Featured Publications
Genetic Underpinnings of the Transition From Alcohol Consumption to Alcohol Use Disorder: Shared and Unique Genetic Architectures in a Cross-Ancestry Sample
Kember R, Vickers-Smith R, Zhou H, Xu H, Jennings M, Dao C, Davis L, Sanchez-Roige S, Justice A, Gelernter J, Vujkovic M, Kranzler H. Genetic Underpinnings of the Transition From Alcohol Consumption to Alcohol Use Disorder: Shared and Unique Genetic Architectures in a Cross-Ancestry Sample. American Journal Of Psychiatry 2023, 180: 584-593. PMID: 37282553, PMCID: PMC10731616, DOI: 10.1176/appi.ajp.21090892.Peer-Reviewed Original ResearchCross-ancestry meta-analysis of opioid use disorder uncovers novel loci with predominant effects in brain regions associated with addiction
Kember RL, Vickers-Smith R, Xu H, Toikumo S, Niarchou M, Zhou H, Hartwell EE, Crist RC, Rentsch CT, Davis L, Justice A, Sanchez-Roige S, Kampman K, Gelernter J, Kranzler H. Cross-ancestry meta-analysis of opioid use disorder uncovers novel loci with predominant effects in brain regions associated with addiction. Nature Neuroscience 2022, 25: 1279-1287. PMID: 36171425, PMCID: PMC9682545, DOI: 10.1038/s41593-022-01160-z.Peer-Reviewed Original ResearchMeSH KeywordsBehavior, AddictiveBrainFurinGenome-Wide Association StudyHumansOpioid-Related DisordersConceptsOpioid use disorderGenome-wide association studiesWide significant lociGene expression enrichmentSignificant genetic correlationsCell type groupSignificant lociAssociation studiesExpression enrichmentMillion Veteran ProgramGenetic correlationsUse disordersLociBrain regionsExonic variantsIntronic variantsSubstance use disordersTraitsBiological basisOpioid epidemicPsychiatric disordersVeteran ProgramBrain diseasesTSNARE1FBXW4Phenome-wide Association Analysis of Substance Use Disorders in a Deeply Phenotyped Sample
Kember RL, Hartwell EE, Xu H, Rotenberg J, Almasy L, Zhou H, Gelernter J, Kranzler HR. Phenome-wide Association Analysis of Substance Use Disorders in a Deeply Phenotyped Sample. Biological Psychiatry 2022, 93: 536-545. PMID: 36273948, PMCID: PMC9931661, DOI: 10.1016/j.biopsych.2022.08.010.Peer-Reviewed Original ResearchMeSH KeywordsAlcohol DrinkingAlcoholismChild, PreschoolGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansMultifactorial InheritancePhenotypeRisk FactorsSubstance-Related DisordersConceptsSubstance use disordersAlcohol use disorderOpioid use disorderPolygenic risk scoresUse disordersCo-occurring psychiatric disordersComprehensive psychiatric interviewSemi-Structured AssessmentElectronic health recordsControl subjectsLow prevalencePsychiatric interviewRisk scorePsychiatric disordersPhenome-wide association analysisDrug dependenceEuropean individualsHealth recordsLifetime cannabisPhenome-wide association studyDisordersAfrican ancestry individualsDSM diagnosesPopulation sampleGenetic liabilityEpigenome-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 ResearchMeSH KeywordsDNA MethylationEpigenomeGenome-Wide Association StudyHumansMaleStress Disorders, Post-TraumaticVeteransConceptsEpigenome-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 veteransGenome-wide meta-analysis of alcohol use disorder in East Asians
