Cerebral small vessel disease genomics and its implications across the lifespan

Muralidharan Sargurupremraj, Hideaki Suzuki, Xueqiu Jian, Chloé Sarnowski, Tavia E Evans, Joshua C. Bis, Gudny Eiriksdottir, Saori Sakaue, Natalie Terzikhan, Mohamad Habes, Wei Zhao, Nicola J Armstrong, Edith Hofer, Lisa R. Yanek, Saskia Hagenaars, Kumar B Rajan, Erik van den Akker, Rebekah E McWhirter, Stella Trompet, Aniket MishraYasaman Saba, Claudia L Satizabal, Gregory Beaudet, Laurent Petit, Ami Tsuchida, Laura Zago, Sabrina Schilling, Sigurdur Sigurdsson, Rebecca F Gottesman, Cora E Lewis, Neelum T Aggarwal, Oscar L Lopez, Jennifer A. Smith, Maria Valdes Hernandez, Jeroen van der Grond, Margaret J Wright, Maria J. Knol, Marcus Dörr, Russell Thomson, Constance Bordes, Quentin Le Grand, Marie-Gabrielle Duperron, Albert V Smith, David S. Knopman, Pamela J Schreiner, Denis A Evans, Jerome I Rotter, Alexa S Beiser, Susana Muñoz Maniega, Marian Beekman, Julian N. Trollor, David J Stott, Meike W Vernooij, Katharina Wittfield, Wiro J. Niessen, Aïcha Soumaré, Eric Boerwinkle, Stephen S Sidney, Stephen T Turner, Gail Davies, Anbupalam Thalamuthu, Uwe Völker, Mark A Van Buchem, R Nick Bryan, Josée Dupuis, Mark Bastin, David Ames, Alexander Teumer, Philippe Amouyel, John B J Kwok, Robin Bülow, Ian Deary, Peter R Schofield, Henry Brodaty, Jiyang Jiang, Yasuharu Tabara, Kazuya Setoh, Susumu Miyamoto, Kazumichi Yoshida, Manabu Nagata, Yoichiro Kamatani, Fumihiko Matsuda, Bruce M. Psaty, David A Bennett, Philip L De Jager, Thomas H Mosley, Perminder S Sachdev, Reinhold Schmidt, Helen R. Warren, Evangelos Evangelou, David Alexandre Trégouët, Mohammad A Ikram, Wei Wen, Charles DeCarli, Velandai K Srikanth, J. Wouter Jukema, P Eline Slagboom, Sharon L R Kardia, Yukinori Okada, Bernard Mazoyer, Joanna Wardlaw, Paul A Nyquist, Karen A Mather, Hans J Grabe, Helena Schmidt, Cornelia van Duijn, Vilmundur Gudnason, William T. Longstreth, Launer J Lenore, G Mark Lathrop, Archie Campbell, Sudha Seshadri, Christophe Tzourio, Hieab H H Adams, Paul M Matthews, Myriam Fornage, Stéphanie Debette

Research output: Contribution to journalArticlepeer-review

Abstract

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral 240 small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 241 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for 242 modification/confounding by hypertension. Aggregated WMH risk variants were associated 243 with altered white matter integrity (p=2.5x10-7) in brain images from 1,738 young healthy 244 adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization 245 suggested causal association of increasing WMH-volume with stroke, Alzheimer-type 246 dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in 247 persons without clinical hypertension. Transcriptome-wide colocalization analyses showed 248 association of WMH-volume with expression of 39 genes, of which four encode known drug 249 targets. Finally, we provide insight into BP-independent biological pathways underlying SVD 250 and suggest potential for genetic stratification of high-risk individuals and for genetically-251 informed prioritization of drug targets for prevention trials.
Original languageEnglish
JournalNature Communications
Early online date8 Dec 2020
DOIs
Publication statusE-pub ahead of print - 8 Dec 2020

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