Edinburgh Research Explorer

Cerebral small vessel disease genomics and its implications across the lifespan

Research output: Contribution to journalArticle

  • 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 Mishra
  • Yasaman 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
  • 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
  • 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
  • Anbupalam Thalamuthu
  • Uwe Völker
  • Mark A Van Buchem
  • R Nick Bryan
  • Josée Dupuis
  • David Ames
  • Alexander Teumer
  • Philippe Amouyel
  • John B J Kwok
  • Robin Bülow
  • 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
  • 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
  • Sudha Seshadri
  • Christophe Tzourio
  • Hieab H H Adams
  • Paul M Matthews
  • Myriam Fornage
  • Stéphanie Debette

Related Edinburgh Organisations

Original languageEnglish
JournalNature Communications
Publication statusAccepted/In press - 10 Sep 2020

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.

ID: 165700317