Zhou H, Kalayasiri R, Sun Y, Nuñez YZ, Deng HW, Chen XD, Justice AC, Kranzler HR, Chang S, Lu L, Shi J, Sanichwankul K, Mutirangura A, Malison RT, Gelernter J. Genome-wide meta-analysis of alcohol use disorder in East Asians. Neuropsychopharmacology 2022, 47: 1791-1797. PMID: 35094024, PMCID: PMC9372033, DOI: 10.1038/s41386-022-01265-w.Peer-Reviewed Original ResearchMeSH KeywordsAlcohol DehydrogenaseAlcohol DrinkingAlcoholismAldehyde Dehydrogenase, MitochondrialGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansPolymorphism, Single NucleotideConceptsAlcohol use disorderAlcohol dependenceUse disordersICD-9-CM diagnosisGenome-wide association studiesEast Asian subjectsElectronic health recordsPack yearsLeading causePolygenic risk scoresThai cohortRisk scoreAlcohol consumptionDSM-IVAsian subjectsCohortMillion Veteran Program sampleHealth recordsLarge genome-wide association studiesEast AsiansOngoing recruitmentRisk genesDisordersRisk lociSubjectsIdentifying and Reducing Bias in Genome-Wide Association Studies of Alcohol-Related Traits
Kranzler HR, Zhou H, Kember RL. Identifying and Reducing Bias in Genome-Wide Association Studies of Alcohol-Related Traits. American Journal Of Psychiatry 2022, 179: 14-16. PMID: 34974756, DOI: 10.1176/appi.ajp.2021.21111107.Peer-Reviewed Original ResearchThe addiction risk factor: A unitary genetic vulnerability characterizes substance use disorders and their associations with common correlates
Hatoum AS, Johnson EC, Colbert SMC, Polimanti R, Zhou H, Walters RK, Gelernter J, Edenberg HJ, Bogdan R, Agrawal A. The addiction risk factor: A unitary genetic vulnerability characterizes substance use disorders and their associations with common correlates. Neuropsychopharmacology 2021, 47: 1739-1745. PMID: 34750568, PMCID: PMC9372072, DOI: 10.1038/s41386-021-01209-w.Peer-Reviewed Original ResearchMeSH KeywordsAlcohol DrinkingBehavior, AddictiveGenome-Wide Association StudyHumansOpioid-Related DisordersRisk FactorsSubstance-Related DisordersBi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions
Levey DF, Stein MB, Wendt FR, Pathak GA, Zhou H, Aslan M, Quaden R, Harrington KM, Nuñez YZ, Overstreet C, Radhakrishnan K, Sanacora G, McIntosh AM, Shi J, Shringarpure SS, Concato J, Polimanti R, Gelernter J. Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions. Nature Neuroscience 2021, 24: 954-963. PMID: 34045744, PMCID: PMC8404304, DOI: 10.1038/s41593-021-00860-2.Peer-Reviewed Original ResearchMeSH KeywordsDepressive Disorder, MajorFemaleGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansMaleVeteransConceptsTranscriptome-wide association studyMillion Veteran ProgramTranscriptome-wide association study (TWAS) analysisGenomic risk lociComplex psychiatric traitsGenetic architectureRisk lociGene expressionAssociation studiesLikely pathogenicityPsychiatric traitsVeteran ProgramNew therapeutic directionEuropean ancestryNew insightsAncestryUK BiobankAfrican ancestrySubstantial replicationExpressionLarge independent cohortsGWASTherapeutic directionsGenesLociThe impact of removing former drinkers from genome‐wide association studies of AUDIT‐C
Dao C, Zhou H, Small A, Gordon KS, Li B, Kember RL, Ye Y, Gelernter J, Xu K, Kranzler HR, Zhao H, Justice AC. The impact of removing former drinkers from genome‐wide association studies of AUDIT‐C. Addiction 2021, 116: 3044-3054. PMID: 33861876, PMCID: PMC9377185, DOI: 10.1111/add.15511.Peer-Reviewed Original ResearchGenome-wide association study of smoking trajectory and meta-analysis of smoking status in 842,000 individuals
