Featured Publications
Synergistic effects of common schizophrenia risk variants
Schrode N, Ho SM, Yamamuro K, Dobbyn A, Huckins L, Matos MR, Cheng E, Deans PJM, Flaherty E, Barretto N, Topol A, Alganem K, Abadali S, Gregory J, Hoelzli E, Phatnani H, Singh V, Girish D, Aronow B, Mccullumsmith R, Hoffman GE, Stahl EA, Morishita H, Sklar P, Brennand KJ. Synergistic effects of common schizophrenia risk variants. Nature Genetics 2019, 51: 1475-1485. PMID: 31548722, PMCID: PMC6778520, DOI: 10.1038/s41588-019-0497-5.Peer-Reviewed Original ResearchMeSH KeywordsChloride ChannelsCRISPR-Cas SystemsFemaleFurinGene EditingGene Expression RegulationGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansInduced Pluripotent Stem CellsMaleMonomeric Clathrin Assembly ProteinsPolymorphism, Single NucleotideQuantitative Trait LociSchizophreniaSNARE ProteinsConceptsExpression quantitative trait lociComplex genetic disorderEQTL genesCommon variantsQuantitative trait lociRisk variantsGene expression differencesPsychiatric disease riskCommon risk variantsPluripotent stem cellsSchizophrenia risk variantsGenetic disordersTrait lociGene perturbationsGenetic approachesExpression differencesGene editingStem cellsGeneralizable phenomenonSynaptic functionGenesVariantsCRISPRLociSpecific effectsNeuron-specific signatures in the chromosomal connectome associated with schizophrenia risk
Rajarajan P, Borrman T, Liao W, Schrode N, Flaherty E, Casiño C, Powell S, Yashaswini C, LaMarca EA, Kassim B, Javidfar B, Espeso-Gil S, Li A, Won H, Geschwind DH, Ho SM, MacDonald M, Hoffman GE, Roussos P, Zhang B, Hahn CG, Weng Z, Brennand KJ, Akbarian S. Neuron-specific signatures in the chromosomal connectome associated with schizophrenia risk. Science 2018, 362 PMID: 30545851, PMCID: PMC6408958, DOI: 10.1126/science.aat4311.Peer-Reviewed Original ResearchMeSH KeywordsBrainCells, CulturedChromatinChromatin Assembly and DisassemblyChromosomes, HumanConnectomeEpigenesis, GeneticGene Expression Regulation, DevelopmentalGenetic Predisposition to DiseaseGenome, HumanGenome-Wide Association StudyHumansMaleNeural Stem CellsNeurogenesisNeurogliaNeuronsNucleic Acid ConformationProtein Interaction MapsProteomicsRiskSchizophreniaTranscription, GeneticTranscriptomeConceptsCoordinated transcriptional regulationThree-dimensional genomeSpatial genome organizationChromosomal contact mapsNeural progenitor cellsSchizophrenia risk variantsGenome organizationChromatin remodelingChromosomal conformationTranscriptional regulationProteomic interactionsDevelopmental remodelingHeritable riskGlial differentiationRisk variantsContact mapsProgenitor cellsVariant sequencesGenesConformation changeNeuronal connectivitySchizophrenia riskSequenceNeuropsychiatric diseasesDistal targets
2023
56. USING HIPSC-NEURONS AND CRISPR TO UNCOVER NON-ADDITIVE EFFECTS OF SCZ RISK GENES
Deans M, Seah C, Johnson J, García-González J, Townsley K, Cao E, Schrode N, Stahl E, O'Reilly P, Huckins L, Brennand K. 56. USING HIPSC-NEURONS AND CRISPR TO UNCOVER NON-ADDITIVE EFFECTS OF SCZ RISK GENES. European Neuropsychopharmacology 2023, 75: s86. DOI: 10.1016/j.euroneuro.2023.08.162.Peer-Reviewed Original ResearchSCZ risk genesNon-additive effectsRisk genesCombinatorial perturbationsTranscriptomic effectsFunctional roleRisk variantsGene expression changesBulk RNA-seqMultiple functional rolesSynaptic functionHigh-throughput imagingFunctional redundancyTranscriptional regulatorsRNA-seqCRISPR activationCellular phenotypesRNA interferenceEGenesGene expressionExpression changesHiPSC neuronsPolygenic risk scoresGenetic studiesGenesBetter together: Non-additive interactions between schizophrenia risk genes
Deans P, Brennand K. Better together: Non-additive interactions between schizophrenia risk genes. Cell Genomics 2023, 3: 100403. PMID: 37719145, PMCID: PMC10504666, DOI: 10.1016/j.xgen.2023.100403.Peer-Reviewed Original Research
2022
Population-level variation in enhancer expression identifies disease mechanisms in the human brain
