2016
Phenome-Wide Association Study for Alcohol and Nicotine Risk Alleles in 26394 Women
Polimanti R, Kranzler HR, Gelernter J. Phenome-Wide Association Study for Alcohol and Nicotine Risk Alleles in 26394 Women. Neuropsychopharmacology 2016, 41: 2688-2696. PMID: 27187070, PMCID: PMC5026736, DOI: 10.1038/npp.2016.72.Peer-Reviewed Original ResearchConceptsHealth initiativesRisk allelesSocioeconomic statusPhenome-wide association studyWomen's Health InitiativeMetabolism-related mechanismsMedication useLung cancerTobacco useDietary habitsSmoking behaviorNicotine useReproductive historyReproductive healthSuggestive findingsAlcohol useAnthropometric characteristicsMental healthHealth conditionsMetabolic conditionsCausative relationshipAssociation studiesDrinking behaviorADH1BAssociationCHRNA4 and ANKK1 Polymorphisms Influence Smoking-Induced Nicotinic Acetylcholine Receptor Upregulation
Esterlis I, Hillmer AT, Bois F, Pittman B, McGovern E, O’Malley S, Picciotto MR, Yang BZ, Gelernter J, Cosgrove KP. CHRNA4 and ANKK1 Polymorphisms Influence Smoking-Induced Nicotinic Acetylcholine Receptor Upregulation. Nicotine & Tobacco Research 2016, 18: 1845-1852. PMID: 27611310, PMCID: PMC4978979, DOI: 10.1093/ntr/ntw081.Peer-Reviewed Original ResearchMeSH KeywordsAdultCase-Control StudiesCorpus StriatumFemaleHumansIodine RadioisotopesMalePolymorphism, Single NucleotideProtein Serine-Threonine KinasesReceptors, NicotinicSmokingSmoking CessationSmoking PreventionTobacco Use DisorderTomography, Emission-Computed, Single-PhotonUp-RegulationWhite PeopleConceptsSmoking-induced changesWeeks of abstinenceNAChR availabilitySmoking cessationNicotine dependenceSex-matched nonsmokersTomography brain scanSingle nucleotide polymorphismsNicotinic acetylcholine receptorsSingle photon emissionDays of abstinenceNonsmoker levelsTobacco smokingReceptor upregulationBlood samplesAcetylcholine receptorsBrain scansCHRNA4 variantsCortical regionsSmokersCarrier statusExtended abstinenceAbstinencePersonalized programsNonsmokersCHRNA5/A3/B4 Variant rs3743078 and Nicotine-Related Phenotypes: Indirect Effects Through Nicotine Craving.
Shmulewitz D, Meyers JL, Wall MM, Aharonovich E, Frisch A, Spivak B, Weizman A, Edenberg HJ, Gelernter J, Hasin DS. CHRNA5/A3/B4 Variant rs3743078 and Nicotine-Related Phenotypes: Indirect Effects Through Nicotine Craving. Journal Of Studies On Alcohol And Drugs 2016, 77: 227-37. PMID: 26997181, PMCID: PMC4803655, DOI: 10.15288/jsad.2016.77.227.Peer-Reviewed Original ResearchMeSH KeywordsAdultCravingFemaleGenetic VariationHumansMaleMiddle AgedNerve Tissue ProteinsPhenotypeReceptors, NicotinicSmokingTobacco Use DisorderYoung AdultConceptsNicotine cravingFTND scoreNeuronal nicotinic acetylcholine receptor geneNicotine use disorderNicotinic acetylcholine receptor genesAcetylcholine receptor genesLifetime smokersCigarette smokingMore cigarettesHigher scoresNicotine dependenceFagerström TestTherapeutic targetUse disordersG alleleAllele GCHRNA5-CHRNA3CravingReceptor geneScoresSizeable proportionFTNDCigarettesHousehold sampleSignificant indirect effect
2015
Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence
Hancock DB, Reginsson GW, Gaddis NC, Chen X, Saccone NL, Lutz SM, Qaiser B, Sherva R, Steinberg S, Zink F, Stacey SN, Glasheen C, Chen J, Gu F, Frederiksen BN, Loukola A, Gudbjartsson DF, Brüske I, Landi MT, Bickeböller H, Madden P, Farrer L, Kaprio J, Kranzler HR, Gelernter J, Baker TB, Kraft P, Amos CI, Caporaso NE, Hokanson JE, Bierut LJ, Thorgeirsson TE, Johnson EO, Stefansson K. Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence. Translational Psychiatry 2015, 5: e651-e651. PMID: 26440539, PMCID: PMC4930126, DOI: 10.1038/tp.2015.149.Peer-Reviewed Original ResearchConceptsGenome-wide association studiesEuropean ancestry samplesNonsense-mediated decayWide significant associationsNicotinic receptor subunit geneReceptor subunit genesImportant regulatory propertiesNicotine dependenceSubunit geneAssociation studiesChromosome 20q13Regulatory propertiesLung cancer riskNovel variantsNormal human brainSmoking-related consequencesLung cancerCancer riskFagerström TestCHRNA4Smoking behaviorSignificant associationVariantsGenomeGenesA CHRNA5 Smoking Risk Variant Decreases the Aversive Effects of Nicotine in Humans
Jensen KP, DeVito EE, Herman AI, Valentine GW, Gelernter J, Sofuoglu M. A CHRNA5 Smoking Risk Variant Decreases the Aversive Effects of Nicotine in Humans. Neuropsychopharmacology 2015, 40: 2813-2821. PMID: 25948103, PMCID: PMC4864657, DOI: 10.1038/npp.2015.131.Peer-Reviewed Original ResearchMeSH KeywordsAdultBlood PressureCognition DisordersCotinineFemaleGenome-Wide Association StudyHeart RateHumansMaleMiddle AgedNerve Tissue ProteinsNeuropsychological TestsNicotineNicotinic AgonistsPolymorphism, Single NucleotideReceptors, NicotinicSmokingSubstance Withdrawal SyndromeSurveys and QuestionnairesConceptsAversive effectsHeavy smokingRisk allelesSmoking-related disordersAfrican American smokersCHRNA5-CHRNA3Doses of nicotineHigh nicotine doseNicotine administrationIntravenous doseNicotine effectsNicotine doseAmerican smokersWithdrawal severityOvernight abstinenceAcute responseAA subjectsCardiovascular reactivityCHRNB4 gene clusterNicotineEuropean AmericansAversive responsesAdministration sessionsSmokingCognitive performance
2014
Rare Human Nicotinic Acetylcholine Receptor α4 Subunit (CHRNA4) Variants Affect Expression and Function of High-Affinity Nicotinic Acetylcholine Receptors
McClure-Begley TD, Papke RL, Stone KL, Stokes C, Levy AD, Gelernter J, Xie P, Lindstrom J, Picciotto MR. Rare Human Nicotinic Acetylcholine Receptor α4 Subunit (CHRNA4) Variants Affect Expression and Function of High-Affinity Nicotinic Acetylcholine Receptors. Journal Of Pharmacology And Experimental Therapeutics 2014, 348: 410-420. PMID: 24385388, PMCID: PMC3935145, DOI: 10.1124/jpet.113.209767.Peer-Reviewed Original ResearchConceptsNicotinic acetylcholine receptorsRare variantsSingle amino acid substitutionLaevis oocytesAmino acid substitutionsΑ4β2 nAChRsAcetylcholine receptorsIntracellular interactomesHEK-293 cellsX. laevis oocytesProteomic analysisGenetic variationHuman α4β2 nAChRsXenopus laevis oocytesVoltage-clamp electrophysiologyNeuronal nicotinic acetylcholine receptorsHigh-affinity nicotinic acetylcholine receptorsSubcellular distributionAcid substitutionsΑ4 nAChR subunitCohort of smokersEffects of nicotineNAChR subunitsCommon variantsΑ4 nAChR
2013
Distinct Loci in the CHRNA5/CHRNA3/CHRNB4 Gene Cluster Are Associated With Onset of Regular Smoking
