2024
Whole-exome sequencing in UK Biobank reveals rare genetic architecture for depression
Tian R, Ge T, Kweon H, Rocha D, Lam M, Liu J, Singh K, Levey D, Gelernter J, Stein M, Tsai E, Huang H, Chabris C, Lencz T, Runz H, Chen C. Whole-exome sequencing in UK Biobank reveals rare genetic architecture for depression. Nature Communications 2024, 15: 1755. PMID: 38409228, PMCID: PMC10897433, DOI: 10.1038/s41467-024-45774-2.Peer-Reviewed Original ResearchConceptsGenome-wide association studiesRare coding variantsWhole-exome sequencingGenetic architectureGenetic relationshipsLoss-of-function intolerant genesContribution of rare coding variantsRare damagingAssociated with risk of depressionElectronic health recordsUK Biobank participantsPolygenic risk scoresRisk of depressionAssociated with riskIntolerant genesRisk lociAssociation studiesCoding variantsBiobank participantsHealth recordsUK BiobankDepression definitionsDepression riskBurden analysisRare variants
2023
Depression pathophysiology, risk prediction of recurrence and comorbid psychiatric disorders using genome-wide analyses
Als T, Kurki M, Grove J, Voloudakis G, Therrien K, Tasanko E, Nielsen T, Naamanka J, Veerapen K, Levey D, Bendl J, Bybjerg-Grauholm J, Zeng B, Demontis D, Rosengren A, Athanasiadis G, Bækved-Hansen M, Qvist P, Bragi Walters G, Thorgeirsson T, Stefánsson H, Musliner K, Rajagopal V, Farajzadeh L, Thirstrup J, Vilhjálmsson B, McGrath J, Mattheisen M, Meier S, Agerbo E, Stefánsson K, Nordentoft M, Werge T, Hougaard D, Mortensen P, Stein M, Gelernter J, Hovatta I, Roussos P, Daly M, Mors O, Palotie A, Børglum A. Depression pathophysiology, risk prediction of recurrence and comorbid psychiatric disorders using genome-wide analyses. Nature Medicine 2023, 29: 1832-1844. PMID: 37464041, PMCID: PMC10839245, DOI: 10.1038/s41591-023-02352-1.Peer-Reviewed Original ResearchConceptsSingle nucleotide polymorphism heritabilityGenome-wide analysisLikely causal genesFunctional genomics dataRisk variantsWide association studyPolygenic burdenPsychiatric disordersCausal genesPolygenic architectureGenomic dataRisk lociAssociation studiesSubgroups of depressionCause of disabilityDepression genetic riskCommon psychiatric disordersPrecision medicine approachCases of depressionOligodendrocyte lineageGenesLociConsiderable sex differencesGABAergic neuronsPsychiatric comorbidityBaseline platelet serotonin in a multi-site treatment study of depression in veterans administration patients: Distribution and effects of demographic variables and serotonin reuptake inhibitors
Anderson G, Ramsey C, Lynch K, Gelernter J, Oslin D. Baseline platelet serotonin in a multi-site treatment study of depression in veterans administration patients: Distribution and effects of demographic variables and serotonin reuptake inhibitors. Journal Of Affective Disorders 2023, 327: 368-377. PMID: 36754092, DOI: 10.1016/j.jad.2023.02.017.Peer-Reviewed Original ResearchConceptsReuptake inhibitorsVeterans Administration patientsTreatment studiesSubset of patientsNorepinephrine reuptake inhibitorsCross-sectional studyEffect of ageDose adjustmentAfrican American individualsDemographic variablesMean plateletDrug exposurePlatelet serotoninSerotonin valuesPatientsClinical implicationsHealth recordsMale groupSSRIsDepressionPlateletsEuropean AmericansInhibitorsSex differencesGroup meansEpidemiologic and Genetic Associations of Endometriosis With Depression, Anxiety, and Eating Disorders