Dong P, Hoffman G, Apontes P, Bendl J, Rahman S, Fernando M, Zeng B, Vicari J, Zhang W, Girdhar K, Townsley K, Misir R, Brennand K, Haroutunian V, Voloudakis G, Fullard J, Roussos P. Population-level variation in enhancer expression identifies disease mechanisms in the human brain. Nature Genetics 2022, 54: 1493-1503. PMID: 36163279, PMCID: PMC9547946, DOI: 10.1038/s41588-022-01170-4.Peer-Reviewed Original ResearchConceptsExpression quantitative trait lociPopulation-level variationTranscriptome-wide association studyQuantitative trait lociSpecific transcriptomeTrait lociTrait heritabilitySpecific transcriptionEnhancer functionGenetic mechanismsTarget genesAssociation studiesDisease locusNeuropsychiatric diseasesRisk variantsGenesRobust expressionTranscriptomeFunctional interpretationDisease mechanismsEnhancerDiseased statesLociHuman brainBrain samplesChromatin profiling in human neurons reveals aberrant roles for histone acetylation and BET family proteins in schizophrenia
Farrelly L, Zheng S, Schrode N, Topol A, Bhanu N, Bastle R, Ramakrishnan A, Chan J, Cetin B, Flaherty E, Shen L, Gleason K, Tamminga C, Garcia B, Li H, Brennand K, Maze I. Chromatin profiling in human neurons reveals aberrant roles for histone acetylation and BET family proteins in schizophrenia. Nature Communications 2022, 13: 2195. PMID: 35459277, PMCID: PMC9033776, DOI: 10.1038/s41467-022-29922-0.Peer-Reviewed Original ResearchConceptsHistone posttranslational modificationsPosttranslational modificationsUnbiased proteomic approachPluripotent stem cellsPatient-derived neuronsH2A.Z acetylationChromatin profilingHyperacetylated histonesFamily proteinsProteomic approachProtein interactionsHistone acetylationTranscriptional abnormalitiesEpigenetic factorsExtraterminal (BET) proteinsSZ casesRisk variantsHuman neuronsStem cellsAberrant roleProtein inhibitionBona fideTreatment of schizophreniaPostmortem human brainCritical roleUsing Stem Cell Models to Explore the Genetics Underlying Psychiatric Disorders: Linking Risk Variants, Genes, and Biology in Brain Disease
Brennand K. Using Stem Cell Models to Explore the Genetics Underlying Psychiatric Disorders: Linking Risk Variants, Genes, and Biology in Brain Disease. American Journal Of Psychiatry 2022, 179: 322-328. PMID: 35491564, DOI: 10.1176/appi.ajp.20220235.Commentaries, Editorials and LettersConceptsRisk variantsFunctional genomic studiesCell typesDiverse cell typesPatient-specific variantsStem cell modelGenomic studiesSignificant lociStem cell-based approachesGenetic studiesExciting questionsCell-based approachesEngineering strategiesGenetic profileNovel therapeutic interventionsCell modelPluripotent stem cell-based approachesVariantsComplex interplayGenetic riskCRISPRGenesLociBiologyTherapeutic interventions
2021
Analysis framework and experimental design for evaluating synergy-driving gene expression
Schrode N, Seah C, Deans P, Hoffman G, Brennand K. Analysis framework and experimental design for evaluating synergy-driving gene expression. Nature Protocols 2021, 16: 812-840. PMID: 33432232, PMCID: PMC8609447, DOI: 10.1038/s41596-020-00436-7.Peer-Reviewed Original ResearchConceptsRaw read countsPluripotent stem cell-derived neuronsRNA sequencing experimentsRNA sequencing datasetsStem cell-derived neuronsDifferential expression analysisCell-derived neuronsComplex genetic disorderNon-additive interactionsGenetic risk variantsChemical perturbagensBioinformatics skillsExpression analysisSequencing datasetsGene expressionTranscriptomic effectsSequencing experimentsComputational pipelineRead countsRisk variantsCareful experimental designCombinatorial manipulationGenetic variantsComplex diseasesPerturbation studiesChapter 30 Functional genomics of psychiatric disease risk using genome engineering
Garcia M, Powell S, LaMarca E, Fernando M, Cohen S, Fang G, Akbarian S, Brennand K. Chapter 30 Functional genomics of psychiatric disease risk using genome engineering. 2021, 711-734. DOI: 10.1016/b978-0-12-823577-5.00021-0.ChaptersRisk variantsDisease-relevant cell typesPsychiatric disease riskPluripotent stem cellsFunctional genomicsGenetic risk architectureGenome engineeringComplex geneticsCRISPR engineeringHiPSC modelsCell typesFunctional explorationStem cellsFunctional impactRisk architecturePossible new avenuesGenetic findingsGenetic screeningNew insightsNovel therapeutic approachesFundamental roleNew avenuesDisease pathophysiologyEpigenomeVariants
2020
Parsing the Functional Impact of Noncoding Genetic Variants in the Brain Epigenome
