2024
Single-cell transcriptomic and proteomic analysis of Parkinson’s disease brains
Zhu B, Park J, Coffey S, Russo A, Hsu I, Wang J, Su C, Chang R, Lam T, Gopal P, Ginsberg S, Zhao H, Hafler D, Chandra S, Zhang L. Single-cell transcriptomic and proteomic analysis of Parkinson’s disease brains. Science Translational Medicine 2024, 16: eabo1997. PMID: 39475571, DOI: 10.1126/scitranslmed.abo1997.Peer-Reviewed Original ResearchConceptsProteomic analysisAlzheimer's diseasePrefrontal cortexBrain cell typesGenetics of PDParkinson's diseaseCell-cell interactionsChaperone expressionSingle-nucleus transcriptomesExpressed genesTranscriptional changesPostmortem human brainPostmortem brain tissueDiseased brainSynaptic proteinsSingle-cellDown-regulationBrain cell populationsBrain regionsCell typesNeurodegenerative disordersLate-stage PDParkinson's disease brainsDisease etiologyNeuronal vulnerability
2023
A genome-wide association study of frailty identifies significant genetic correlation with neuropsychiatric, cardiovascular, and inflammation pathways
Ye Y, Noche R, Szejko N, Both C, Acosta J, Leasure A, Brown S, Sheth K, Gill T, Zhao H, Falcone G. A genome-wide association study of frailty identifies significant genetic correlation with neuropsychiatric, cardiovascular, and inflammation pathways. GeroScience 2023, 45: 2511-2523. PMID: 36928559, PMCID: PMC10651618, DOI: 10.1007/s11357-023-00771-z.Peer-Reviewed Original ResearchConceptsFried frailty scoreBiology of frailtyEuropean descent participantsOccurrence of frailtyGenome-wide association studiesMendelian randomization analysisFrailty scoreChronic painJoint disordersPolygenic risk scoresRespiratory diseaseInflammation pathwaysRisk scoreClinical phenotypeBrain tissueCausal associationFrailtyAge-related pathwaysRandomization analysisGenetic factorsAssociation studiesUK BiobankRetirement StudyPerson's vulnerabilitySignificant genetic correlations
2022
Genome-Wide Investigation of Maximum Habitual Alcohol Intake in US Veterans in Relation to Alcohol Consumption Traits and Alcohol Use Disorder
Deak JD, Levey DF, Wendt FR, Zhou H, Galimberti M, Kranzler HR, Gaziano JM, Stein MB, Polimanti R, Gelernter J, Muralidhar S, Moser J, Deen J, Gaziano J, Beckham J, Chang K, Tsao P, Luoh S, Casas J, Churby L, Whitbourne S, Brewer J, Brophy M, Selva L, Shayan S, Cho K, Pyarajan S, DuVall S, Connor T, Argyres D, Aslan M, Stephens B, Concato J, Gelernter J, Gleason T, Huang G, Koenen K, Marx C, Radhakrishnan K, Schork N, Stein M, Zhao H, Kaufman J, Nunez Y, Pietrzak R, Beck D, Cissell S, Crutchfield P, Lance W, Cheung K, Li Y, Sun N, Chen Q, Rajeevan N, Sayward F, Gagnon D, Harrington K, Quaden R, O'Leary T, Ramoni R. Genome-Wide Investigation of Maximum Habitual Alcohol Intake in US Veterans in Relation to Alcohol Consumption Traits and Alcohol Use Disorder. JAMA Network Open 2022, 5: e2238880. PMID: 36301540, PMCID: PMC9614582, DOI: 10.1001/jamanetworkopen.2022.38880.Peer-Reviewed Original ResearchConceptsGenome-wide association studiesGenome-wide significant lociGenomic structural equation modelingSignificant lociAlcohol traitsAssociation studiesAfrican ancestry participantsGenome-wide investigationAncestry-specific genome-wide association studiesGenetic correlationsPsychiatric traitsLinkage disequilibrium score regressionGenetic associationStrong genetic correlationSingle nucleotide variantsGenetic architectureGenetic association studiesGenetic lociTop associationsNegative rgEuropean ancestry participantsNucleotide variantsFunctional variantsScore regressionTraitsSingle-cell multi-omics reveals dyssynchrony of the innate and adaptive immune system in progressive COVID-19
