expression / Genetic Loci / Genome-Wide Association Study / Genomics / Health risk assessment / Humanities and Social Sciences / Humans / Hypertension / Hypertension - epidemiology / Hypertension - genetics / Life span / Male / Medical History Taking / Medical imaging / Mendelian Randomization Analysis / Middle Aged / multidisciplinary / Neuroimaging / Neuroscience / Risk analysis / Risk Assessment / Risk Factors / Science / Science (multidisciplinary) / Stroke - epidemiology / Stroke - genetics / Substantia alba / Therapeutic targets / Vascular diseases / White Matter - diagnostic imaging / Young Adult