Koller D, Pathak G, Wendt F, Tylee D, Levey D, Overstreet C, Gelernter J, Taylor H, Polimanti R. Epidemiologic and Genetic Associations of Endometriosis With Depression, Anxiety, and Eating Disorders. JAMA Network Open 2023, 6: e2251214. PMID: 36652249, PMCID: PMC9856929, DOI: 10.1001/jamanetworkopen.2022.51214.Peer-Reviewed Original ResearchMeSH KeywordsAnxietyDepressionEndometriosisFeeding and Eating DisordersFemaleGenome-Wide Association StudyHumansConceptsPsychiatric comorbidityMAIN OUTCOMEMental healthIrritable bowel syndromeBody mass indexAssociation of endometriosisOdds of depressionSevere physical symptomsPain-related phenotypesWomen's mental healthMultivariate regression analysisOdds of endometriosisBowel syndromeGenetic associationMass indexGynecologic pathologyMillion Veteran ProgramEndometriosisPsychiatric disordersWomen's healthFemale controlsPleiotropic mechanismsPhysical symptomsComorbiditiesFinnGen study
2022
Unique and joint associations of polygenic risk for major depression and opioid use disorder with endogenous opioid system function
Love T, Shabalin AA, Kember RL, Docherty AR, Zhou H, Koppelmans V, Gelernter J, Baker AK, Hartwell E, Dubroff J, Zubieta JK, Kranzler HR. Unique and joint associations of polygenic risk for major depression and opioid use disorder with endogenous opioid system function. Neuropsychopharmacology 2022, 47: 1784-1790. PMID: 35545664, PMCID: PMC9372136, DOI: 10.1038/s41386-022-01325-1.Peer-Reviewed Original ResearchConceptsOpioid use disorderMajor depressive disorderPolygenic risk scoresUse disordersEndogenous opioid system functionOpioid system functionOpioid system activityMDD polygenic risk scoresPolygenic riskAssociation of PRSEndogenous opioid responseOpioid system activationNon-displaceable bindingPathophysiologic linkOpioid responseMOR availabilityOpioid releaseDepressive disorderMajor depressionNeurotransmitter systemsVentral pallidumRisk scoreReceptor concentrationSystem activationRegion of interest
2021
Polygenic risk for major depression is associated with lifetime suicide attempt in US soldiers independent of personal and parental history of major depression
Stein MB, Jain S, Campbell‐Sills L, Ware EB, Choi KW, He F, Ge T, Gelernter J, Smoller JW, Kessler RC, Ursano RJ. Polygenic risk for major depression is associated with lifetime suicide attempt in US soldiers independent of personal and parental history of major depression. American Journal Of Medical Genetics Part B Neuropsychiatric Genetics 2021, 186: 469-475. PMID: 34288400, PMCID: PMC8692314, DOI: 10.1002/ajmg.b.32868.Peer-Reviewed Original ResearchConceptsMajor depressive disorderLifetime suicide attemptsParental historySuicide attemptsMajor depressionMDD-PRSMultivariable modelLifetime historyMajor public health problemIncident suicide attemptsPolygenic riskPublic health problemUS Army soldiersRisk stratificationDepressive disorderPolygenic risk scoresRisk scoreSecond cohortHealth problemsCommon genetic variantsFirst cohortPersonal historyCohortGenetic variantsArmy soldiers
2018
Methylation 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 transcriptomics
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
Evaluating the role of a galanin enhancer genotype on a range of metabolic, depressive and addictive phenotypes
Richardson TG, Minica C, Heron J, Tavare J, MacKenzie A, Day I, Lewis G, Hickman M, Vink JM, Gelernter J, Kranzler HR, Farrer LA, Munafò M, Wynick D. Evaluating the role of a galanin enhancer genotype on a range of metabolic, depressive and addictive phenotypes. American Journal Of Medical Genetics Part B Neuropsychiatric Genetics 2014, 165: 654-664. PMID: 25228436, PMCID: PMC4388908, DOI: 10.1002/ajmg.b.32270.Peer-Reviewed Original ResearchConceptsRat hypothalamic neuronsAvon Longitudinal StudyGalaninergic systemGalanin expressionNeuropeptide galaninHypothalamic neuronsClinical dataChild CohortEnhancer region upstreamGG alleleCannabis usageYoung adultsCA alleleLongitudinal studyPathological functionsTransfection studiesInitial findingsGalaninCohortNeuronsChild Abuse, Depression, and Methylation in Genes Involved With Stress, Neural Plasticity, and Brain Circuitry