Unterman A, Sumida TS, Nouri N, Yan X, Zhao AY, Gasque V, Schupp JC, Asashima H, Liu Y, Cosme C, Deng W, Chen M, Raredon MSB, Hoehn KB, Wang G, Wang Z, DeIuliis G, Ravindra NG, Li N, Castaldi C, Wong P, Fournier J, Bermejo S, Sharma L, Casanovas-Massana A, Vogels CBF, Wyllie AL, Grubaugh ND, Melillo A, Meng H, Stein Y, Minasyan M, Mohanty S, Ruff WE, Cohen I, Raddassi K, Niklason L, Ko A, Montgomery R, Farhadian S, Iwasaki A, Shaw A, van Dijk D, Zhao H, Kleinstein S, Hafler D, Kaminski N, Dela Cruz C. Single-cell multi-omics reveals dyssynchrony of the innate and adaptive immune system in progressive COVID-19. Nature Communications 2022, 13: 440. PMID: 35064122, PMCID: PMC8782894, DOI: 10.1038/s41467-021-27716-4.Peer-Reviewed Original ResearchMeSH KeywordsAdaptive ImmunityAgedAntibodies, Monoclonal, HumanizedCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCells, CulturedCOVID-19COVID-19 Drug TreatmentFemaleGene Expression ProfilingGene Expression RegulationHumansImmunity, InnateMaleReceptors, Antigen, B-CellReceptors, Antigen, T-CellRNA-SeqSARS-CoV-2Single-Cell AnalysisConceptsProgressive COVID-19B cell clonesSingle-cell analysisT cellsImmune responseMulti-omics single-cell analysisCOVID-19Cell clonesAdaptive immune interactionsSevere COVID-19Dynamic immune responsesGene expressionSARS-CoV-2 virusAdaptive immune systemSomatic hypermutation frequenciesCellular effectsProtein markersEffector CD8Immune signaturesProgressive diseaseHypermutation frequencyProgressive courseClassical monocytesClonesImmune interactions
2021
Hematopoietic mosaic chromosomal alterations increase the risk for diverse types of infection
Zekavat SM, Lin SH, Bick AG, Liu A, Paruchuri K, Wang C, Uddin MM, Ye Y, Yu Z, Liu X, Kamatani Y, Bhattacharya R, Pirruccello JP, Pampana A, Loh PR, Kohli P, McCarroll SA, Kiryluk K, Neale B, Ionita-Laza I, Engels EA, Brown DW, Smoller JW, Green R, Karlson EW, Lebo M, Ellinor PT, Weiss ST, Daly MJ, Terao C, Zhao H, Ebert B, Reilly M, Ganna A, Machiela M, Genovese G, Natarajan P. Hematopoietic mosaic chromosomal alterations increase the risk for diverse types of infection. Nature Medicine 2021, 27: 1012-1024. PMID: 34099924, PMCID: PMC8245201, DOI: 10.1038/s41591-021-01371-0.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAgedAged, 80 and overAgingBiological Specimen BanksChromosome AberrationsCommunicable DiseasesDigestive System DiseasesFemaleGenetic Predisposition to DiseaseGenome-Wide Association StudyGenotypeHematologic NeoplasmsHumansMaleMiddle AgedMosaicismPneumoniaRisk FactorsSepsisUrogenital AbnormalitiesYoung AdultConceptsMosaic chromosomal alterationsLeukocyte cell countDominant risk factorChromosomal alterationsBlood-derived DNAInfectious disease riskIncident infectionsSystem infectionGenitourinary infectionsImmune cellsRisk factorsHematological malignanciesHematological cancersCell countDisease riskInfectionInfectious diseasesClonal hematopoiesisSomatic variantsAgeRiskAlterationsWide association studyAutosomal mosaic chromosomal alterationsAssociation studiesInteractions Between Enhanced Polygenic Risk Scores and Lifestyle for Cardiovascular Disease, Diabetes, and Lipid Levels