Stephens SH, Hartz SM, Hoft NR, Saccone NL, Corley RC, Hewitt JK, Hopfer CJ, Breslau N, Coon H, Chen X, Ducci F, Dueker N, Franceschini N, Frank J, Han Y, Hansel NN, Jiang C, Korhonen T, Lind PA, Liu J, Lyytikäinen L, Michel M, Shaffer JR, Short SE, Sun J, Teumer A, Thompson JR, Vogelzangs N, Vink JM, Wenzlaff A, Wheeler W, Yang B, Aggen SH, Balmforth AJ, Baumeister SE, Beaty TH, Benjamin DJ, Bergen AW, Broms U, Cesarini D, Chatterjee N, Chen J, Cheng Y, Cichon S, Couper D, Cucca F, Dick D, Foroud T, Furberg H, Giegling I, Gillespie NA, Gu F, Hall AS, Hällfors J, Han S, Hartmann AM, Heikkilä K, Hickie IB, Hottenga JJ, Jousilahti P, Kaakinen M, Kähönen M, Koellinger PD, Kittner S, Konte B, Landi M, Laatikainen T, Leppert M, Levy SM, Mathias RA, McNeil DW, Medland SE, Montgomery GW, Murray T, Nauck M, North KE, Paré PD, Pergadia M, Ruczinski I, Salomaa V, Viikari J, Willemsen G, Barnes KC, Boerwinkle E, Boomsma DI, Caporaso N, Edenberg HJ, Francks C, Gelernter J, Grabe HJ, Hops H, Jarvelin M, Johannesson M, Kendler KS, Lehtimäki T, Magnusson PK, Marazita ML, Marchini J, Mitchell BD, Nöthen MM, Penninx BW, Raitakari O, Rietschel M, Rujescu D, Samani NJ, Schwartz AG, Shete S, Spitz M, Swan GE, Völzke H, Veijola J, Wei Q, Amos C, Cannon DS, Grucza R, Hatsukami D, Heath A, Johnson EO, Kaprio J, Madden P, Martin NG, Stevens VL, Weiss RB, Kraft P, Bierut LJ, Ehringer MA. Distinct Loci in the CHRNA5/CHRNA3/CHRNB4 Gene Cluster Are Associated With Onset of Regular Smoking. Genetic Epidemiology 2013, 37: 846-859. PMID: 24186853, PMCID: PMC3947535, DOI: 10.1002/gepi.21760.Peer-Reviewed Original ResearchConceptsGene clusterAssociation signalsEarly smoking behaviourSmoking behaviorCHRNA5/A3/B4 gene clusterNicotinic acetylcholine receptor genesRobust association signalsNeuronal nicotinic acetylcholine receptor geneAcetylcholine receptor genesNicotine dependenceCHRNB4 gene clusterSignificant associationB4 gene clusterDistinct lociLung cancer riskRegular tobacco useAssociation resultsNicotine dependence phenotypesDependence phenotypesReceptor geneCotinine levelsRs1948PhenotypeRegular smokingProtective effectProfiling of Childhood Adversity-Associated DNA Methylation Changes in Alcoholic Patients and Healthy Controls
Zhang H, Wang F, Kranzler HR, Zhao H, Gelernter J. Profiling of Childhood Adversity-Associated DNA Methylation Changes in Alcoholic Patients and Healthy Controls. PLOS ONE 2013, 8: e65648. PMID: 23799031, PMCID: PMC3683055, DOI: 10.1371/journal.pone.0065648.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAlcoholismAldehyde DehydrogenaseAldehyde Dehydrogenase 1 FamilyBlack or African AmericanCase-Control StudiesChild AbuseCpG IslandsDNA MethylationEpigenesis, GeneticFemaleGenetic Association StudiesGenetic Predisposition to DiseaseHumansMaleMiddle AgedNerve Tissue ProteinsNociceptin ReceptorPolymorphism, Single NucleotidePromoter Regions, GeneticReceptors, NicotinicReceptors, OpioidRetinal DehydrogenaseRGS ProteinsSequence Analysis, DNATranscription, GeneticWhite PeopleYoung AdultConceptsHealthy controlsAD patientsChildhood adversityDNA methylation changesIllumina GoldenGate methylation arrayPeripheral blood DNA methylation levelsBlood DNA methylation levelsAlcoholic patientsControl subjectsLinear regression analysisMethylation changesPatientsMethylation levelsPromoter regionEA casesBonferroni correctionRegression analysisP-valueAfrican AmericansOverall methylation levelsA Complex Interplay between Personality Domains, Marital Status and a Variant in CHRNA5 on the Risks of Cocaine, Nicotine Dependences and Cocaine-Induced Paranoia
