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

dc.rights.licenseopenen_US
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorMISHRA, Aniket
hal.structure.identifierBiologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases
dc.contributor.authorDUPLAA, Cecile
dc.contributor.authorVOJINOVIC, Dina
dc.contributor.authorSUZUKI, Hideaki
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorSARGURUPREMRAJ, Muralidharan
dc.contributor.authorZILHAO, Nuno R.
dc.contributor.authorLI, Shuo
dc.contributor.authorBARTZ, Traci M
dc.contributor.authorJIAN, Xueqiu
dc.contributor.authorZHAO, Wei
dc.contributor.authorHOFER, Edith
dc.contributor.authorWITTFELD, Katharina
dc.contributor.authorHARRIS, Sarah E
dc.contributor.authorVAN DER AUWERA-PALITSCHKA, Sandra
dc.contributor.authorLUCIANO, Michelle
dc.contributor.authorBIS, Joshua C
dc.contributor.authorADAMS, Hieab H H
dc.contributor.authorSATIZABAL, Claudia L
dc.contributor.authorGOTTESMAN, Rebecca F
dc.contributor.authorGAMPAWAR, Piyush G
dc.contributor.authorBÜLOW, Robin
dc.contributor.authorWEISS, Stefan
dc.contributor.authorYU, Miao
dc.contributor.authorBASTIN, Mark E
dc.contributor.authorLOPEZ, Oscar L
dc.contributor.authorVERNOOIJ, Meike W
dc.contributor.authorBEISER, Alexa S
dc.contributor.authorVÖLKER, Uwe
dc.contributor.authorKACPROWSKI, Tim
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorSOUMARE, Aicha
dc.contributor.authorSMITH, Jennifer A.
dc.contributor.authorKNOPMAN, David S.
dc.contributor.authorMORRIS, Zoe
dc.contributor.authorZHU, Yicheng
dc.contributor.authorROTTER, Jerome I.
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorDUFOUIL, Carole
dc.contributor.authorVALDES HERNANDEZ, Maria
dc.contributor.authorMUNOZ MANIEGA, Susana
dc.contributor.authorLATHROP, Mark
dc.contributor.authorBOERWINKLE, Erik
dc.contributor.authorSCHMIDT, Reinhold
dc.contributor.authorIHARA, Masafumi
hal.structure.identifierInstitut des Maladies Neurodégénératives [Bordeaux] [IMN]
dc.contributor.authorMAZOYER, Bernard
dc.contributor.authorYANG, Qiong
dc.contributor.authorJOUTEL, Anne
dc.contributor.authorTOURNIER-LASSERVE, Elizabeth
dc.contributor.authorLAUNER, Lenore J
dc.contributor.authorDEARY, Ian J
dc.contributor.authorMOSLEY, Thomas H
dc.contributor.authorAMOUYEL, Philippe
dc.contributor.authorDECARLI, Charles S
dc.contributor.authorPSATY, Bruce M
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorTZOURIO, Christophe
dc.contributor.authorKARDIA, Sharon L R
dc.contributor.authorGRABE, Hans J
dc.contributor.authorTEUMER, Alexander
dc.contributor.authorVAN DUIJN, Cornelia M
dc.contributor.authorSCHMIDT, Helena
dc.contributor.authorWARDLAW, Joanna M
dc.contributor.authorIKRAM, M Arfan
dc.contributor.authorFORNAGE, Myriam
dc.contributor.authorGUDNASON, Vilmundur
dc.contributor.authorSESHADRI, Sudha
dc.contributor.authorMATTHEWS, Paul M
dc.contributor.authorLONGSTRETH, William T
hal.structure.identifierBiologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases
dc.contributor.authorCOUFFINHAL, Thierry
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorDEBETTE, Stephanie
dc.date.accessioned2022-05-13T10:43:20Z
dc.date.available2022-05-13T10:43:20Z
dc.date.issued2022-05-02
dc.identifier.issn1460-2156en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/140055
dc.description.abstractEnCerebral 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.
dc.language.isoENen_US
dc.subjectARTICLE RECHERCHE
dc.subject.enGWAS
dc.subject.enTRIM47
dc.subject.enCerebral small vessel disease
dc.subject.enWhole-exome association study
dc.title.enGene-mapping study of extremes of cerebral small vessel disease reveals TRIM47 as a strong candidate.
dc.title.alternativeBrainen_US
dc.typeArticle de revueen_US
dc.identifier.doi10.1093/brain/awab432en_US
dc.subject.halSciences du Vivant [q-bio]/Médecine humaine et pathologieen_US
dc.identifier.pubmed35511193en_US
bordeaux.journalBrain - A Journal of Neurologyen_US
bordeaux.hal.laboratoriesBiologie des maladies cardiovasculaires (BMC) - UMR 1034en_US
bordeaux.hal.laboratoriesBordeaux Population Health Research Center (BPH) - UMR 1219
bordeaux.hal.laboratoriesInstitut des Maladies Neurodégénératives (IMN) - UMR 5293
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
bordeaux.import.sourcepubmed
hal.identifierhal-03667343
hal.version1
hal.date.transferred2022-05-13T10:43:25Z
hal.exporttrue
workflow.import.sourcepubmed
dc.rights.ccPas de Licence CCen_US
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