2024
Multi-omics profiling of DNA methylation and gene expression alterations in human cocaine use disorder
Zillich E, Belschner H, Avetyan D, Andrade-Brito D, Martínez-Magaña J, Frank J, Mechawar N, Turecki G, Cabana-Domínguez J, Fernàndez-Castillo N, Cormand B, Montalvo-Ortiz J, Nöthen M, Hansson A, Rietschel M, Spanagel R, Witt S, Zillich L. Multi-omics profiling of DNA methylation and gene expression alterations in human cocaine use disorder. Translational Psychiatry 2024, 14: 428. PMID: 39384764, PMCID: PMC11464785, DOI: 10.1038/s41398-024-03139-9.Peer-Reviewed Original ResearchConceptsCocaine use disorderUse disorderAlternative splicingHuman prefrontal cortexProfiling of DNA methylationBrodmann area 9Differential alternative splicingDeregulated biological processesPostmortem brain tissueMulti-omics approachCocaine intakeMulti-omics studiesPrefrontal cortexBrain alterationsMulti-omics profilingGene expression alterationsArea 9Fatty acid metabolismReceptor-targeting drugsSpliced transcriptsEpigenome-wideDNA methylationNeuronal morphogenesisAS changesDrug repositioning analysisA phenome-wide association and Mendelian randomisation study of alcohol use variants in a diverse cohort comprising over 3 million individuals
Jennings M, Martínez-Magaña J, Courchesne-Krak N, Cupertino R, Vilar-Ribó L, Bianchi S, Hatoum A, Atkinson E, Giusti-Rodriguez P, Montalvo-Ortiz J, Gelernter J, Artigas M, 23andMe I, Aslibekyan S, Auton A, Babalola E, Bell R, Bielenberg J, Bryc K, Bullis E, Coker D, Partida G, Dhamija D, Das S, Elson S, Eriksson N, Filshtein T, Fitch A, Fletez-Brant K, Fontanillas P, Freyman W, Granka J, Heilbron K, Hernandez A, Hicks B, Hinds D, Jewett E, Jiang Y, Kukar K, Kwong A, Lin K, Llamas B, Lowe M, McCreight J, McIntyre M, Micheletti S, Moreno M, Nandakumar P, Nguyen D, Noblin E, O'Connell J, Petrakovitz A, Poznik G, Reynoso A, Schumacher M, Shastri A, Shelton J, Shi J, Shringarpure S, Su Q, Tat S, Tchakouté C, Tran V, Tung J, Wang X, Wang W, Weldon C, Wilton P, Wong C, Elson S, Edenberg H, Fontanillas P, Palmer A, Sanchez-Roige S. A phenome-wide association and Mendelian randomisation study of alcohol use variants in a diverse cohort comprising over 3 million individuals. EBioMedicine 2024, 103: 105086. PMID: 38580523, PMCID: PMC11121167, DOI: 10.1016/j.ebiom.2024.105086.Peer-Reviewed Original ResearchConceptsMultiple domains of healthDomains of healthEffects of alcohol consumptionAlcohol consumptionHealth outcomesPhenome-wide association studyAlcohol-related behaviorsCardio-metabolic healthPotential causal effectMendelian randomisation studiesGenome-wide association studiesPhenome-wide associationMR analysisPheWAS associationsMultiple domainsHypothesis-free approachPreventive medicineDiverse cohortPheWASAssociation studiesHealthReproductive healthAlcohol behaviorConsequences of drinkingEuropean cohort
2023
Profiling neuronal methylome and hydroxymethylome of opioid use disorder in the human orbitofrontal cortex
