Journal Articles Nature Communications Year : 2020

Cerebral small vessel disease genomics and its implications across the lifespan

Muralidharan Sargurupremraj (1) , Hideaki Suzuki , Xueqiu Jian , Chloé Sarnowski , Tavia E. Evans , Joshua C Bis , Gudny Eiriksdottir , Saori Sakaue , Natalie Terzikhan , Mohamad Habes , Zhao Wei , Nicola J Armstrong , Edith Hofer , Lisa R Yanek , Saskia Hagenaars , Rajan Kumar , Erik B van den Akker , Rebekah Mcwhirter , Stella Trompet , Aniket Mishra , Yasaman Saba , Claudia L Satizabal , Gregory Beaudet (2) , Laurent Petit (2) , Ami Tsuchida (2) , Laure Zago (2) , Sabrina Schilling , Sigurdur Sigurdsson , Rebecca F Gottesman , Cora E Lewis , Neelum T Aggarwal , Oscar L Lopez , Jennifer A Smith , Maria Valdés Hernández , 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 Scott , Meike W Vernooij , Katharina Wittfeld , Wiro J Niessen , Aicha Soumare , Eric Boerwinkle , Stephen Sidney , Stephen T Turner , Gail Davies , Anbupalam Thalamuthu , Uwe U. 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 , Matsuda Fumihiko , Bruce M Psaty , David A Bennett , Philip L de Jager , Thomas H Mosley , Perminder S Sachdev , Reinhold Schmidt , Helen Warren , Evangelos Evangelou , David-Alexandre Trégouët , International Network Against Thrombosis (invent) Consortium, International Headache Genomics Consortium (ihgc) , Mohammad Arfan Ikram , Wei Wen , Charles Decarli , Velandai Srikanth , J Wouter Jukema , P Eline Slagboom , Sharon L R Kardia , Yukinori Okada , Bernard Mazoyer (2) , Joanna M Wardlaw , Paul A Nyquist , Karen A Mather , Hans J Grabe , Helena Schmidt , Cornelia M van Duijn , Vilmundur Gudnason , William T. Longstreth , Mark Lathrop , Sudha Seshadri , Tzourio Christophe , Hieab H Adams , Paul M. Matthews , Myriam Fornage , Stéphanie Debette
Hideaki Suzuki
  • Function : Author
Xueqiu Jian
  • Function : Author
Chloé Sarnowski
  • Function : Author
Tavia E. Evans
  • Function : Author
Joshua C Bis
  • Function : Author
Gudny Eiriksdottir
  • Function : Author
Saori Sakaue
  • Function : Author
Natalie Terzikhan
  • Function : Author
Mohamad Habes
  • Function : Author
Zhao Wei
  • Function : Author
Nicola J Armstrong
  • Function : Author
Edith Hofer
  • Function : Author
Lisa R Yanek
  • Function : Author
Saskia Hagenaars
  • Function : Author
Rajan Kumar
  • Function : Author
Erik B van den Akker
  • Function : Author
Rebekah Mcwhirter
  • Function : Author
Stella Trompet
  • Function : Author
Aniket Mishra
  • Function : Author
Yasaman Saba
  • Function : Author
Claudia L Satizabal
  • Function : Author
Laurent Petit
Laure Zago
Sabrina Schilling
  • Function : Author
Sigurdur Sigurdsson
  • Function : Author
Rebecca F Gottesman
  • Function : Author
Cora E Lewis
  • Function : Author
Neelum T Aggarwal
  • Function : Author
Oscar L Lopez
  • Function : Author
Jennifer A Smith
  • Function : Author
Maria Valdés Hernández
  • Function : Author
Jeroen van Der Grond
  • Function : Author
Margaret J Wright
  • Function : Author
Maria J Knol
  • Function : Author
Marcus Dörr
  • Function : Author
Russell Thomson
  • Function : Author
Constance Bordes
Quentin Le Grand
  • Function : Author
Marie-Gabrielle Duperron
  • Function : Author
Albert V Smith
  • Function : Author
David S Knopman
  • Function : Author
Pamela J Schreiner
  • Function : Author
Denis A Evans
  • Function : Author
Jerome I Rotter
  • Function : Author
Alexa S Beiser
  • Function : Author
Susana Muñoz Maniega
  • Function : Author
Marian Beekman
  • Function : Author
Julian N Trollor
  • Function : Author
David J Scott
  • Function : Author
Meike W Vernooij
  • Function : Author
Katharina Wittfeld
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Wiro J Niessen
  • Function : Author
Aicha Soumare
  • Function : Author
Eric Boerwinkle
  • Function : Author
Stephen Sidney
  • Function : Author
Stephen T Turner
  • Function : Author
Gail Davies
  • Function : Author
Anbupalam Thalamuthu
  • Function : Author
Uwe U. Völker
  • Function : Author
Mark A van Buchem
  • Function : Author
R Nick Bryan
  • Function : Author
Josée Dupuis
  • Function : Author
Mark E Bastin
  • Function : Author
David Ames
  • Function : Author
Alexander Teumer
  • Function : Author
Philippe Amouyel
John B Kwok
  • Function : Author
Robin Bülow
  • Function : Author
Ian J Deary
  • Function : Author
Peter R Schofield
  • Function : Author
Henry Brodaty
  • Function : Author
Jiyang Jiang
  • Function : Author
Yasuharu Tabara
Kazuya Setoh
  • Function : Author
Susumu Miyamoto
  • Function : Author
Kazumichi Yoshida
  • Function : Author
Manabu Nagata
  • Function : Author
Yoichiro Kamatani
  • Function : Author
Matsuda Fumihiko
  • Function : Author
Bruce M Psaty
  • Function : Author
David A Bennett
  • Function : Author
Philip L de Jager
  • Function : Author
Thomas H Mosley
  • Function : Author
Perminder S Sachdev
  • Function : Author
Reinhold Schmidt
  • Function : Author
Helen Warren
  • Function : Author
Evangelos Evangelou
  • Function : Author
David-Alexandre Trégouët
Mohammad Arfan Ikram
  • Function : Author
Wei Wen
  • Function : Author
Charles Decarli
  • Function : Author
Velandai Srikanth
  • Function : Author
J Wouter Jukema
  • Function : Author
P Eline Slagboom
  • Function : Author
Sharon L R Kardia
  • Function : Author
Yukinori Okada
  • Function : Author
Joanna M Wardlaw
  • Function : Author
Paul A Nyquist
  • Function : Author
Karen A Mather
  • Function : Author
Hans J Grabe
  • Function : Author
Helena Schmidt
  • Function : Author
Cornelia M van Duijn
  • Function : Author
Vilmundur Gudnason
  • Function : Author
William T. Longstreth
  • Function : Author
Mark Lathrop
  • Function : Author
Sudha Seshadri
  • Function : Author
Tzourio Christophe
  • Function : Author
Hieab H Adams
  • Function : Author
Paul M. Matthews
  • Function : Author
Myriam Fornage
  • Function : Author
Stéphanie Debette
  • Function : Author
  • PersonId : 1050442

Abstract

Cerebral small vessel disease genomics and its implications across the lifespan Muralidharan Sargurupremraj et al. # 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.

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hal-03121357 , version 1 (26-01-2021)

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Muralidharan Sargurupremraj, Hideaki Suzuki, Xueqiu Jian, Chloé Sarnowski, Tavia E. Evans, et al.. Cerebral small vessel disease genomics and its implications across the lifespan. Nature Communications, 2020, 11, ⟨10.1038/s41467-020-19111-2⟩. ⟨hal-03121357⟩
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