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Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI

dc.rights.licenseopenen_US
dc.contributor.authorYANG, Yunju
dc.contributor.authorKNOL, Maria J.
dc.contributor.authorWANG, Ruiqi
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorMISHRA, Aniket
dc.contributor.authorLIU, Dan
dc.contributor.authorLUCIANO, Michelle
dc.contributor.authorTEUMER, Alexander
dc.contributor.authorARMSTRONG, Nicola
dc.contributor.authorBIS, Joshua C.
dc.contributor.authorJHUN, Min A.
dc.contributor.authorLI, Shuo
dc.contributor.authorADAMS, Hieab H. H.
dc.contributor.authorAZIZ, Nasir Ahmad
dc.contributor.authorBASTIN, Mark E.
dc.contributor.authorBOURGEY, Mathieu
dc.contributor.authorBRODY, Jennifer A.
dc.contributor.authorFRENZEL, Stefan
dc.contributor.authorGOTTESMAN, Rebecca F.
dc.contributor.authorHOSTEN, Norbert
dc.contributor.authorHOU, Lifang
dc.contributor.authorKARDIA, Sharon L. R.
dc.contributor.authorLOHNER, Valerie
dc.contributor.authorMARQUIS, Pascale
dc.contributor.authorMANIEGA, Susana Munoz
dc.contributor.authorSATIZABAL, Claudia L.
dc.contributor.authorSOROND, Farzaneh A.
dc.contributor.authorVALDES HERNANDEZ, Maria C.
dc.contributor.authorVAN DUIJN, Cornelia M.
dc.contributor.authorVERNOOIJ, Meike W.
dc.contributor.authorWITTFELD, Katharina
dc.contributor.authorYANG, Qiong
dc.contributor.authorZHAO, Wei
dc.contributor.authorBOERWINKLE, Eric
dc.contributor.authorLEVY, Daniel
dc.contributor.authorDEARY, Ian J.
dc.contributor.authorJIANG, Jiyang
dc.contributor.authorMATHER, Karen A.
dc.contributor.authorMOSLEY, Thomas H.
dc.contributor.authorPSATY, Bruce M.
dc.contributor.authorSACHDEV, Perminder S.
dc.contributor.authorSMITH, Jennifer A.
dc.contributor.authorSOTOODEHNIA, Nona
dc.contributor.authorDECARLI, Charles S.
dc.contributor.authorBRETELER, Monique M. B.
dc.contributor.authorARFAN IKRAM, M.
dc.contributor.authorGRABE, Hans J.
dc.contributor.authorWARDLAW, Joanna
dc.contributor.authorLONGSTRETH, William T.
dc.contributor.authorLAUNER, Lenore J.
dc.contributor.authorSESHADRI, Sudha
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorDEBETTE, Stephanie
dc.contributor.authorFORNAGE, Myriam
dc.date.accessioned2022-10-29T10:24:01Z
dc.date.available2022-10-29T10:24:01Z
dc.date.issued2022-08-09
dc.identifier.issn1460-2156 (Electronic) 0006-8950 (Linking)en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/170160
dc.description.abstractEnCerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at approximately 450,000 CpG sites in 9,732 middle-aged to older adults from 14 community-based studies. Single-CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single-CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10-8), was associated with F2 expression in blood (P = 6.4 × 10-5), and colocalized with FOLH1 expression in brain (posterior probability =0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single-CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis, and multi-omics colocalization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug repositioning analysis indicated antihyperlipidemic agents, more specifically peroxisome proliferator-activated receptor alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood brain barrier disruption.
dc.language.isoENen_US
dc.rightsAttribution-NonCommercial 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by-nc/3.0/us/*
dc.subject.enEpigenome-wide association study
dc.subject.enWhite matter hyperintensities
dc.subject.enCerebral small vessel disease
dc.subject.enIntegrative cross-omics analysis
dc.subject.enBlood-brain barrier dysfunction
dc.title.enEpigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI
dc.typeArticle de revueen_US
dc.identifier.doi10.1093/brain/awac290en_US
dc.subject.halSciences du Vivant [q-bio]/Santé publique et épidémiologieen_US
dc.identifier.pubmed35943854en_US
bordeaux.journalBrain - A Journal of Neurologyen_US
bordeaux.hal.laboratoriesBordeaux Population Health Research Center (BPH) - UMR 1219en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.teamELEANOR_BPHen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
hal.identifierhal-03834309
hal.version1
hal.date.transferred2022-10-29T10:24:13Z
hal.exporttrue
dc.rights.ccPas de Licence CCen_US
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