Xu K, Li B, McGinnis KA, Vickers-Smith R, Dao C, Sun N, Kember RL, Zhou H, Becker WC, Gelernter J, Kranzler HR, Zhao H, Justice AC. Genome-wide association study of smoking trajectory and meta-analysis of smoking status in 842,000 individuals. Nature Communications 2020, 11: 5302. PMID: 33082346, PMCID: PMC7598939, DOI: 10.1038/s41467-020-18489-3.Peer-Reviewed Original ResearchConceptsGenome-wide association studiesLarge genome-wide association studiesMillion Veteran ProgramAssociation studiesExpression quantitative trait lociQuantitative trait lociChromatin interactionsComplex traitsFunctional annotationTrait lociSequencing ConsortiumDozen genesSignificant lociSmoking phenotypesLociMultiple populationsNew insightsPhenotypeVeteran ProgramGenetic vulnerabilityGenesTraitsAnnotationEuropean AmericansConsortiumAssociation of OPRM1 Functional Coding Variant With Opioid Use Disorder
Zhou H, Rentsch CT, Cheng Z, Kember RL, Nunez YZ, Sherva RM, Tate JP, Dao C, Xu K, Polimanti R, Farrer LA, Justice AC, Kranzler HR, Gelernter J. Association of OPRM1 Functional Coding Variant With Opioid Use Disorder. JAMA Psychiatry 2020, 77: 1072-1080. PMID: 32492095, PMCID: PMC7270886, DOI: 10.1001/jamapsychiatry.2020.1206.Peer-Reviewed Original ResearchMeSH KeywordsAgedFemaleGenome-Wide Association StudyHumansMaleMiddle AgedOpioid-Related DisordersReceptors, Opioid, muUnited StatesUnited States Department of Veterans AffairsConceptsOpioid use disorderUse disordersMendelian randomization analysisAfrican American individualsMAIN OUTCOMEFunctional coding variantSignificant associationCausal associationRandomization analysisElectronic health record dataCurrent opioid crisisAmerican individualsHealth record dataCognitive performanceInternational Statistical ClassificationRelated Health ProblemsPotential causal associationAmerican controlsEuropean American controlsAfrican-American controlsCoding variantBuprenorphine treatmentOUD diagnosisTobacco smokingNinth RevisionReproducible Genetic Risk Loci for Anxiety: Results From ∼200,000 Participants in the Million Veteran Program
Levey DF, Gelernter J, Polimanti R, Zhou H, Cheng Z, Aslan M, Quaden R, Concato J, Radhakrishnan K, Bryois J, Sullivan PF, Stein M. Reproducible Genetic Risk Loci for Anxiety: Results From ∼200,000 Participants in the Million Veteran Program. American Journal Of Psychiatry 2020, 177: 223-232. PMID: 31906708, PMCID: PMC7869502, DOI: 10.1176/appi.ajp.2019.19030256.Peer-Reviewed Original ResearchMeSH KeywordsAgedAnxietyAnxiety DisordersFemaleGenetic LociGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansMaleMiddle AgedPhenotypePolymorphism, Single NucleotideVeteransConceptsNovel genome-wide significant associationsGene expressionGenome-wide significant signalsGenome-wide significant associationMillion Veteran ProgramWide association studyGenetic risk lociSignificant genetic correlationsGenetic risk mechanismsGenetic architectureGlobal regulatorChromosome 3Risk lociChromosome 6Chromosome 7Association studiesLargest GWASLarge biobanksGlobal regulationGenetic correlationsContinuous traitsVeteran ProgramGWASsLociPrevious GWASsGenome-wide association study of alcohol consumption and use disorder in 274,424 individuals from multiple populations