Zayats T, Yang BZ, Xie P, Poling J, Farrer LA, Gelernter J. A Complex Interplay between Personality Domains, Marital Status and a Variant in CHRNA5 on the Risks of Cocaine, Nicotine Dependences and Cocaine-Induced Paranoia. PLOS ONE 2013, 8: e49368. PMID: 23308091, PMCID: PMC3538653, DOI: 10.1371/journal.pone.0049368.Peer-Reviewed Original Research
2012
Increased Genetic Vulnerability to Smoking at CHRNA5 in Early-Onset Smokers
Hartz SM, Short SE, Saccone NL, Culverhouse R, Chen L, Schwantes-An TH, Coon H, Han Y, Stephens SH, Sun J, Chen X, Ducci F, Dueker N, Franceschini N, Frank J, Geller F, Gubjartsson D, Hansel NN, Jiang C, Keskitalo-Vuokko K, Liu Z, Lyytikäinen LP, Michel M, Rawal R, Rosenberger A, Scheet P, Shaffer JR, Teumer A, Thompson JR, Vink JM, Vogelzangs N, Wenzlaff AS, Wheeler W, Xiao X, Yang BZ, Aggen SH, Balmforth AJ, Baumeister SE, Beaty T, Bennett S, Bergen AW, Boyd HA, Broms U, Campbell H, Chatterjee N, Chen J, Cheng YC, Cichon S, Couper D, Cucca F, Dick DM, Foroud T, Furberg H, Giegling I, Gu F, Hall AS, Hällfors J, Han S, Hartmann AM, Hayward C, Heikkilä K, Hewitt JK, Hottenga JJ, Jensen MK, Jousilahti P, Kaakinen M, Kittner SJ, Konte B, Korhonen T, Landi MT, Laatikainen T, Leppert M, Levy SM, Mathias RA, McNeil DW, Medland SE, Montgomery GW, Muley T, Murray T, Nauck M, North K, Pergadia M, Polasek O, Ramos EM, Ripatti S, Risch A, Ruczinski I, Rudan I, Salomaa V, Schlessinger D, Styrkársdóttir U, Terracciano A, Uda M, Willemsen G, Wu X, Abecasis G, Barnes K, Bickeböller H, Boerwinkle E, Boomsma DI, Caporaso N, Duan J, Edenberg HJ, Francks C, Gejman PV, Gelernter J, Grabe HJ, Hops H, Jarvelin MR, Viikari J, Kähönen M, Kendler KS, Lehtimäki T, Levinson DF, Marazita ML, Marchini J, Melbye M, Mitchell BD, Murray JC, Nöthen MM, Penninx BW, Raitakari O, Rietschel M, Rujescu D, Samani NJ, Sanders AR, Schwartz AG, Shete S, Shi J, Spitz M, Stefansson K, Swan GE, Thorgeirsson T, Völzke H, Wei Q, Wichmann H, Amos CI, Breslau N, Cannon DS, Ehringer M, Grucza R, Hatsukami D, Heath A, Johnson EO, Kaprio J, Madden P, Martin NG, Stevens VL, Stitzel JA, Weiss RB, Kraft P, Bierut LJ. Increased Genetic Vulnerability to Smoking at CHRNA5 in Early-Onset Smokers. JAMA Psychiatry 2012, 69: 854-860. PMID: 22868939, PMCID: PMC3482121, DOI: 10.1001/archgenpsychiatry.2012.124.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdolescent DevelopmentAdultAge of OnsetEuropeFemaleGene-Environment InteractionGenetic Association StudiesGenetic Predisposition to DiseaseHumansMaleNerve Tissue ProteinsNicotinePolymorphism, Single NucleotideReceptors, NicotinicSeverity of Illness IndexSmokingTobacco Use DisorderConceptsEarly-onset smokersLate-onset smokersHeavy smokersRisk allelesGenetic vulnerabilityRs16969968 genotypeLight smokersLight smokingRegular smokingSmokersSmokingMeta-AnalysisLogistic regressionRs16969968Single nucleotide polymorphismsAgeNonsynonymous single nucleotide polymorphismsCHRNA5Recent studiesAvailable genetic studiesAssociationSample sizeStudyCigarettesGenetic studies
2011
ACSL6 Is Associated with the Number of Cigarettes Smoked and Its Expression Is Altered by Chronic Nicotine Exposure
