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The PHF21B gene is associated with major depression and modulates the stress response

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dc.creatorWong, M-Lspa
dc.creatorArcos-Burgos, Mspa
dc.creatorLiu, Sspa
dc.creatorVélez, J Ispa
dc.creatorYu, Cspa
dc.creatorBaune, B Tspa
dc.creatorJawahar, M Cspa
dc.creatorArolt, Vspa
dc.creatorDannlowski, Uspa
dc.creatorChuah, Aspa
dc.creatorHuttley, G Aspa
dc.creatorFogarty, Rspa
dc.creatorLewis, M Dspa
dc.creatorBornstein, S Rspa
dc.creatorLicinio, Jspa
dc.date.accessioned2020-05-25T23:57:11Z
dc.date.available2020-05-25T23:57:11Z
dc.date.created2017spa
dc.description.abstractMajor depressive disorder (MDD) affects around 350 million people worldwide; however, the underlying genetic basis remains largely unknown. In this study, we took into account that MDD is a gene-environment disorder, in which stress is a critical component, and used whole-genome screening of functional variants to investigate the â missing heritability' in MDD. Genome-wide association studies (GWAS) using single- A nd multi-locus linear mixed-effect models were performed in a Los Angeles Mexican-American cohort (196 controls, 203 MDD) and in a replication European-ancestry cohort (499 controls, 473 MDD). Our analyses took into consideration the stress levels in the control populations. The Mexican-American controls, comprised primarily of recent immigrants, had high levels of stress due to acculturation issues and the European-ancestry controls with high stress levels were given higher weights in our analysis. We identified 44 common and rare functional variants associated with mild to moderate MDD in the Mexican-American cohort (genome-wide false discovery rate, FDR, less than 0.05), and their pathway analysis revealed that the three top overrepresented Gene Ontology (GO) processes were innate immune response, glutamate receptor signaling and detection of chemical stimulus in smell sensory perception. Rare variant analysis replicated the association of the PHF21B gene in the ethnically unrelated European-ancestry cohort. The TRPM2 gene, previously implicated in mood disorders, may also be considered replicated by our analyses. Whole-genome sequencing analyses of a subset of the cohorts revealed that European-ancestry individuals have a significantly reduced (50%) number of single nucleotide variants compared with Mexican-American individuals, and for this reason the role of rare variants may vary across populations. PHF21b variants contribute significantly to differences in the levels of expression of this gene in several brain areas, including the hippocampus. Furthermore, using an animal model of stress, we found that Phf21b hippocampal gene expression is significantly decreased in animals resilient to chronic restraint stress when compared with non-chronically stressed animals. Together, our results reveal that including stress level data enables the identification of novel rare functional variants associated with MDD. © 2017 Macmillan Publishers Limited.eng
dc.format.mimetypeapplication/pdf
dc.identifier.doihttps://doi.org/10.1038/mp.2016.174
dc.identifier.issn14765578
dc.identifier.issn13594184
dc.identifier.urihttps://repository.urosario.edu.co/handle/10336/22624
dc.language.isoengspa
dc.publisherNature Publishing Groupspa
dc.relation.citationEndPage1025
dc.relation.citationIssueNo. 7
dc.relation.citationStartPage1015
dc.relation.citationTitleMolecular Psychiatry
dc.relation.citationVolumeVol. 22
dc.relation.ispartofMolecular Psychiatry, ISSN:14765578, 13594184, Vol.22, No.7 (2017); pp. 1015-1025spa
dc.relation.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-84992365606&doi=10.1038%2fmp.2016.174&partnerID=40&md5=59346f5cfc6b60fe3bd7e63cf07bb206spa
dc.rights.accesRightsinfo:eu-repo/semantics/openAccess
dc.rights.accesoAbierto (Texto Completo)spa
dc.source.instnameinstname:Universidad del Rosariospa
dc.source.reponamereponame:Repositorio Institucional EdocURspa
dc.subject.keywordGlutamate receptorspa
dc.subject.keywordmajoreng
dc.subject.keywordTransient receptor potential channel m2spa
dc.subject.keywordUbiquitin protein ligasespa
dc.subject.keywordUnclassified drugspa
dc.subject.keywordAdultspa
dc.subject.keywordAgedspa
dc.subject.keywordAnimal experimentspa
dc.subject.keywordAnimal tissuespa
dc.subject.keywordArticlespa
dc.subject.keywordBrain regionspa
dc.subject.keywordCaliforniaspa
dc.subject.keywordChronic stressspa
dc.subject.keywordClinical trial (topic)spa
dc.subject.keywordCohort analysisspa
dc.subject.keywordControlled studyspa
dc.subject.keywordDisease severityspa
dc.subject.keywordEuropeanspa
dc.subject.keywordGene expressionspa
dc.subject.keywordGene locusspa
dc.subject.keywordGene ontologyspa
dc.subject.keywordGenetic associationspa
dc.subject.keywordGenetic variabilityspa
dc.subject.keywordGenome-wide association studyspa
dc.subject.keywordGenotype environment interactionspa
dc.subject.keywordHaplotypespa
dc.subject.keywordHeritabilityspa
dc.subject.keywordHippocampusspa
dc.subject.keywordHumanspa
dc.subject.keywordImmigrantspa
dc.subject.keywordImmobilization stressspa
dc.subject.keywordInnate immunityspa
dc.subject.keywordMajor clinical studyspa
dc.subject.keywordMajor depressionspa
dc.subject.keywordMalespa
dc.subject.keywordMexican americanspa
dc.subject.keywordMolecular pathologyspa
dc.subject.keywordNonhumanspa
dc.subject.keywordPhf21b genespa
dc.subject.keywordPriority journalspa
dc.subject.keywordRatspa
dc.subject.keywordSensory perception testspa
dc.subject.keywordSingle nucleotide polymorphismspa
dc.subject.keywordStressspa
dc.subject.keywordTrpm2 genespa
dc.subject.keywordWhole genome sequencingspa
dc.subject.keywordCase control studyspa
dc.subject.keywordCaucasianspa
dc.subject.keywordFemalespa
dc.subject.keywordGenetic predispositionspa
dc.subject.keywordGeneticsspa
dc.subject.keywordMajor depressionspa
dc.subject.keywordMental stressspa
dc.subject.keywordMiddle agedspa
dc.subject.keywordRisk factorspa
dc.subject.keywordAdultspa
dc.subject.keywordCase-control studiesspa
dc.subject.keywordDepressive disordereng
dc.subject.keywordEuropean continental ancestry groupspa
dc.subject.keywordFemalespa
dc.subject.keywordGene expressionspa
dc.subject.keywordGenetic predisposition to diseasespa
dc.subject.keywordGenome-wide association studyspa
dc.subject.keywordHumansspa
dc.subject.keywordLos angelesspa
dc.subject.keywordMalespa
dc.subject.keywordMexican americansspa
dc.subject.keywordMiddle agedspa
dc.subject.keywordPolymorphismeng
dc.subject.keywordRisk factorsspa
dc.subject.keywordStresseng
dc.titleThe PHF21B gene is associated with major depression and modulates the stress responsespa
dc.typearticleeng
dc.type.hasVersioninfo:eu-repo/semantics/publishedVersion
dc.type.spaArtículospa
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