Rompala G, Nagamatsu S, Martínez-Magaña J, Nuñez-Ríos D, Wang J, Girgenti M, Krystal J, Gelernter J, Hurd Y, Montalvo-Ortiz J. Profiling neuronal methylome and hydroxymethylome of opioid use disorder in the human orbitofrontal cortex. Nature Communications 2023, 14: 4544. PMID: 37507366, PMCID: PMC10382503, DOI: 10.1038/s41467-023-40285-y.Peer-Reviewed Original ResearchConceptsOpioid use disorderMulti-omics findingsGene expression patternsCo-methylation analysisGene expression profilesMulti-omics profilingGene networksDNA methylationNeuronal methylomesDNA hydroxymethylationMethylomic analysisExpression patternsExpression profilesEpigenetic disturbancesUse disordersPsychiatric traitsOrbitofrontal cortexOpioid-related drugsPostmortem orbitofrontal cortexEnvironmental factorsDrug interaction analysisOUD treatmentHuman orbitofrontal cortexOpioid signalingInteraction analysis
2022
Dissecting the epigenomic differences between smoking and nicotine dependence in a veteran cohort
Nagamatsu S, Pietrzak R, Xu K, Krystal J, Gelernter J, Montalvo‐Ortiz J. Dissecting the epigenomic differences between smoking and nicotine dependence in a veteran cohort. Addiction Biology 2022, 28: e13259. PMID: 36577721, DOI: 10.1111/adb.13259.Peer-Reviewed Original ResearchConceptsSmoking statusNicotine dependenceVeteran cohortNon-current smokersSerious public health issueNovel treatment strategiesPublic health issueUS military veteransEpigenome-wide association studiesCurrent smokersTreatment strategiesFagerström TestNicotine addictionSmokingHealth issuesRole of epigeneticsMilitary veteransMethylationEPIC BeadChip arraySmokersContinuous variablesF2RL3 geneCohortBiomarkersBeadChip arrayPrevious findingsPsychosocial Factors Associated With Accelerated GrimAge in Male U.S. Military Veterans
Tamman AJF, Nagamatsu S, Krystal JH, Gelernter J, Montalvo-Ortiz JL, Pietrzak RH. Psychosocial Factors Associated With Accelerated GrimAge in Male U.S. Military Veterans. American Journal Of Geriatric Psychiatry 2022, 31: 97-109. PMID: 36210262, DOI: 10.1016/j.jagp.2022.09.002.Peer-Reviewed Original ResearchConceptsRisk factorsPremature mortalityU.S. veteransPsychosocial variablesNovel epigenetic clockLifetime substance use disorderRisk stratification modelMale U.S. veteransCross-sectional studyU.S. veteran populationWeekly physical exerciseSubstance use disordersMale U.S. military veteransBiological agingU.S. military veteransHealth morbidityModifiable correlatesMortality riskSleep qualityHigh riskGreater oddsUse disordersPhysical exercisePsychosocial factorsVeteran populationEpigenome-wide association study of posttraumatic stress disorder identifies novel loci in U.S. military veterans
Montalvo-Ortiz JL, Gelernter J, Cheng Z, Girgenti MJ, Xu K, Zhang X, Gopalan S, Zhou H, Duman RS, Southwick SM, Krystal JH, Pietrzak R. Epigenome-wide association study of posttraumatic stress disorder identifies novel loci in U.S. military veterans. Translational Psychiatry 2022, 12: 65. PMID: 35177594, PMCID: PMC8854688, DOI: 10.1038/s41398-022-01822-3.Peer-Reviewed Original ResearchConceptsEpigenome-wide association studiesAssociation studiesTranscription regulationCpG sitesGenome-wide association studiesCell type proportionsPosttraumatic stress disorderPotential epigenetic biomarkersSignificant CpG sitesEpigenetic mechanismsDNA methylationNovel lociCell signalingEpigenetic biomarkersMethylation analysisAxonal guidanceNovel molecular biomarkersEPIC BeadChipLifetime posttraumatic stress disorderMilitary veteransPostmortem brain tissueMedial orbitofrontal cortexMolecular biomarkersRegulationU.S. military veterans
2020