Chen J, Brunzell DH, Jackson K, van der Vaart A, Z. J, Payne TJ, Sherva R, Farrer LA, Gejman P, Levinson DF, Holmans P, Aggen SH, Damaj I, Kuo PH, Webb BT, Anton R, Kranzler HR, Gelernter J, Li MD, Kendler KS, Chen X. ACSL6 Is Associated with the Number of Cigarettes Smoked and Its Expression Is Altered by Chronic Nicotine Exposure. PLOS ONE 2011, 6: e28790. PMID: 22205969, PMCID: PMC3243669, DOI: 10.1371/journal.pone.0028790.Peer-Reviewed Original ResearchConceptsACSL6 geneNicotine exposureNicotinic receptor antagonist mecamylaminePrevious schizophrenia studiesChronic nicotine exposureNicotinic receptor activationHippocampus of miceNumber of cigarettesOsmotic mini pumpsQuantity of cigarettesNon-schizophrenic subjectsAssociation of schizophreniaCigarettes SmokedHeavy smokersTobacco smokingNicotine administrationAntagonist mecamylamineControl subjectsIndependent associationTobacco dependenceFTND scoreHigh riskMini pumpsChronic exposureReceptor activationChildhood Adversity Increases Risk for Nicotine Dependence and Interacts with α5 Nicotinic Acetylcholine Receptor Genotype Specifically in Males
Xie P, Kranzler HR, Zhang H, Oslin D, Anton RF, Farrer LA, Gelernter J. Childhood Adversity Increases Risk for Nicotine Dependence and Interacts with α5 Nicotinic Acetylcholine Receptor Genotype Specifically in Males. Neuropsychopharmacology 2011, 37: 669-676. PMID: 22012472, PMCID: PMC3260970, DOI: 10.1038/npp.2011.240.Peer-Reviewed Original ResearchConceptsChildhood adversityRs16969968 genotypeND riskSex differencesNicotinic acetylcholine receptor genesAcetylcholine receptor genesPotential sex differencesNicotine dependence riskFagerstrom TestNicotine intakeSmoking riskIncrease riskNicotine dependenceRodent modelsReceptor genotypeND scoresEarly life experiencesEuropean AmericansReceptor geneWomenRiskGene × environment effectsMenRare Nonsynonymous Variants in Alpha-4 Nicotinic Acetylcholine Receptor Gene Protect Against Nicotine Dependence
Xie P, Kranzler HR, Krauthammer M, Cosgrove KP, Oslin D, Anton RF, Farrer LA, Picciotto MR, Krystal JH, Zhao H, Gelernter J. Rare Nonsynonymous Variants in Alpha-4 Nicotinic Acetylcholine Receptor Gene Protect Against Nicotine Dependence. Biological Psychiatry 2011, 70: 528-536. PMID: 21683344, PMCID: PMC3199609, DOI: 10.1016/j.biopsych.2011.04.017.Peer-Reviewed Original ResearchAssociation of CHRNA4 polymorphisms with smoking behavior in two populations
Han S, Yang B, Kranzler HR, Oslin D, Anton R, Gelernter J. Association of CHRNA4 polymorphisms with smoking behavior in two populations. American Journal Of Medical Genetics Part B Neuropsychiatric Genetics 2011, 156: 421-429. PMID: 21445957, PMCID: PMC3742073, DOI: 10.1002/ajmg.b.31177.Peer-Reviewed Original Research
2010
Multiple Independent Loci at Chromosome 15q25.1 Affect Smoking Quantity: a Meta-Analysis and Comparison with Lung Cancer and COPD
