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Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects.

dc.rights.licenseopenen_US
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorMISHRA, Aniket
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorCHAUHAN, Ganesh
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorVIOLLEAU, Marie-Helene
dc.contributor.authorVOJINOVIC, Dina
dc.contributor.authorJIAN, Xueqiu
dc.contributor.authorBIS, Joshua C
dc.contributor.authorLI, Shuo
dc.contributor.authorSABA, Yasaman
dc.contributor.authorGRENIER-BOLEY, Benjamin
dc.contributor.authorYANG, Qiong
dc.contributor.authorBARTZ, Traci M
dc.contributor.authorHOFER, Edith
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorSOUMARÉ, Aïcha
dc.contributor.authorPENG, Fen
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorDUPERRON, Marie-Gabrielle
dc.contributor.authorFOGLIO, Mario
dc.contributor.authorMOSLEY, Thomas H
dc.contributor.authorSCHMIDT, Reinhold
dc.contributor.authorPSATY, Bruce M
dc.contributor.authorLAUNER, Lenore J
dc.contributor.authorBOERWINKLE, Eric
dc.contributor.authorZHU, Yicheng
dc.contributor.authorMAZOYER, Bernard
dc.contributor.authorLATHROP, Mark
dc.contributor.authorBELLENGUEZ, Celine
dc.contributor.authorVAN DUIJN, Cornelia M
dc.contributor.authorIKRAM, M Arfan
dc.contributor.authorSCHMIDT, Helena
dc.contributor.authorLONGSTRETH, W T
dc.contributor.authorFORNAGE, Myriam
dc.contributor.authorSESHADRI, Sudha
dc.contributor.authorJOUTEL, Anne
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorTZOURIO, Christophe
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorDEBETTE, Stephanie
dc.date.accessioned2020-04-02T09:40:34Z
dc.date.available2020-04-02T09:40:34Z
dc.date.issued2019-04-01
dc.identifier.issn1460-2156en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/4071
dc.description.abstractEnWe report a composite extreme phenotype design using distribution of white matter hyperintensities and brain infarcts in a population-based cohort of older persons for gene-mapping of cerebral small vessel disease. We demonstrate its application in the 3C-Dijon whole exome sequencing (WES) study (n = 1924, nWESextremes = 512), with both single variant and gene-based association tests. We used other population-based cohort studies participating in the CHARGE consortium for replication, using whole exome sequencing (nWES = 2,868, nWESextremes = 956) and genome-wide genotypes (nGW = 9924, nGWextremes = 3308). We restricted our study to candidate genes known to harbour mutations for Mendelian small vessel disease: NOTCH3, HTRA1, COL4A1, COL4A2 and TREX1. We identified significant associations of a common intronic variant in HTRA1, rs2293871 using single variant association testing (Pdiscovery = 8.21 × 10-5, Preplication = 5.25 × 10-3, Pcombined = 4.72 × 10-5) and of NOTCH3 using gene-based tests (Pdiscovery = 1.61 × 10-2, Preplication = 3.99 × 10-2, Pcombined = 5.31 × 10-3). Follow-up analysis identified significant association of rs2293871 with small vessel ischaemic stroke, and two blood expression quantitative trait loci of HTRA1 in linkage disequilibrium. Additionally, we identified two participants in the 3C-Dijon cohort (0.4%) carrying heterozygote genotypes at known pathogenic variants for familial small vessel disease within NOTCH3 and HTRA1. In conclusion, our proof-of-concept study provides strong evidence that using a novel composite MRI-derived phenotype for extremes of small vessel disease can facilitate the identification of genetic variants underlying small vessel disease, both common variants and those with rare and low frequency. The findings demonstrate shared mechanisms and a continuum between genes underlying Mendelian small vessel disease and those contributing to the common, multifactorial form of the disease.
dc.language.isoENen_US
dc.rightsAttribution-NonCommercial 3.0 United States
dc.rights.urihttps://creativecommons.org/licenses/by-nc/3.0/us/
dc.subjectAged
dc.subjectAged
dc.subject80 and over
dc.subjectBrain Ischemia
dc.subjectCerebral Small Vessel Diseases
dc.subjectCohort Studies
dc.subjectFemale
dc.subjectHeterozygote
dc.subjectHigh-Temperature Requirement A Serine Peptidase 1
dc.subjectHumans
dc.subjectMagnetic Resonance Imaging
dc.subjectMale
dc.subjectMiddle Aged
dc.subjectMutation
dc.subjectPolymorphism
dc.subjectSingle Nucleotide
dc.subjectReceptor
dc.subjectNotch3
dc.subjectStroke
dc.subjectWhite Matter
dc.subjectWhole Exome Sequencing
dc.subject.encerebral small vessel disease
dc.subject.enexome sequencing study
dc.subject.enextreme phenotype
dc.subject.enlacunes of presumed vascular origin
dc.subject.enwhite matter hyperintensity
dc.titleAssociation of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects.
dc.title.alternativeBrainen_US
dc.typeArticle de revueen_US
dc.identifier.doi10.1093/brain/awz024
dc.subject.halSciences du Vivant [q-bio]/Santé publique et épidémiologie
dc.identifier.pubmed30859180en_US
bordeaux.journalBrain - A Journal of Neurologyen_US
bordeaux.page1009-1023en_US
bordeaux.volume142en_US
bordeaux.hal.laboratoriesBordeaux Population Health Research Center (BPH) - U1219en_US
bordeaux.issue4en_US
bordeaux.institutionUniversité de Bordeaux
bordeaux.teamHEALTHY_BPH
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
bordeaux.import.sourcepubmed
hal.identifierhal-03162406
hal.version1
hal.date.transferred2021-03-08T13:46:51Z
hal.exporttrue
workflow.import.sourcepubmed
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