Tubulin Polymerization Promoting Protein (TPPP) gene methylation and corpus callosum measures in maltreated children
de Araújo CM, Hudziak J, Crocetti D, Wymbs NF, Montalvo-Ortiz JL, Orr C, Albaugh MD, Althoff RR, O'Loughlin K, Holbrook H, Garavan H, Yang BZ, Mostofsky S, Jackowski A, Lee RS, Gelernter J, Kaufman J. Tubulin Polymerization Promoting Protein (TPPP) gene methylation and corpus callosum measures in maltreated children. Psychiatry Research Neuroimaging 2020, 298: 111058. PMID: 32120304, PMCID: PMC11079625, DOI: 10.1016/j.pscychresns.2020.111058.Peer-Reviewed Original ResearchConceptsStress-related psychiatric disordersCorpus callosum measuresFractional anisotropyPsychiatric disordersTrauma experiencesWhite matter tractsChild trauma experiencesBrain changesLarger studyRelevant covariatesAtlas-based approachSplenium fractional anisotropyDNA specimensMultiple comparisonsGene methylationDisordersChildrenCurrent studySocial supports moderate the effects of child adversity on neural correlates of threat processing
Wymbs NF, Orr C, Albaugh MD, Althoff RR, O’Loughlin K, Holbrook H, Garavan H, Montalvo-Ortiz JL, Mostofsky S, Hudziak J, Kaufman J. Social supports moderate the effects of child adversity on neural correlates of threat processing. Child Abuse & Neglect 2020, 102: 104413. PMID: 32065988, PMCID: PMC8060780, DOI: 10.1016/j.chiabu.2020.104413.Peer-Reviewed Original ResearchConceptsFunctional magnetic resonance imagingThreat processingAnterior cingulate cortexSocial supportEmotion regulationNeural correlatesEmotional Go-Nogo taskGo-NoGo taskPositive social supportChildren ages 7Forms of adversityKey brain regionsAdverse experiencesFacial stimuliThreat stimuliNeural processingBrain systemsBrain activationModerate adversitySevere adversityAnterior insulaConjunction analysisLeft amygdalaOrbitofrontal cortexActivation foci
2019
Epigenome‐Wide DNA Methylation Association Analysis Identified Novel Loci in Peripheral Cells for Alcohol Consumption Among European American Male Veterans
Xu K, Montalvo‐Ortiz J, Zhang X, Southwick SM, Krystal JH, Pietrzak RH, Gelernter J. Epigenome‐Wide DNA Methylation Association Analysis Identified Novel Loci in Peripheral Cells for Alcohol Consumption Among European American Male Veterans. Alcohol Clinical And Experimental Research 2019, 43: 2111-2121. PMID: 31386212, PMCID: PMC9377208, DOI: 10.1111/acer.14168.Peer-Reviewed Original ResearchConceptsEpigenome-wide association studiesDNA methylationCpG sitesSignificant CpG sitesHigh-density methylation arraysNovel DNA methylation sitesNew CpG sitesDNA methylation sitesEpigenome-wide DNA methylationAmino acid transportIndividual CpG sitesGene lengthPeripheral cellsNovel lociDNA sitesKEGG databaseMethylation sitesEnrichment analysisMethylation arraysAssociation studiesAssociation analysisGenesMethylationAcid transportFalse discovery rateAccelerated DNA Methylation Aging in U.S. Military Veterans: Results From the National Health and Resilience in Veterans Study
