Nat Commun
Published

Cerebral small vessel disease genomics and its implications across the lifespan.

Authors

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 P Hagenaars, Rajan B Kumar, Erik B van den Akker, Rebekah E McWhirter, Stella Trompet, Aniket Mishra, Yasaman Saba, Claudia L Satizabal, Gregory Beaudet, Laurent Petit, Ami Tsuchida, Laure Zago, Sabrina Schilling, Sigurdur Sigurdsson, Rebecca F Gottesman, Cora E Lewis, Neelum T Aggarwal, Oscar L Lopez, Jennifer A Smith, Maria C Valdés Hernández, Jeroen van der Grond, Margaret J Wright, Maria J Knol, Marcus Dörr, Russell J 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 Trollor, David J Stott, Meike W Vernooij, Katharina Wittfeld, Wiro J Niessen, Aicha Soumaré, Eric Boerwinkle, Stephen Sidney, Stephen T Turner, Gail Davies, Anbupalam Thalamuthu, Uwe Völker, Mark A van Buchem, R Nick Bryan, Josée Dupuis, Mark E Bastin, David Ames, Alexander Teumer, Philippe Amouyel, John B Kwok, Robin Bülow, Ian J 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, Eline P Slagboom, Sharon L R Kardia, Yukinori Okada, Bernard Mazoyer, Joanna M Wardlaw, Paul A Nyquist, Karen A Mather, Hans J Grabe, Helena Schmidt, Cornelia M Van Duijn, Vilmundur Gudnason, William T Longstreth, Lenore J Launer, Mark Lathrop, Sudha Seshadri, Christophe Tzourio, Hieab H Adams, Paul M Matthews, Myriam Fornage, Stéphanie Debette
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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.

PMID:33293549 | DOI:10.1038/s41467-020-19111-2

UK DRI Authors

Stéphanie Debette

Prof Stéphanie Debette

Professor of Epidemiology and Director of the Bordeaux Population Health research center, University of Bordeaux

Prof Stéphanie Debette