Weder N, Zhang H, Jensen K, Yang BZ, Simen A, Jackowski A, Lipschitz D, Douglas-Palumberi H, Ge M, Perepletchikova F, O'Loughlin K, Hudziak JJ, Gelernter J, Kaufman J. Child Abuse, Depression, and Methylation in Genes Involved With Stress, Neural Plasticity, and Brain Circuitry. Journal Of The American Academy Of Child & Adolescent Psychiatry 2014, 53: 417-424.e5. PMID: 24655651, PMCID: PMC4126411, DOI: 10.1016/j.jaac.2013.12.025.Peer-Reviewed Original ResearchConceptsTubulin Polymerization Promoting ProteinCandidate genesEpigenetic changesMethylation sitesGenome-wide methylation studyMultiple methylation sitesK BeadChip arraySaliva-derived DNAEpigenetic mechanismsK BeadChipBeadChip arrayEpigenetic markersStress responseMethylation studiesCpG sitesGenesNeural circuitry developmentMethylationId-3Whole genome testingNeural plasticityGRIN1Genome testingPlasticityGlutamate receptors
2011
A CRHR1 haplotype moderates the effect of adverse childhood experiences on lifetime risk of major depressive episode in African‐American women
Kranzler HR, Feinn R, Nelson EC, Covault J, Anton RF, Farrer L, Gelernter J. A CRHR1 haplotype moderates the effect of adverse childhood experiences on lifetime risk of major depressive episode in African‐American women. American Journal Of Medical Genetics Part B Neuropsychiatric Genetics 2011, 156: 960-968. PMID: 21998007, PMCID: PMC3227028, DOI: 10.1002/ajmg.b.31243.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAlcohol DrinkingBlack or African AmericanChildChild AbuseDepressionDepressive Disorder, MajorFemaleGene FrequencyGenetic Predisposition to DiseaseHaplotypesHumansMiddle AgedPolymorphism, Single NucleotideReceptors, Corticotropin-Releasing HormoneStress, PsychologicalSubstance-Related DisordersConceptsMajor depressive episodeAdverse childhood experiencesRisk of depressionTAT haplotypeAlcohol dependenceDepressive episodeLifetime riskAA womenCorticotropin-releasing hormone type 1 receptorOdds of MDERisk of MDELifetime substance use disorderType 1 receptorSubstance use disordersAfrican AmericansAfrican American womenChildhood experiencesDepression riskThree-SNP haplotypeAD riskUse disordersAdult depressionAlcohol consumptionCRHR1 haplotypeCRHR1
2010
A Prospective Cohort Study Investigating Factors Associated With Depression During Medical Internship
Sen S, Kranzler HR, Krystal JH, Speller H, Chan G, Gelernter J, Guille C. A Prospective Cohort Study Investigating Factors Associated With Depression During Medical Internship. JAMA Psychiatry 2010, 67: 557-565. PMID: 20368500, PMCID: PMC4036806, DOI: 10.1001/archgenpsychiatry.2010.41.Peer-Reviewed Original ResearchMeSH KeywordsAdultCohort StudiesDepressionDepressive DisorderDepressive Disorder, MajorFemaleGenotypeHealth StatusHumansInternship and ResidencyLife Change EventsMaleMedicinePolymorphism, Single NucleotidePrevalenceProspective StudiesRisk FactorsSerotonin Plasma Membrane Transport ProteinsStress, PsychologicalStudents, MedicalSurveys and QuestionnairesConceptsDepressive symptomsPHQ-9 depression scoresProspective cohort studyPrevalence of depressionPatient Health QuestionnaireProportion of participantsMedical internsMedical internshipGreater increasePHQ-9 criteriaCohort studyHealth QuestionnaireMood symptomsGeneral populationDepression scoresUS hospitalsSymptomsSerotonin transporter protein geneGenetic polymorphismsDepressionGenetic factorsLife stressMarked increaseRecent reportsResidency programs
2009
Arguable Assumptions, Debatable Conclusions
Kaufman J, Gelernter J, Kaffman A, Caspi A, Moffitt T. Arguable Assumptions, Debatable Conclusions. Biological Psychiatry 2009, 67: e19-e20. PMID: 20006323, PMCID: PMC3784000, DOI: 10.1016/j.biopsych.2009.07.041.Peer-Reviewed Original ResearchInteraction of Childhood Maltreatment with the Corticotropin-Releasing Hormone Receptor Gene: Effects on Hypothalamic-Pituitary-Adrenal Axis Reactivity