Tamman AJF, Montalvo-Ortiz JL, Southwick SM, Krystal JH, Levy BR, Pietrzak RH. Accelerated DNA Methylation Aging in U.S. Military Veterans: Results From the National Health and Resilience in Veterans Study. American Journal Of Geriatric Psychiatry 2019, 27: 528-532. PMID: 30792041, DOI: 10.1016/j.jagp.2019.01.001.Peer-Reviewed Original ResearchConceptsNational HealthPsychosocial factorsVeterans StudyMale U.S. veteransLifetime trauma burdenAccelerated DNA methylation agingDNA methylation agingU.S. military veteransMethylation agingTrauma burdenU.S. veteransPrevention effortsAdditional correlatesNegative beliefsMilitary veteransSexual traumaVeteransTraumatic stressDNA methylationHealthChild sexual traumaBody massRepresentative sample
2018
Adverse Childhood Experiences, Epigenetic Measures, and Obesity in Youth
Kaufman J, Montalvo-Ortiz JL, Holbrook H, O'Loughlin K, Orr C, Kearney C, Yang BZ, Wang T, Zhao H, Althoff R, Garavan H, Gelernter J, Hudziak J. Adverse Childhood Experiences, Epigenetic Measures, and Obesity in Youth. The Journal Of Pediatrics 2018, 202: 150-156.e3. PMID: 30177354, PMCID: PMC6513669, DOI: 10.1016/j.jpeds.2018.06.051.Peer-Reviewed Original ResearchConceptsBody mass indexAdverse childhood experiencesMass indexIndices of obesityAssessment of obesityChildhood experiencesFuture longitudinal studiesObesity riskHealth burdenPsychiatric outcomesSecond cohortObesityNovel interventionsCohortEarly adversityCross-sectional measuresEpigenetic predictorsLongitudinal studySaliva DNAEpigenetic measuresWhole genome testingDiscovery sampleReplication sampleChildrenRiskMethylation in OTX2 and related genes, maltreatment, and depression in children
Kaufman J, Wymbs NF, Montalvo-Ortiz JL, Orr C, Albaugh MD, Althoff R, O’Loughlin K, Holbrook H, Garavan H, Kearney C, Yang BZ, Zhao H, Peña C, Nestler EJ, Lee RS, Mostofsky S, Gelernter J, Hudziak J. Methylation in OTX2 and related genes, maltreatment, and depression in children. Neuropsychopharmacology 2018, 43: 2204-2211. PMID: 30089883, PMCID: PMC6135753, DOI: 10.1038/s41386-018-0157-y.Peer-Reviewed Original ResearchConceptsMouse modelStress-related depressive disordersResting-state functional connectivity dataResting-state functional MRI dataDepressive-like behaviorEarly life stressSubset of childrenDNA specimensMedial frontal cortexPeripheral markersMeasures of depressionHomeobox 2 geneSubcallosal gyrusFunctional connectivity dataDepressive disorderFrontal cortexChild adversityMultiple molecular toolsFunctional MRI dataFrontal poleLarger studyFunctional connectivitySaliva samplesBilateral regionsUnbiased transcriptomicsTranslational studies support a role for serotonin 2B receptor (HTR2B) gene in aggression-related cannabis response
Montalvo-Ortiz JL, Zhou H, D’Andrea I, Maroteaux L, Lori A, Smith A, Ressler KJ, Nuñez YZ, Farrer LA, Zhao H, Kranzler HR, Gelernter J. Translational studies support a role for serotonin 2B receptor (HTR2B) gene in aggression-related cannabis response. Molecular Psychiatry 2018, 23: 2277-2286. PMID: 29875475, PMCID: PMC6281782, DOI: 10.1038/s41380-018-0077-6.Peer-Reviewed Original ResearchConceptsGrady Trauma ProjectAfrican AmericansWild-type miceReceptor geneEffects of cannabisWide significant risk lociResident-intruder paradigmImpulsivity/aggressionConcordant findingsTHC administrationKnockout miceTranslational studiesAA subjectsCannabis useStudy designTrauma ProjectAdverse effectsMiceCannabisAggressive behaviorEuropean AmericansNominal associationAdverse consequencesGenome-wide association study (GWAS) designRisk lociCorticotrophin releasing factor receptor 1 antagonists prevent chronic stress-induced behavioral changes and synapse loss in aged rats
