2022
Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond
Gaddis N, Mathur R, Marks J, Zhou L, Quach B, Waldrop A, Levran O, Agrawal A, Randesi M, Adelson M, Jeffries PW, Martin NG, Degenhardt L, Montgomery GW, Wetherill L, Lai D, Bucholz K, Foroud T, Porjesz B, Runarsdottir V, Tyrfingsson T, Einarsson G, Gudbjartsson DF, Webb BT, Crist RC, Kranzler HR, Sherva R, Zhou H, Hulse G, Wildenauer D, Kelty E, Attia J, Holliday EG, McEvoy M, Scott RJ, Schwab SG, Maher BS, Gruza R, Kreek MJ, Nelson EC, Thorgeirsson T, Stefansson K, Berrettini WH, Gelernter J, Edenberg HJ, Bierut L, Hancock DB, Johnson EO. Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond. Scientific Reports 2022, 12: 16873. PMID: 36207451, PMCID: PMC9546890, DOI: 10.1038/s41598-022-21003-y.Peer-Reviewed Original ResearchConceptsGenome-wide significant associationMulti-trait genome-wide association studyNovel genome-wide significant associationsGenome-wide association studiesGenomic structural equationGene-based analysisRelated traitsAssociation studiesGenetic correlationsEuropean ancestryA118G variantConsortium dataNew geneticsG variantGWASPPP6CLociPleiotropicGeneticsVariantsTraitsPhenotypeOA phenotypeFurinAncestry
2020
Association 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 ResearchConceptsOpioid 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 Revision
2017
Genome-wide association study of therapeutic opioid dosing identifies a novel locus upstream of OPRM1
Smith AH, Jensen KP, Li J, Nunez Y, Farrer LA, Hakonarson H, Cook-Sather SD, Kranzler HR, Gelernter J. Genome-wide association study of therapeutic opioid dosing identifies a novel locus upstream of OPRM1. Molecular Psychiatry 2017, 22: 346-352. PMID: 28115739, PMCID: PMC5407902, DOI: 10.1038/mp.2016.257.Peer-Reviewed Original ResearchMeSH KeywordsAdultAllelesAnalgesics, OpioidBlack or African AmericanDose-Response Relationship, DrugFemaleGene FrequencyGenetic Predisposition to DiseaseGenome-Wide Association StudyGenotypeHumansMaleMethadoneMiddle AgedMorphineOpioid-Related DisordersPainPolymorphism, Single NucleotideReceptors, Opioid, muUnited StatesWhite PeopleConceptsMethadone doseOD subjectsOpioid dependenceSignificant associationDaily methadone doseMethadone maintenance doseOpioid analgesic doseDose of morphineHigher methadone doseDifferent clinical settingsΜ-opioid receptorAnalgesic doseMaintenance doseOral methadoneEffective analgesicSurgical painOpioid sensitivityPrecision pharmacotherapySelective agonistGenome-wide association studiesAA childrenClinical settingDoseMinor alleleOPRM1
2015
Association of the OPRM1 Variant rs1799971 (A118G) with Non-Specific Liability to Substance Dependence in a Collaborative de novo Meta-Analysis of European-Ancestry Cohorts
Schwantes-An TH, Zhang J, Chen LS, Hartz SM, Culverhouse RC, Chen X, Coon H, Frank J, Kamens HM, Konte B, Kovanen L, Latvala A, Legrand LN, Maher BS, Melroy WE, Nelson EC, Reid MW, Robinson JD, Shen PH, Yang BZ, Andrews JA, Aveyard P, Beltcheva O, Brown SA, Cannon DS, Cichon S, Corley RP, Dahmen N, Degenhardt L, Foroud T, Gaebel W, Giegling I, Glatt SJ, Grucza RA, Hardin J, Hartmann AM, Heath AC, Herms S, Hodgkinson CA, Hoffmann P, Hops H, Huizinga D, Ising M, Johnson EO, Johnstone E, Kaneva RP, Kendler KS, Kiefer F, Kranzler HR, Krauter