Kranzler HR, Zhou H, Kember RL, Vickers Smith R, Justice AC, Damrauer S, Tsao PS, Klarin D, Baras A, Reid J, Overton J, Rader DJ, Cheng Z, Tate JP, Becker WC, Concato J, Xu K, Polimanti R, Zhao H, Gelernter J. Genome-wide association study of alcohol consumption and use disorder in 274,424 individuals from multiple populations. Nature Communications 2019, 10: 1499. PMID: 30940813, PMCID: PMC6445072, DOI: 10.1038/s41467-019-09480-8.Peer-Reviewed Original ResearchConceptsGenome-wide association studiesAssociation studiesMillion Veteran Program sampleGenetic correlationsWide significant lociSignificant genetic correlationsPolygenic risk scoresCell type groupSignificant lociHeritable traitEnrichment analysisTraitsMultiple populationsLociPhenotypeProgram samplesGenome-wide association study identifies glutamate ionotropic receptor GRIA4 as a risk gene for comorbid nicotine dependence and major depression
Zhou H, Cheng Z, Bass N, Krystal JH, Farrer LA, Kranzler HR, Gelernter J. Genome-wide association study identifies glutamate ionotropic receptor GRIA4 as a risk gene for comorbid nicotine dependence and major depression. Translational Psychiatry 2018, 8: 208. PMID: 30287806, PMCID: PMC6172277, DOI: 10.1038/s41398-018-0258-8.Peer-Reviewed Original ResearchConceptsGenome-wide association studiesGenome-wide association study identifiesRisk genesTop risk genesCalcium ion bindingGenomes reference panelFast excitatory synaptic transmissionGenetic risk variantsGenetic basisEnrichment analysisAssociation studiesExome arrayCell adhesionRisk variantsGenesReference panelGenetic riskAMPA-sensitive glutamate receptorsIntronic variantsIon bindingBiological mechanismsConditional analysisGRIA4Excitatory synaptic transmissionSynaptic transmissionTranslational 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 lociPolygenic Scores for Major Depressive Disorder and Risk of Alcohol Dependence
Andersen AM, Pietrzak RH, Kranzler HR, Ma L, Zhou H, Liu X, Kramer J, Kuperman S, Edenberg HJ, Nurnberger JI, Rice JP, Tischfield JA, Goate A, Foroud TM, Meyers JL, Porjesz B, Dick DM, Hesselbrock V, Boerwinkle E, Southwick SM, Krystal JH, Weissman MM, Levinson DF, Potash JB, Gelernter J, Han S. Polygenic Scores for Major Depressive Disorder and Risk of Alcohol Dependence. JAMA Psychiatry 2017, 74: 1153-1160. PMID: 28813562, PMCID: PMC5710224, DOI: 10.1001/jamapsychiatry.2017.2269.Peer-Reviewed Original ResearchMeSH KeywordsAdultAlcoholismComorbidityDepressive Disorder, MajorFemaleGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansMaleMiddle AgedMultifactorial InheritanceUnited StatesWhite PeopleConceptsMDD polygenic risk scoresMajor depressive disorderPolygenic risk scoresAlcohol dependenceDepressive disorderSignificant public health burdenPublic health burdenAD comorbidityNational HealthHealth burdenMAIN OUTCOMECase-control statusRisk scoreRisk of ADVeterans StudyYale-PennGenetic susceptibilityMDD statusCommon genetic factorsSubstance dependenceMDD casesAD samplesPolygenic riskGenetic factorsHeritable disorder
2024
Human genetics and epigenetics of alcohol use disorder
Zhou H, Gelernter J. Human genetics and epigenetics of alcohol use disorder. Journal Of Clinical Investigation 2024, 134: e172885. PMID: 39145449, PMCID: PMC11324314, DOI: 10.1172/jci172885.Peer-Reviewed Original ResearchMeSH KeywordsAlcoholismEpigenesis, GeneticGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansConceptsEpigenome-wide association studiesEWAS studiesPower of GWASTranscriptome-wide associationGenome-wide scanAlcohol use disorderWhole-genome sequencingDrug-gene interactionsSingle-cell sequencingAssociation studiesDownstream analysisHuman geneticsGenetic variantsEpigenetic risk factorsVariant functionEpigenetic changesSpatial transcriptomicsUse disorderEpigeneticsDisease risk predictionGenetic correlationsDiversity of populationGeneticsComplex etiologyEnvironmental factorsGenome-wide association study of the common retinal disorder epiretinal membrane: Significant risk loci in each of three American populations