Dong H, Keegan JM, Hong E, Gallardo C, Montalvo-Ortiz J, Wang B, Rice KC, Csernansky J. Corticotrophin releasing factor receptor 1 antagonists prevent chronic stress-induced behavioral changes and synapse loss in aged rats. Psychoneuroendocrinology 2018, 90: 92-101. PMID: 29477954, PMCID: PMC5864558, DOI: 10.1016/j.psyneuen.2018.02.013.Peer-Reviewed Original ResearchMeSH KeywordsAge FactorsAnimalsAnxietyBehaviorBehavior, AnimalCorticotropin-Releasing HormoneDepressionDisease Models, AnimalFemaleHypothalamo-Hypophyseal SystemMalePituitary-Adrenal SystemPyrimidinesPyrrolesRatsRats, Sprague-DawleyReceptors, Corticotropin-Releasing HormoneStress, PsychologicalSynapsesConceptsStress-induced behavioral changesStress-induced anxietyAnxiety-related behaviorMemory deficitsChronic stressSynapse lossCRF1 antagonistsFactor receptor 1 antagonistCortical dendritic spinesHPA axis dysfunctionBody weight lossReceptor 1 antagonistMonths of ageSubset of animalsBehavioral changesFactor receptor 1Axis dysfunctionAged brainAged ratsPotential therapyDendritic spinesAnimal modelsCorticosterone levelsAlzheimer's diseaseReceptor 1
2017
Genome-Wide DNA Methylation Changes Associated with Intermittent Explosive Disorder: A Gene-Based Functional Enrichment Analysis
Montalvo-Ortiz JL, Zhang H, Chen C, Liu C, Coccaro EF. Genome-Wide DNA Methylation Changes Associated with Intermittent Explosive Disorder: A Gene-Based Functional Enrichment Analysis. The International Journal Of Neuropsychopharmacology 2017, 21: 12-20. PMID: 29106553, PMCID: PMC5789263, DOI: 10.1093/ijnp/pyx087.Peer-Reviewed Original ResearchConceptsGenome-wide DNA methylation changesFunctional enrichment analysisDNA methylation changesEnrichment analysisCpG sitesMethylation changesGenome-wide significant thresholdIllumina Infinium HumanMethylation450 BeadChipBlood DNA methylomeNovel biological processesInfinium HumanMethylation450 BeadChipDNA methylomeEpigenetic mechanismsPathway analysisBiological processesGenetic studiesNeuronal differentiationHumanMethylation450 BeadChipGenesBehavioral genetic studiesR packageImportant mechanismGenetic influencesEndocrine systemMethylomeHistone deacetylase inhibitors reverse age-related increases in side effects of haloperidol in mice
Montalvo-Ortiz JL, Fisher DW, Rodríguez G, Fang D, Csernansky JG, Dong H. Histone deacetylase inhibitors reverse age-related increases in side effects of haloperidol in mice. Psychopharmacology 2017, 234: 2385-2398. PMID: 28421257, PMCID: PMC5538925, DOI: 10.1007/s00213-017-4629-2.Peer-Reviewed Original ResearchConceptsMotor side effectsAged miceSide effectsValproic acidAge-related increaseHDAC inhibitorsAntipsychotic-induced side effectsDrd2 promoterAdjunct treatment strategyHistone deacetylase inhibitor valproic acidProtein levelsDopamine D2 receptorsInhibitor valproic acidHistone deacetylase inhibitorsDrug-dependent decreaseBackgroundOlder patientsMotor deficitsC57BL/6 miceAntagonist haloperidolTreatment strategiesYoung miceD2 receptorsPharmacodynamic mechanismsHaloperidolDeacetylase inhibitors
2016
The role of genes involved in stress, neural plasticity, and brain circuitry in depressive phenotypes: Convergent findings in a mouse model of neglect