KS, Levran O, Lucae S, Lynskey MT, Maier W, Mann K, Martin NG, Mattheisen M, Montgomery GW, Müller-Myhsok B, Murphy MF, Neale MC, Nikolov MA, Nishita D, Nöthen MM, Nurnberger J, Partonen T, Pergadia ML, Reynolds M, Ridinger M, Rose RJ, Rouvinen-Lagerström N, Scherbaum N, Schmäl C, Soyka M, Stallings MC, Steffens M, Treutlein J, Tsuang M, Wall TL, Wodarz N, Yuferov V, Zill P, Bergen AW, Chen J, Cinciripini PM, Edenberg HJ, Ehringer MA, Ferrell RE, Gelernter J, Goldman D, Hewitt JK, Hopfer CJ, Iacono WG, Kaprio J, Kreek MJ, Kremensky IM, Madden PA, McGue M, Munafò MR, Philibert RA, Rietschel M, Roy A, Rujescu D, Saarikoski ST, Swan GE, Todorov AA, Vanyukov MM, Weiss RB, Bierut LJ, Saccone NL. Association of the OPRM1 Variant rs1799971 (A118G) with Non-Specific Liability to Substance Dependence in a Collaborative de novo Meta-Analysis of European-Ancestry Cohorts. Behavior Genetics 2015, 46: 151-169. PMID: 26392368, PMCID: PMC4752855, DOI: 10.1007/s10519-015-9737-3.Peer-Reviewed Original ResearchConceptsSubstance dependenceModest protective effectDSM-IV alcoholOpioid receptor geneLight smokingProtective effectNicotine dependenceAddiction liabilityDifferent addictive substancesG alleleMeta-AnalysisCocaine dependenceRs1799971Addictive substancesHuman genetic studiesReceptor genePotential functional significanceEuropean ancestry cohortsOPRM1Substance dependence riskSimilar effectsEuropean ancestry subjectsFunctional significanceAddictive behaviorsRisk
2014
Pharmacogenetics of naltrexone and disulfiram in alcohol dependent, dually diagnosed veterans
Arias AJ, Gelernter J, Gueorguieva R, Ralevski E, Petrakis IL. Pharmacogenetics of naltrexone and disulfiram in alcohol dependent, dually diagnosed veterans. American Journal On Addictions 2014, 23: 288-293. PMID: 24724887, PMCID: PMC4600600, DOI: 10.1111/j.1521-0391.2014.12102.x.Peer-Reviewed Original ResearchMeSH KeywordsAlcohol DeterrentsAlcoholismDiagnosis, Dual (Psychiatry)DisulfiramDopamine beta-HydroxylaseDrug Therapy, CombinationFemaleGenotypeHeterozygoteHumansMaleMental DisordersMiddle AgedNaltrexoneNarcotic AntagonistsPolymorphism, Single NucleotideReceptors, Opioid, muTreatment OutcomeVeteransWhite PeopleConceptsAllele carriersHeavy drinkingCo-occurring alcohol dependenceT allele carriersAlcohol-dependent subjectsAD treatment responseTreatment of individualsPrimary outcomePharmacogenetic interactionsHigher overall rateTreatment responseAxis INaltrexoneT carriersEuropean-American subjectsOPRM1 rs1799971Favorable responseMore abstinenceAlcohol dependenceDependent subjectsDBH rs1611115DisulfiramGenotyped subjectsAbstinenceLess drinking
2012
Hypermethylation of OPRM1 promoter region in European Americans with alcohol dependence
Zhang H, Herman AI, Kranzler HR, Anton RF, Simen AA, Gelernter J. Hypermethylation of OPRM1 promoter region in European Americans with alcohol dependence. Journal Of Human Genetics 2012, 57: 670-675. PMID: 22914673, PMCID: PMC3481015, DOI: 10.1038/jhg.2012.98.Peer-Reviewed Original ResearchMeSH KeywordsAdultAlcoholismCase-Control StudiesCocaine-Related DisordersComorbidityCpG IslandsDNA MethylationFemaleGenetic Predisposition to DiseaseGenetics, PopulationGenome, HumanHumansMaleMarijuana AbuseMiddle AgedMultivariate AnalysisPromoter Regions, GeneticReceptors, Opioid, muRisk