Saccone NL, Culverhouse RC, Schwantes-An TH, Cannon DS, Chen X, Cichon S, Giegling I, Han S, Han Y, Keskitalo-Vuokko K, Kong X, Landi MT, Z. J, Short SE, Stephens SH, Stevens VL, Sun L, Wang Y, Wenzlaff AS, Aggen SH, Breslau N, Broderick P, Chatterjee N, Chen J, Heath AC, Heliövaara M, Hoft NR, Hunter DJ, Jensen MK, Martin NG, Montgomery GW, Niu T, Payne TJ, Peltonen L, Pergadia ML, Rice JP, Sherva R, Spitz MR, Sun J, Wang JC, Weiss RB, Wheeler W, Witt SH, Yang BZ, Caporaso NE, Ehringer MA, Eisen T, Gapstur SM, Gelernter J, Houlston R, Kaprio J, Kendler KS, Kraft P, Leppert MF, Li MD, Madden PA, Nöthen MM, Pillai S, Rietschel M, Rujescu D, Schwartz A, Amos CI, Bierut LJ. Multiple Independent Loci at Chromosome 15q25.1 Affect Smoking Quantity: a Meta-Analysis and Comparison with Lung Cancer and COPD. PLOS Genetics 2010, 6: e1001053. PMID: 20700436, PMCID: PMC2916847, DOI: 10.1371/journal.pgen.1001053.Peer-Reviewed Original ResearchConceptsChronic obstructive pulmonary diseaseLung cancerNicotine dependenceSmoking behaviorSmoking quantityObstructive pulmonary diseaseSmoking-related diseasesLung cancer casesPulmonary diseaseNicotinic receptor subunit geneCOPD casesIndependent associationLung tissueCancer casesReceptor subunit genesMeta-AnalysisSignificant associationSmokingRs16969968CancerSmoking phenotypesGenetic association findingsSNP rs16969968MRNA levelsCHRNA5-CHRNA3Variation in the Nicotinic Acetylcholine Receptor Gene Cluster CHRNA5–CHRNA3–CHRNB4 and Its Interaction with Recent Tobacco Use Influence Cognitive Flexibility
Zhang H, Kranzler HR, Poling J, Gelernter J. Variation in the Nicotinic Acetylcholine Receptor Gene Cluster CHRNA5–CHRNA3–CHRNB4 and Its Interaction with Recent Tobacco Use Influence Cognitive Flexibility. Neuropsychopharmacology 2010, 35: 2211-2224. PMID: 20631687, PMCID: PMC3055317, DOI: 10.1038/npp.2010.95.Peer-Reviewed Original ResearchVariation in Nicotinic Acetylcholine Receptor Genes is Associated with Multiple Substance Dependence Phenotypes
Sherva R, Kranzler HR, Yu Y, Logue MW, Poling J, Arias AJ, Anton RF, Oslin D, Farrer LA, Gelernter J. Variation in Nicotinic Acetylcholine Receptor Genes is Associated with Multiple Substance Dependence Phenotypes. Neuropsychopharmacology 2010, 35: 1921-1931. PMID: 20485328, PMCID: PMC3055642, DOI: 10.1038/npp.2010.64.Peer-Reviewed Original ResearchMeSH KeywordsAdultBlack or African AmericanChromosomes, Human, Pair 15Family HealthFemaleGene FrequencyGenetic Predisposition to DiseaseGenome-Wide Association StudyGenotypeHumansLinkage DisequilibriumMaleMiddle AgedPhenotypePolymorphism, Single NucleotideReceptors, NicotinicSubstance-Related DisordersWhite PeopleConceptsGene clusterAssociation studiesNicotinic receptor gene clusterNicotinic acetylcholine receptor genesAcetylcholine receptor genesReceptor gene clusterStrongest association signalSubstance dependence phenotypesAssociation signalsImportance of variationChromosome 15q25.1Opposite risk allelePermutation-based correctionDependence phenotypesReplication setReceptor geneMultiple polymorphismsSNPsMeta-Analysis of 15 Genome-Wide Linkage Scans of Smoking Behavior
Han S, Gelernter J, Luo X, Yang BZ. Meta-Analysis of 15 Genome-Wide Linkage Scans of Smoking Behavior. Biological Psychiatry 2010, 67: 12-19. PMID: 19819424, PMCID: PMC2975396, DOI: 10.1016/j.biopsych.2009.08.028.Peer-Reviewed Original ResearchConceptsSmoking behaviorGenome-wide suggestive linkageGenome-wide linkage scanSubgroup analysisGenome scan resultsScan resultsLinkage scanSuggestive linkageGenome-wide significant linkageFagerstrom TestCandidate gene identificationNicotine dependenceRe-sequencing studiesMeta-AnalysisSecondary analysis