Cerebral small vessel disease genomics and its implications across the lifespan

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  • 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
  • Wiro J. Niessen
  • Pers, Tune H
  • Andres Ingason
  • Anne Francke Christensen
  • Hansen, Thomas Folkmann
  • Werge, Thomas
  • Olesen, Jes
  • International Network against Thrombosis (INVENT) Consortium
  • International Headache Genomics Consortium (IHGC)

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.

Original languageEnglish
Article number6285
JournalNature Communications
Volume11
Issue number1
Number of pages18
ISSN2041-1723
DOIs
Publication statusPublished - 2020

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