Ye Y, Chen X, Han J, Jiang W, Natarajan P, Zhao H. Interactions Between Enhanced Polygenic Risk Scores and Lifestyle for Cardiovascular Disease, Diabetes, and Lipid Levels. Circulation Genomic And Precision Medicine 2021, 14: e003128. PMID: 33433237, PMCID: PMC7887077, DOI: 10.1161/circgen.120.003128.Peer-Reviewed Original ResearchConceptsType 2 diabetesAbsolute risk reductionPolygenic risk scoresLifestyle adherenceCardiovascular diseaseGenetic riskRisk scoreCoronary artery diseaseBody mass indexGreater absolute benefitHigher polygenic risk scoreHigh genetic riskAdditive interactionRisk reductionArtery diseaseLDL cholesterolTotal cholesterolAtrial fibrillationMass indexAbsolute benefitTriglyceride levelsRisk factorsLipid levelsPhysical activityLifestyle status
2019
Gender Differences in Demographic and Health Characteristics of the Million Veteran Program Cohort
Harrington K, Nguyen X, Song R, Hannagan K, Quaden R, Gagnon D, Cho K, Deen J, Muralidhar S, O’Leary T, Gaziano J, Whitbourne S, Gaziano J, Ramoni R, Breeling J, Chang K, Huang G, Muralidhar S, O’Donnell C, Tsao P, Muralidhar S, Moser J, Whitbourne S, Brewer J, Concato J, Warren S, Pharm D, Argyres D, Tsao P, Gaziano J, Stephens B, Brophy M, Humphries D, Do N, Shayan S, Nguyen X, O’Donnell C, Pyarajan S, Tsao P, Cho K, Pyarajan S, Hauser E, Sun Y, Zhao H, Wilson P, McArdle R, Dellitalia L, Harley J, Whittle J, Beckham J, Wells J, Gutierrez S, Gibson G, Kaminsky L, Villareal G, Kinlay S, Xu J, Hamner M, Haddock K, Bhushan S, Iruvanti P, Godschalk M, Ballas Z, Buford M, Mastorides S, Klein J, Ratcliffe N, Florez H, Swann A, Murdoch M, Sriram P, Yeh S, Washburn R, Jhala D, Aguayo S, Cohen D, Sharma S, Callaghan J, Oursler K, Whooley M, Ahuja S, Gutierrez A, Schifman R, Greco J, Rauchman M, Servatius R, Oehlert M, Wallbom A, Fernando R, Morgan T, Stapley T, Sherman S, Anderson G, Tsao P, Sonel E, Boyko E, Meyer L, Gupta S, Fayad J, Hung A, Lichy J, Hurley R, Robey B, Striker R. Gender Differences in Demographic and Health Characteristics of the Million Veteran Program Cohort. Women's Health Issues 2019, 29: s56-s66. PMID: 31253243, PMCID: PMC7061933, DOI: 10.1016/j.whi.2019.04.012.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedCardiovascular DiseasesCohort StudiesFemaleHealth StatusHumansMaleMental DisordersMiddle AgedMigraine DisordersMusculoskeletal DiseasesPhysical FitnessPrevalenceSex DistributionSex FactorsSmokingSurveys and QuestionnairesUnited StatesUnited States Department of Veterans AffairsVeteransVeterans HealthYoung AdultConceptsMillion Veteran ProgramHealth characteristicsHealth statusSelf-reported health conditionsHealth conditionsHealth care characteristicsResearch participation ratesWomen Veteran populationExcellent health statusMillion Veteran Program cohortVeterans Health AdministrationPoor physical fitnessMental health disordersMVP cohortGender differencesSurvey completion rateResponder rateDecreased prevalenceMusculoskeletal conditionsMedical historyHigh cholesterolCardiovascular diseaseMigraine headacheCare characteristicsLifetime smokingGenome-wide Association Study of Maximum Habitual Alcohol Intake in >140,000 U.S. European and African American Veterans Yields Novel Risk Loci
