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

TitleGene-mapping study of extremes of cerebral small vessel disease reveals TRIM47 as a strong candidate.
Publication TypeJournal Article
Year of Publication2022
AuthorsMishra A, Duplaà C, Vojinovic D, Suzuki H, Sargurupremraj M, Zilhão NR, Li S, Bartz TM, Jian X, Zhao W, Hofer E, Wittfeld K, Harris SE, van der Auwera-Palitschka S, Luciano M, Bis JC, Adams HHH, Satizabal CL, Gottesman RF, Gampawar PG, Bülow R, Weiss S, Yu M, Bastin ME, Lopez OL, Vernooij MW, Beiser AS, Völker U, Kacprowski T, Soumaré A, Smith JA, Knopman DS, Morris Z, Zhu Y, Rotter JI, Dufouil C, Hernández MValdés, Maniega SMuñoz, Lathrop M, Boerwinkle E, Schmidt R, Ihara M, Mazoyer B, Yang Q, Joutel A, Tournier-Lasserve E, Launer LJ, Deary IJ, Mosley TH, Amouyel P, DeCarli CS, Psaty BM, Tzourio C, Kardia SLR, Grabe HJ, Teumer A, van Duijn CM, Schmidt H, Wardlaw JM, M Ikram A, Fornage M, Gudnason V, Seshadri S, Matthews PM, Longstreth WT, Couffinhal T, Debette S
JournalBrain
Volume145
Issue6
Pagination1992-2007
Date Published2022 06 30
ISSN1460-2156
KeywordsAnimals, Brain Ischemia, Cerebral Small Vessel Diseases, Endothelial Cells, Genome-Wide Association Study, Mice, Stroke
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 = 41 326), whole-exome sequencing (n = 15 965), or exome chip (n = 5249) data contributed 13 776 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.

DOI10.1093/brain/awab432
Alternate JournalBrain
PubMed ID35511193
PubMed Central IDPMC9255380
Grant ListRF1 AG059421 / AG / NIA NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
U01 AG058589 / AG / NIA NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States
U01 AG052409 / AG / NIA NIH HHS / United States