FactorsSequence Analysis, DNAWhite PeopleConceptsChildhood adversityOPRM1 promoter regionAD casesΜ-opioid receptor geneSubstance dependence disordersΜ-opioid receptorDays of intoxicationEffects of alcoholEuropean American controlsPromoter methylation levelsPeripheral bloodMethylation levelsDependence disordersAlcohol dependenceMultivariate analysisPromoter regionPromoter hypermethylationReceptor geneIllicit drugsEuropean AmericansMultiple comparisonsBisulfite sequencing analysisOverall methylation levelsAmerican controlsSex
2011
Variation in OPRM1 and Risk of Suicidal Behavior in Drug‐Dependent Individuals
Arias AJ, Chan G, Gelernter J, Farrer L, Kranzler HR. Variation in OPRM1 and Risk of Suicidal Behavior in Drug‐Dependent Individuals. American Journal On Addictions 2011, 21: 5-10. PMID: 22211341, PMCID: PMC3674102, DOI: 10.1111/j.1521-0391.2011.00195.x.Peer-Reviewed Original Research
2008
Multiple OPR genes influence personality traits in substance dependent and healthy subjects in two American populations
Luo X, Zuo L, Kranzler H, Zhang H, Wang S, Gelernter J. Multiple OPR genes influence personality traits in substance dependent and healthy subjects in two American populations. American Journal Of Medical Genetics Part B Neuropsychiatric Genetics 2008, 147B: 1028-1039. PMID: 18213616, PMCID: PMC3162230, DOI: 10.1002/ajmg.b.30701.Peer-Reviewed Original Research
2007
Population-specific effects of the Asn40Asp polymorphism at the μ-opioid receptor gene (OPRM1) on HPA-axis activation
Hernandez-Avila CA, Covault J, Wand G, Zhang H, Gelernter J, Kranzler HR. Population-specific effects of the Asn40Asp polymorphism at the μ-opioid receptor gene (OPRM1) on HPA-axis activation. Pharmacogenetics And Genomics 2007, 17: 1031-1038. PMID: 18004207, DOI: 10.1097/fpc.0b013e3282f0b99c.Peer-Reviewed Original ResearchMeSH KeywordsAdrenocorticotropic HormoneAdultAllelesAmino Acid SubstitutionAsian PeopleDouble-Blind MethodFemaleGenetics, PopulationGenotypeHumansHydrocortisoneHypothalamo-Hypophyseal SystemMaleNaloxonePharmacogeneticsPituitary-Adrenal SystemPolymorphism, Single NucleotideReceptors, Opioid, muWhite PeopleConceptsHPA axis activationCortisol responseAsn40 homozygotesAsn40Asp polymorphismAsp40 alleleSingle nucleotide polymorphism A118GHPA axis responsePlacebo-controlled administrationΜ-opioid receptor geneGreater cortisol responseIntravenous naloxoneOpioid blockadeAxis activationAdrenocorticotropic hormoneA118GHealthy individualsOPRM1 SNPsNaloxoneCortisol concentrationsHormonal responsesEuropean AmericansObserved associationsHealthy participantsWhole bloodReceptor geneOpioid Receptor Gene (OPRM1, OPRK1, and OPRD1) Variants and Response to Naltrexone Treatment for Alcohol Dependence: Results From the VA Cooperative Study
Gelernter J, Gueorguieva R, Kranzler HR, Zhang H, Cramer J, Rosenheck R, Krystal JH, Group T. Opioid Receptor Gene (OPRM1, OPRK1, and OPRD1) Variants and Response to Naltrexone Treatment for Alcohol Dependence: Results From the VA Cooperative Study. Alcohol Clinical And Experimental Research 2007, 31: 555-563. PMID: 17374034, DOI: 10.1111/j.1530-0277.2007.00339.x.Peer-Reviewed Original ResearchMeSH KeywordsAdultAlcoholismConfidence IntervalsDNADouble-Blind MethodExonsFemaleGenetic VariationGenotypeHumansLinear