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Gene-mapping study of extremes of cerebral small vessel disease reveals TRIM47 as a strong candidate

Gene-mapping study of extremes of cerebral small vessel disease reveals TRIM47 as a strong candidate


Title: Gene-mapping study of extremes of cerebral small vessel disease reveals TRIM47 as a strong candidate
Author: Mishra, Aniket
Duplaà, Cecile
Vojinovic, Dina
Suzuki, Hideaki
Sargurupremraj, Muralidharan
Zilhão, Nuno R.
Li, Shuo
Bartz, Traci M.
Jian, Xueqiu
Zhao, Wei
... 40 more authors Show all authors
Date: 2022-06-01
Language: English
Scope: 16
Department: Faculty of Medicine
Series: Brain; 145(6)
ISSN: 0006-8950
DOI: https://doi.org/10.1093/brain/awab432
Subject: cerebral small vessel disease; endothelial cells; GWAS; TRIM47; whole-exome association study; Genome-Wide Association Study; Stroke/complications; Animals; Brain Ischemia/complications; Mice; Cerebral Small Vessel Diseases/complications; Endothelial Cells/pathology; Medicine (all)
URI: https://hdl.handle.net/20.500.11815/3867

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Citation:

Mishra , A , Duplaà , C , Vojinovic , D , Suzuki , H , Sargurupremraj , M , Zilhão , N R , Li , S , Bartz , T M , Jian , X , Zhao , W , Hofer , E , Wittfeld , K , Harris , S E , Van Der Auwera-Palitschka , S , Luciano , M , Bis , J C , Adams , H H H , Satizabal , C L , Gottesman , R F , Gampawar , P G , Bülow , R , Weiss , S , Yu , M , Bastin , M E , Lopez , O L , Vernooij , M W , Beiser , A S , Völker , U , Kacprowski , T , Soumare , A , Smith , J A , Knopman , D S , Morris , Z , Zhu , Y , Rotter , J I , Dufouil , C , Valdes Hernández , M , Muñoz Maniega , S , Lathrop , M , Boerwinkle , E , Schmidt , R , Ihara , M , Mazoyer , B , Yang , Q , Joutel , A , Tournier-Lasserve , E , Launer , L J , Deary , I J , Mosley , T H & Gudnason , V 2022 , ' Gene-mapping study of extremes of cerebral small vessel disease reveals TRIM47 as a strong candidate ' , Brain , vol. 145 , no. 6 , pp. 1992-2007 . https://doi.org/10.1093/brain/awab432

Abstract:

Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cerebral small vessel disease derived from its most common MRI features: white matter hyperintensities and lacunes. Seventeen population-based cohorts of older persons with MRI measurements and genome-wide genotyping (n = 41326), whole-exome sequencing (n = 15965), or exome chip (n = 5249) data contributed 13776 and 7079 extreme small vessel disease samples for the genome-wide association study and whole-exome association study, respectively. The genome-wide association study identified significant association of common variants in 11 loci with extreme small vessel disease, of which the chr12q24.11 locus was not previously reported to be associated with any MRI marker of cerebral small vessel disease. The whole-exome association study identified significant associations of extreme small vessel disease with common variants in the 5′ UTR region of EFEMP1 (chr2p16.1) and one probably damaging common missense variant in TRIM47 (chr17q25.1). Mendelian randomization supports the causal association of extensive small vessel disease severity with increased risk of stroke and Alzheimer's disease. Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between TRIM47 expression in the brain and blood vessels and extensive small vessel disease severity. We observed significant enrichment of Trim47 in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing Trim47 enrichment in brain endothelial cells at single cell level. Functional evaluation of TRIM47 by small interfering RNAs-mediated knockdown in human brain endothelial cells showed increased endothelial permeability, an important hallmark of cerebral small vessel disease pathology. Overall, our comprehensive gene-mapping study and preliminary functional evaluation suggests a putative role of TRIM47 in the pathophysiology of cerebral small vessel disease, making it an important candidate for extensive in vivo explorations and future translational work.

Description:

Funding Information: This project is an EU Joint Programme Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organisations under the aegis of JPND www.jpnd. eu: Australia, National Health and Medical Research Council, Austria, Federal Ministry of Science, Research and Economy; Canada, Canadian Institutes of Health Research; France, French National Research Agency; Germany, Federal Ministry of Education and Research; Netherlands, The Netherlands Organization for Health Research and Development; United Kingdom, Medical Research Council. This project has received funding from the European Union s Horizon 2020 research and innovation programme under grant agreement No 643417. This project has also received funding from the European Research Council (ERC) under the European Union s Horizon 2020 research and innovation programme under grant agreement No. 640643 and from the European Union s Horizon 2020 research and innovation programme under grant agreements Nos. 667375 and 754517. This work was also supported by a grant overseen by the French National Research Agency (ANR) as part of ANR-14-CE12-60016 and the Investment for the Future Programme ANR-18-RHUS-0002. Part of the computations were performed at the Bordeaux Bioinformatics Centre (CBiB), University of Bordeaux and at the CREDIM (Centre de Ressource et Dffeveloppement en Informatique Medicale) at University of Bordeaux, on a server infrastructure supported by the Fondation Claude Pompidou. The neurology Working Group in the CHARGE Consortium is partly funded by the CHARGE infrastructure grant R01HL105756 and grants from the National Institute on Aging, AG033193, AG049505, AG052409 and AG059421. P.M.M. acknowledges personal support from the Edmond J Safra Foundation and Lily Safra and an NIHR Senior Investigator Award and research support from the UK Dementia Research Institute and NIHR Imperial College Healthcare Trust Biomedical Research Centre. Study-specific funding information is provided in the Supplementary material. Publisher Copyright: © 2022 The Author(s) (2022). Published by Oxford University Press on behalf of the Guarantors of Brain.

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