Montalvo-Ortiz JL, Bordner KA, Carlyle BC, Gelernter J, Simen AA, Kaufman J. The role of genes involved in stress, neural plasticity, and brain circuitry in depressive phenotypes: Convergent findings in a mouse model of neglect. Behavioural Brain Research 2016, 315: 71-74. PMID: 27506655, PMCID: PMC5396458, DOI: 10.1016/j.bbr.2016.08.010.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDepressionDisease Models, AnimalGene Expression RegulationInhibitor of Differentiation ProteinsMaleMaternal DeprivationMaze LearningMiceMice, Inbred C57BLMice, Inbred DBAMicroarray AnalysisNerve Tissue ProteinsNeuronal PlasticityPrefrontal CortexReceptors, N-Methyl-D-AspartateRNA, MessengerStress, PsychologicalSwimmingConceptsTubulin Polymerization Promoting ProteinRole of genesGene expression dataEpigenetic changesGene expressionPhenotype dataExpression dataPrefrontal cortex tissueGenesSecondary analysisMedial prefrontal cortex (mPFC) tissueGlutamate NMDA receptorsAdult male miceId-3Early life stressPhenotypeSwimming testMale miceNMDA receptorsDepression riskMaternal separationMouse modelDepressive phenotypeBrain circuitryBehavioral differences
2014
Effects of corticotrophin-releasing factor receptor 1 antagonists on amyloid-β and behavior in Tg2576 mice
Dong H, Wang S, Zeng Z, Li F, Montalvo-Ortiz J, Tucker C, Akhtar S, Shi J, Meltzer HY, Rice KC, Csernansky JG. Effects of corticotrophin-releasing factor receptor 1 antagonists on amyloid-β and behavior in Tg2576 mice. Psychopharmacology 2014, 231: 4711-4722. PMID: 24862368, PMCID: PMC4233002, DOI: 10.1007/s00213-014-3629-8.Peer-Reviewed Original ResearchMeSH KeywordsAlzheimer DiseaseAmyloid beta-Protein PrecursorAnimalsCorticotropin-Releasing HormoneCyclic AMPCyclic AMP-Dependent Protein KinasesDisease Models, AnimalHippocampusMaleMemoryMiceMice, TransgenicNeuronsPlaque, AmyloidPyrimidinesPyrrolesReceptors, Corticotropin-Releasing HormoneSignal TransductionConceptsAβ1-42 levelsCorticotrophin-releasing factorReceptor 1 antagonistPlaque depositionCRF1 antagonistsMouse modelDays of ageAlzheimer's diseaseMouse pupsIsolation stressCRF receptor 1 antagonistFactor receptor 1 antagonistAdministration of antalarminExogenous CRF administrationCultured primary hippocampal neuronsDaily intraperitoneal injectionsIncubation of neuronsCohort of micePlasma corticosterone levelsPrimary hippocampal neuronsMonths of ageCRF administrationAβ levelsIntraperitoneal injectionHippocampal neurons
2013
HDAC Inhibitors Restore the Capacity of Aged Mice to Respond to Haloperidol through Modulation of Histone Acetylation
Montalvo-Ortiz JL, Keegan J, Gallardo C, Gerst N, Tetsuka K, Tucker C, Matsumoto M, Fang D, Csernansky JG, Dong H. HDAC Inhibitors Restore the Capacity of Aged Mice to Respond to Haloperidol through Modulation of Histone Acetylation. Neuropsychopharmacology 2013, 39: 1469-1478. PMID: 24366052, PMCID: PMC3988551, DOI: 10.1038/npp.2013.346.Peer-Reviewed Original ResearchConceptsC-fos expressionAged miceValproic acidNucleus accumbensPrefrontal cortexYoung miceMS-275HDAC inhibitorsC-Fos expression patternHDAC inhibitor valproic acidAntipsychotic drug actionEffects of haloperidolAge-related decreaseInhibitor valproic acidHistone deacetylase inhibitorsElderly patientsHAL administrationHistone acetylationAntipsychotic drugsAvoidance responseBehavioral disturbancesElderly individualsClinical experienceHaloperidolEpigenetic changes