Gelernter J, Levey D, Galimberti M, Harrington K, Zhou H, Adhikari K, Gupta P, Program V, Gaziano J, Eliott D, Stein M. Genome-wide association study of the common retinal disorder epiretinal membrane: Significant risk loci in each of three American populations. Cell Genomics 2024, 4: 100582. PMID: 38870908, PMCID: PMC11228954, DOI: 10.1016/j.xgen.2024.100582.Peer-Reviewed Original ResearchConceptsGenome-wide association studiesMillion Veteran ProgramRisk lociAssociation studiesTrans-ancestry meta-analysisSignificant risk lociPathway enrichment analysisEpiretinal membraneTrans-ancestryGenome-wideMultiple traitsGenetic associationEnrichment analysisGene expressionEuropean AmericansLoss of visual acuityVeteran ProgramGenetic correlationsLociBiological mechanismsAmerican populationVisual acuityRetinal conditionsControl individualsRetinal surfaceGenetic contribution to the comorbidity between attention-deficit/hyperactivity disorder and substance use disorders
Koller D, Mitjans M, Kouakou M, Friligkou E, Cabrera-Mendoza B, Deak J, Llonga N, Pathak G, Stiltner B, Løkhammer S, Levey D, Zhou H, Hatoum A, Kember R, Kranzler H, Stein M, Corominas R, Demontis D, Artigas M, Ramos-Quiroga J, Gelernter J, Ribasés M, Cormand B, Polimanti R. Genetic contribution to the comorbidity between attention-deficit/hyperactivity disorder and substance use disorders. Psychiatry Research 2024, 333: 115758. PMID: 38335780, PMCID: PMC11157987, DOI: 10.1016/j.psychres.2024.115758.Peer-Reviewed Original ResearchMeSH KeywordsAlcoholismAttention Deficit Disorder with HyperactivityComorbidityGenome-Wide Association StudyHumansOpioid-Related DisordersSubstance-Related DisordersConceptsUse disorderGenome-wide association studiesGenomic structural equation modelingCannabis use disorderAlcohol Use Disorders Identification TestAttention-deficit/hyperactivity disorderAlcohol use disorderProblematic alcohol useSubstance use disordersTwo-sample Mendelian randomization analysisLinkage disequilibrium score regression analysisDisorders Identification TestMendelian randomization analysisAssociated with increased oddsOdds of ADHDOpioid use disorderAttention-deficit/hyperactivityGWAS meta-analysesAlcohol dependenceStructural equation modelingNicotine dependenceInvestigate genetic correlationsADHDPolygenic riskStrength of evidence
2023
Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals
Zhou H, Kember R, Deak J, Xu H, Toikumo S, Yuan K, Lind P, Farajzadeh L, Wang L, Hatoum A, Johnson J, Lee H, Mallard T, Xu J, Johnston K, Johnson E, Nielsen T, Galimberti M, Dao C, Levey D, Overstreet C, Byrne E, Gillespie N, Gordon S, Hickie I, Whitfield J, Xu K, Zhao H, Huckins L, Davis L, Sanchez-Roige S, Madden P, Heath A, Medland S, Martin N, Ge T, Smoller J, Hougaard D, Børglum A, Demontis D, Krystal J, Gaziano J, Edenberg H, Agrawal A, Justice A, Stein M, Kranzler H, Gelernter J. Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals. Nature Medicine 2023, 29: 3184-3192. PMID: 38062264, PMCID: PMC10719093, DOI: 10.1038/s41591-023-02653-5.Peer-Reviewed Original ResearchAlcoholismGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansPhenotypePolymorphism, Single NucleotideRacial Groups