학술논문
Cerebral small vessel disease genomics and its implications across the lifespan.
Document Type
article
Author
Sargurupremraj, Muralidharan; Suzuki, Hideaki; Jian, Xueqiu; Sarnowski, Chloé; Evans, Tavia E; Bis, Joshua C; Eiriksdottir, Gudny; Sakaue, Saori; Terzikhan, Natalie; Habes, Mohamad; Zhao, Wei; Armstrong, Nicola J; Hofer, Edith; Yanek, Lisa R; Hagenaars, Saskia P; Kumar, Rajan B; van den Akker, Erik B; McWhirter, Rebekah E; Trompet, Stella; Mishra, Aniket; Saba, Yasaman; Satizabal, Claudia L; Beaudet, Gregory; Petit, Laurent; Tsuchida, Ami; Zago, Laure; Schilling, Sabrina; Sigurdsson, Sigurdur; Gottesman, Rebecca F; Lewis, Cora E; Aggarwal, Neelum T; Lopez, Oscar L; Smith, Jennifer A; Valdés Hernández, Maria C; van der Grond, Jeroen; Wright, Margaret J; Knol, Maria J; Dörr, Marcus; Thomson, Russell J; Bordes, Constance; Le Grand, Quentin; Duperron, Marie-Gabrielle; Smith, Albert V; Knopman, David S; Schreiner, Pamela J; Evans, Denis A; Rotter, Jerome I; Beiser, Alexa S; Maniega, Susana Muñoz; Beekman, Marian; Trollor, Julian; Stott, David J; Vernooij, Meike W; Wittfeld, Katharina; Niessen, Wiro J; Soumaré, Aicha; Boerwinkle, Eric; Sidney, Stephen; Turner, Stephen T; Davies, Gail; Thalamuthu, Anbupalam; Völker, Uwe; van Buchem, Mark A; Bryan, R Nick; Dupuis, Josée; Bastin, Mark E; Ames, David; Teumer, Alexander; Amouyel, Philippe; Kwok, John B; Bülow, Robin; Deary, Ian J; Schofield, Peter R; Brodaty, Henry; Jiang, Jiyang; Tabara, Yasuharu; Setoh, Kazuya; Miyamoto, Susumu; Yoshida, Kazumichi; Nagata, Manabu; Kamatani, Yoichiro; Matsuda, Fumihiko; Psaty, Bruce M; Bennett, David A; De Jager, Philip L; Mosley, Thomas H; Sachdev, Perminder S; Schmidt, Reinhold; Warren, Helen R; Evangelou, Evangelos; Trégouët, David-Alexandre; International Network against Thrombosis (INVENT) Consortium; International Headache Genomics Consortium (IHGC); Ikram, Mohammad A; Wen, Wei; DeCarli, Charles; Srikanth, Velandai K; Jukema, J Wouter; Slagboom, Eline P; Kardia, Sharon LR
Source
Nature communications. 11(1)
Subject
Language
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.