ModelsLogistic ModelsMaleMiddle AgedNaltrexoneNarcotic AntagonistsOdds RatioProportional Hazards ModelsPsychiatric Status Rating ScalesReceptors, Opioid, deltaReceptors, Opioid, kappaReceptors, Opioid, muSmokingTreatment OutcomeUnited StatesUnited States Department of Veterans AffairsConceptsAlcohol dependenceOpioid receptorsTreatment responseVA Cooperative StudyRate of relapsePredictors of responseAlcohol-dependent male subjectsMu-opioid receptorsKappa-opioid receptorsCourse of treatmentShort-term treatmentReceptor gene variantsOpioid receptor geneAsn40Asp polymorphismAvailable medicationsNaltrexone treatmentSpecific pharmacotherapyPretreatment numberDrug naltrexoneNaltrexoneMale subjectsCooperative StudyRelapseHeavy drinkingIndividual single nucleotide polymorphisms
2006
Association between two µ-opioid receptor gene (OPRM1) haplotype blocks and drug or alcohol dependence
Zhang H, Luo X, Kranzler HR, Lappalainen J, Yang BZ, Krupitsky E, Zvartau E, Gelernter J. Association between two µ-opioid receptor gene (OPRM1) haplotype blocks and drug or alcohol dependence. Human Molecular Genetics 2006, 15: 807-819. PMID: 16476706, PMCID: PMC3164878, DOI: 10.1093/hmg/ddl024.Peer-Reviewed Original Research
2005
Response to Dr. Kopke's comments on haplotypes at the OPRM1 locus
Luo X, Gelernter J, Zhao H, Kranzler HR. Response to Dr. Kopke's comments on haplotypes at the OPRM1 locus. American Journal Of Medical Genetics Part B Neuropsychiatric Genetics 2005, 135B: 102-102. PMID: 15806579, DOI: 10.1002/ajmg.b.30060.Peer-Reviewed Original Research
2004
Association study of personality factors and the Asn40Asp polymorphism at the μ-opioid receptor gene (OPRM1)
Hernandez-Avila CA, Covault J, Gelernter J, Kranzler HR. Association study of personality factors and the Asn40Asp polymorphism at the μ-opioid receptor gene (OPRM1). Psychiatric Genetics 2004, 14: 89-92. PMID: 15167694, DOI: 10.1097/01.ypg.0000107931.32051.c7.Peer-Reviewed Original ResearchConceptsMu-opioid receptor proteinΜ-opioid receptor geneSubstance-dependent subjectsAsn40Asp polymorphismSubstance dependence diagnosesHealthy subjectsAllelic associationBlood samplesDependence diagnosisDiagnostic InterviewDemographic featuresExtracellular domainFunctional polymorphismsReceptor geneReceptor extracellular domainReceptor proteinAssociationNEO-Five Factor InventorySubjectsAssociation studiesFive-Factor InventoryPolymorphismAsn40AspPersonality factorsDiagnosis
2003
Haplotypes at the OPRM1 locus are associated with susceptibility to substance dependence in European‐Americans
Luo X, Kranzler HR, Zhao H, Gelernter J. Haplotypes at the OPRM1 locus are associated with susceptibility to substance dependence in European‐Americans. American Journal Of Medical Genetics Part B Neuropsychiatric Genetics 2003, 120B: 97-108. PMID: 12815747, DOI: 10.1002/ajmg.b.20034.Peer-Reviewed Original ResearchAlcoholismBlack PeopleCocaine-Related DisordersExonsFemaleGene FrequencyGenetic Predisposition to DiseaseGenetic VariationGenotypeHaplotypesHumansLinkage DisequilibriumMaleOpioid-Related DisordersPolymorphism, Single NucleotideReceptors, Opioid, muSubstance-Related DisordersUnited StatesWhite PeopleA Functional Polymorphism of the μ-Opioid Receptor Gene is Associated with Naltrexone Response in Alcohol-Dependent Patients