Powell SK, O'Shea C, Brennand KJ, Akbarian S. Parsing the Functional Impact of Noncoding Genetic Variants in the Brain Epigenome. Biological Psychiatry 2020, 89: 65-75. PMID: 33131715, PMCID: PMC7718420, DOI: 10.1016/j.biopsych.2020.06.033.Peer-Reviewed Original ResearchConceptsGenetic variantsDisease-associated genetic variationProtein-coding lociRisk-associated genetic variantsGene regulatory lociThousands of variantsFunctional impactRare genetic variantsEpigenomic mappingRegulatory lociBrain epigenomeGenetic variationDNA sequencesNoncoding variantsGene expressionIntegrative analysisEpigenomic architectureMolecular pathwaysPsychiatric geneticsFunctional readoutRisk variantsLociVariantsHighlight findingsEpigenomeModeling the complex genetic architectures of brain disease
Fernando MB, Ahfeldt T, Brennand KJ. Modeling the complex genetic architectures of brain disease. Nature Genetics 2020, 52: 363-369. PMID: 32203467, PMCID: PMC7909729, DOI: 10.1038/s41588-020-0596-3.Peer-Reviewed Original ResearchConceptsGenetic architectureComplex genetic architectureFunctional validation studiesRelevant disease biologyIntersection of genomicsComplex genetic diseasesCombination of genesPluripotent stem cellsGene perturbationsIsogenic comparisonsMolecular mechanismsPhenotypic drug discoveryCell typesGenetic diseasesFunctional consequencesGenetic backgroundRisk variantsStem cellsCRISPRDisease biologyDrug discoveryRare variantsConfer riskGenetic diagnosisVariantsA computational tool (H-MAGMA) for improved prediction of brain-disorder risk genes by incorporating brain chromatin interaction profiles
Sey NYA, Hu B, Mah W, Fauni H, McAfee JC, Rajarajan P, Brennand KJ, Akbarian S, Won H. A computational tool (H-MAGMA) for improved prediction of brain-disorder risk genes by incorporating brain chromatin interaction profiles. Nature Neuroscience 2020, 23: 583-593. PMID: 32152537, PMCID: PMC7131892, DOI: 10.1038/s41593-020-0603-0.Peer-Reviewed Original ResearchConceptsChromatin interaction profilesH-MAGMARisk genesMost risk variantsGenome-wide association studiesCell typesGene regulatory relationshipsRelevant target genesCell-type specificitySingle nucleotide polymorphism associationsBrain cell typesDisease-relevant tissuesInteraction profilesGenomic annotationsNearest geneTarget genesRegulatory relationshipsAssociation studiesBiological pathwaysGenesRisk variantsDevelopmental windowBiological mechanismsNeurodegenerative disordersHuman brain tissue
2019
CRISPR-based functional evaluation of schizophrenia risk variants
Rajarajan P, Flaherty E, Akbarian S, Brennand KJ. CRISPR-based functional evaluation of schizophrenia risk variants. Schizophrenia Research 2019, 217: 26-36. PMID: 31277978, PMCID: PMC6939156, DOI: 10.1016/j.schres.2019.06.017.Peer-Reviewed Original ResearchConceptsSchizophrenia-associated variantsPluripotent stem cellsCRISPR genome engineeringSchizophrenia risk variantsCellular functionsGenome engineeringGenomic studiesSchizophrenia lociList of variantsGene expressionPatient-specific humanGenotype dataRisk variantsStem cellsFunctional impactCommon variantsCRISPRPost-mortem brain tissueRecent findingsVariantsNeuropsychiatric diseasesPoint of convergenceGenetic riskLociSpecific effects
2017
Evaluating Synthetic Activation and Repression of Neuropsychiatric-Related Genes in hiPSC-Derived NPCs, Neurons, and Astrocytes
Ho S, Hartley B, Flaherty E, Rajarajan P, Abdelaal R, Obiorah I, Barretto N, Muhammad H, Phatnani H, Akbarian S, Brennand K. Evaluating Synthetic Activation and Repression of Neuropsychiatric-Related Genes in hiPSC-Derived NPCs, Neurons, and Astrocytes. Stem Cell Reports 2017, 9: 615-628. PMID: 28757163, PMCID: PMC5550013, DOI: 10.1016/j.stemcr.2017.06.012.Peer-Reviewed Original ResearchConceptsSynthetic activationRisk genesCell typesModulation of transcriptionNeuropsychiatric risk genesCommon single nucleotide variantsCas9 fusion proteinsEndogenous expression levelsNeural cell typesPluripotent stem cell-derived neural progenitor cellsRare copy number variationsCopy number variationsSingle nucleotide variantsNeural progenitor cellsGene functionFunctional annotationGenetic studiesGenesRisk variantsProgenitor cellsExpression levelsTranscriptionRepressionPositional effectsProtein