Tyrka AR, Price LH, Gelernter J, Schepker C, Anderson GM, Carpenter LL. Interaction of Childhood Maltreatment with the Corticotropin-Releasing Hormone Receptor Gene: Effects on Hypothalamic-Pituitary-Adrenal Axis Reactivity. Biological Psychiatry 2009, 66: 681-685. PMID: 19596121, PMCID: PMC2881567, DOI: 10.1016/j.biopsych.2009.05.012.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAdult Survivors of Child AbuseCorticotropin-Releasing HormoneDepressionDexamethasoneFemaleGenotypeHumansHydrocortisoneHypothalamo-Hypophyseal SystemLinear ModelsLinkage DisequilibriumMaleMiddle AgedPituitary-Adrenal SystemPolymorphism, GeneticReceptors, Corticotropin-Releasing HormoneStress, PsychologicalSurveys and QuestionnairesYoung AdultConceptsDEX/CRH testAdrenal (HPA) axis reactivityEarly life stressCortisol responseCRH testAxis reactivityDexamethasone/corticotropin-releasing hormone testCorticotropin-releasing hormone testChildhood maltreatmentCRHR1 polymorphismsHormone receptor geneHPA axis activationLife stressReceptor geneElevated cortisol responseDevelopment of moodChildhood Trauma QuestionnaireHormone testAxis activationHypothalamic-PituitaryNon-Hispanic adultsBlood samplesGG genotypeAdult depressionAnxiety disordersGenetic variation in 5HTTLPR is associated with emotional resilience
Stein MB, Campbell‐Sills L, Gelernter J. Genetic variation in 5HTTLPR is associated with emotional resilience. American Journal Of Medical Genetics Part B Neuropsychiatric Genetics 2009, 150B: 900-906. PMID: 19152387, PMCID: PMC2885845, DOI: 10.1002/ajmg.b.30916.Peer-Reviewed Original ResearchConceptsEmotional resilienceSelf-report measuresAdverse mental health outcomesMental health outcomesUndergraduate college studentsPsychological functioningIndividual differencesSerotonin transporter promoter polymorphismTransporter promoter polymorphismIndividual's abilityLife stressorsCollege studentsResilience
2006
Brain-Derived Neurotrophic Factor–5-HTTLPR Gene Interactions and Environmental Modifiers of Depression in Children
Kaufman J, Yang BZ, Douglas-Palumberi H, Grasso D, Lipschitz D, Houshyar S, Krystal JH, Gelernter J. Brain-Derived Neurotrophic Factor–5-HTTLPR Gene Interactions and Environmental Modifiers of Depression in Children. Biological Psychiatry 2006, 59: 673-680. PMID: 16458264, DOI: 10.1016/j.biopsych.2005.10.026.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentBrain-Derived Neurotrophic FactorCase-Control StudiesChildChild AbuseChild, PreschoolChi-Square DistributionDepressionDNA Mutational AnalysisEnvironmentFemaleGene FrequencyGenetic VariationGenotypeHumansMaleMethioninePredictive Value of TestsPsychiatric Status Rating ScalesRisk FactorsSerotonin Plasma Membrane Transport ProteinsSeverity of Illness IndexSocial SupportSurveys and QuestionnairesValineConceptsBrain-derived neurotrophic factor (BDNF) genotypeNeurotrophic factor genotypeSocial supportHigher depression scoresBDNF genotypeProportion scoreBDNF geneProtective effectDepression scoresComparison subjectsPsychiatric symptomatologyModerate riskEnvironmental modifiersDepressionFactor genotypeChildrenDNA specimensStandard research instrumentsShort alleleRiskMaltreatment historyCurrent dataScoresAncestry informative markersChild abuse
2004
Social supports and serotonin transporter gene moderate depression in maltreated children
Kaufman J, Yang BZ, Douglas-Palumberi H, Houshyar S, Lipschitz D, Krystal JH, Gelernter J. Social supports and serotonin transporter gene moderate depression in maltreated children. Proceedings Of The National Academy Of Sciences Of The United States Of America 2004, 101: 17316-17321. PMID: 15563601, PMCID: PMC534414, DOI: 10.1073/pnas.0404376101.Peer-Reviewed Original ResearchConceptsSocial supportDevelopment of depressionGene promoter polymorphismTransporter gene promoter polymorphismSerotonin transporter gene promoter polymorphismHigher depression ratingsDepression ratingsClinical dataModerate depressionPsychiatric disordersDepression scoresPromoter polymorphismNegative sequelaeModerate riskDepressionEarly stressChildrenS genotypeHistory of maltreatmentRiskShort allele