Gelernter J, Sun N, Polimanti R, Pietrzak RH, Levey DF, Lu Q, Hu Y, Li B, Radhakrishnan K, Aslan M, Cheung KH, Li Y, Rajeevan N, Sayward F, Harrington K, Chen Q, Cho K, Honerlaw J, Pyarajan S, Lencz T, Quaden R, Shi Y, Hunter-Zinck H, Gaziano JM, Kranzler HR, Concato J, Zhao H, Stein MB, Program D, Program M. Genome-wide Association Study of Maximum Habitual Alcohol Intake in >140,000 U.S. European and African American Veterans Yields Novel Risk Loci. Biological Psychiatry 2019, 86: 365-376. PMID: 31151762, PMCID: PMC6919570, DOI: 10.1016/j.biopsych.2019.03.984.Peer-Reviewed Original ResearchConceptsAdditional genome-wide significant lociRisk lociWide association study (GWAS) analysisAssociation studiesGenome-wide significant lociGenome-wide association studiesGenetic correlationsWide association studyNovel risk lociAlcohol-related traitsStrong statistical supportSmoking-related traitsAdditional genomesSignificant lociPancreatic delta cellsChromosome 4Chromosome 11Protein productsChromosome 8Quantitative phenotypesMillion Veteran ProgramVeterans Affairs Million Veteran ProgramLociCell typesChromosome 17Genome-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 samples
2018
Effects of Genetic Variants Associated with Familial Hypercholesterolemia on Low-Density Lipoprotein-Cholesterol Levels and Cardiovascular Outcomes in the Million Veteran Program
Sun Y, Damrauer S, Hui Q, Assimes T, Ho Y, Natarajan P, Klarin D, Huang J, Lynch J, DuVall S, Pyarajan S, Honerlaw J, Gaziano J, Cho K, Rader D, O’Donnell C, Tsao P, Wilson P, Ramoni R, Breeling J, Chang K, Huang G, Muralidhar S, Muralidhar S, Moser J, Whitbourne S, Brewer J, Concato J, Warren S, Argyres D, Stephens B, Brophy M, Humphries D, Do N, Shayan S, Nguyen X, Hauser E, Sun Y, Zhao H, Wilson P, McArdle R, Dellitalia L, Harley J, Whittle J, Beckham J, Wells J, Gutierrez S, Gibson G, Kaminsky L, Villareal G, Kinlay S, Xu J, Hamner M, Haddock K, Bhushan S, Iruvanti P, Godschalk M, Ballas Z, Buford M, Mastorides S, Klein J, Ratcliffe N, Florez H, Swann A, Murdoch M, Sriram P, Yeh S, Washburn R, Jhala D, Aguayo S, Cohen D, Sharma S, Callaghan J, Oursler K, Whooley M, Ahuja S, Gutierrez A, Schifman R, Greco J, Rauchman M, Servatius R, Oehlert M, Wallbom A, Fernando R, Morgan T, Stapley T, Sherman S, Anderson G, Tsao P, Sonel E, Boyko E, Meyer L, Gupta S, Fayad J, Hung A, Lichy J, Hurley R, Robey B, Striker R. Effects of Genetic Variants Associated with Familial Hypercholesterolemia on Low-Density Lipoprotein-Cholesterol Levels and Cardiovascular Outcomes in the Million Veteran Program. Circulation Genomic And Precision Medicine 2018, 11 PMID: 31106297, PMCID: PMC6516478, DOI: 10.1161/circgen.118.002192.Peer-Reviewed Original ResearchConceptsCoronary heart diseasePathogenic FH variantsFamilial hypercholesterolemiaFH variantsClinical outcomesHigh prevalenceLow-density lipoprotein cholesterolPremature coronary heart diseasePeripheral artery diseaseLDL-C levelsLow-density lipoproteinMulti-ethnic populationCardiovascular outcomesArtery diseaseLipoprotein cholesterolCholesterol levelsHeart diseaseMillion Veteran ProgramRisk individualsPhenome-wide scanGenetic Variants AssociatedClinical diagnosisClinical encountersHypercholesterolemiaMulti-ethnic participants