Oslin DW, Berrettini W, Kranzler HR, Pettinati H, Gelernter J, Volpicelli JR, O'Brien CP. A Functional Polymorphism of the μ-Opioid Receptor Gene is Associated with Naltrexone Response in Alcohol-Dependent Patients. Neuropsychopharmacology 2003, 28: 1546-1552. PMID: 12813472, DOI: 10.1038/sj.npp.1300219.Peer-Reviewed Original ResearchConceptsΜ-opioid receptorAlcohol-dependent patientsAbstinence ratesPlacebo-controlled clinical trialOverall abstinence ratesΜ-receptor antagonistWeeks of treatmentΜ-opioid receptor geneAlcohol-dependent individualsAsn40 alleleAsp40 alleleProperties of alcoholRelapse rateNaltrexone responseOpioid systemClinical trialsTreatment outcomesNaltrexoneFunctional polymorphismsGenotype groupsPatientsHeavy drinkingDrinking outcomesReceptor geneSpecific polymorphismsAssociation between the cortisol response to opioid blockade and the Asn40Asp polymorphism at the μ‐opioid receptor locus (OPRM1)
Hernandez‐Avila C, Wand G, Luo X, Gelernter J, Kranzler HR. Association between the cortisol response to opioid blockade and the Asn40Asp polymorphism at the μ‐opioid receptor locus (OPRM1). American Journal Of Medical Genetics Part B Neuropsychiatric Genetics 2003, 118B: 60-65. PMID: 12627468, DOI: 10.1002/ajmg.b.10054.Peer-Reviewed Original ResearchConceptsCortisol responseAsn40 alleleAsn40Asp polymorphismAsp40 alleleCortisol concentrationsCortisol time curveMu-opioid receptor proteinOpioid antagonist naloxoneMin post infusionPeak cortisol responsePlasma ACTH concentrationsEnhanced cortisol responseHigher cortisol concentrationsWarrants further investigationAsp40 variantIntravenous naloxoneOpioid blockadeNaloxone infusionAntagonist naloxonePlasma ACTHACTH concentrationsAgonist effectsPost infusionHealthy subjectsClinical relevance
1999
Genetics of two μ opioid receptor gene (OPRM1) exon I polymorphisms: population studies, and allele frequencies in alcohol- and drug-dependent subjects
Gelernter J, Kranzler H, Cubells J. Genetics of two μ opioid receptor gene (OPRM1) exon I polymorphisms: population studies, and allele frequencies in alcohol- and drug-dependent subjects. Molecular Psychiatry 1999, 4: 476-483. PMID: 10523821, DOI: 10.1038/sj.mp.4000556.Peer-Reviewed Original Research
1998
Population Studies of Polymorphisms at Loci of Neuropsychiatric Interest (Tryptophan Hydroxylase (TPH), Dopamine Transporter Protein (SLC6A3), D3 Dopamine Receptor (DRD3), Apolipoprotein E (APOE), μ Opioid Receptor (OPRM1), and Ciliary Neurotrophic Factor (CNTF))
Gelernter J, Kranzler H, Lacobelle J. Population Studies of Polymorphisms at Loci of Neuropsychiatric Interest (Tryptophan Hydroxylase (TPH), Dopamine Transporter Protein (SLC6A3), D3 Dopamine Receptor (DRD3), Apolipoprotein E (APOE), μ Opioid Receptor (OPRM1), and Ciliary Neurotrophic Factor (CNTF)). Genomics 1998, 52: 289-297. PMID: 9790747, DOI: 10.1006/geno.1998.5454.Peer-Reviewed Original ResearchMeSH KeywordsAllelesApolipoproteins ECarrier ProteinsCiliary Neurotrophic FactorDopamine Plasma Membrane Transport ProteinsGenetics, PopulationGenotypeHumansMembrane GlycoproteinsMembrane Transport ProteinsNerve Tissue ProteinsPolymorphism, GeneticReceptors, Dopamine D2Receptors, Dopamine D3Receptors, Opioid, muTryptophan HydroxylaseConceptsCiliary neurotrophic factor