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 effectsNeuronal impact of patient-specific aberrant NRXN1α splicing
Flaherty E, Zhu S, Barretto N, Cheng E, Deans PJM, Fernando MB, Schrode N, Francoeur N, Antoine A, Alganem K, Halpern M, Deikus G, Shah H, Fitzgerald M, Ladran I, Gochman P, Rapoport J, Tsankova NM, McCullumsmith R, Hoffman GE, Sebra R, Fang G, Brennand KJ. Neuronal impact of patient-specific aberrant NRXN1α splicing. Nature Genetics 2019, 51: 1679-1690. PMID: 31784728, PMCID: PMC7451045, DOI: 10.1038/s41588-019-0539-z.Peer-Reviewed Original ResearchMeSH KeywordsAlternative SplicingAnimalsAutism Spectrum DisorderBipolar DisorderCalcium-Binding ProteinsCase-Control StudiesDepressive Disorder, MajorFemaleGene ExpressionHeterozygoteHumansInduced Pluripotent Stem CellsMaleMiceNeural Cell Adhesion MoleculesProtein IsoformsSchizophreniaSequence DeletionModelling schizophrenia using human induced pluripotent stem cells
Brennand K, Simone A, Jou J, Gelboin-Burkhart C, Tran N, Sangar S, Li Y, Mu Y, Chen G, Yu D, McCarthy S, Sebat J, Gage F. Modelling schizophrenia using human induced pluripotent stem cells. Nature 2011, 473: 221-225. PMID: 21490598, PMCID: PMC3392969, DOI: 10.1038/nature09915.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAntipsychotic AgentsCell DifferentiationCells, CulturedCellular ReprogrammingChildDisks Large Homolog 4 ProteinFemaleFibroblastsGene Expression ProfilingGene Expression RegulationHumansIntracellular Signaling Peptides and ProteinsLoxapineMaleMembrane ProteinsModels, BiologicalNeuritesNeuronsPhenotypePluripotent Stem CellsReceptors, GlutamateSchizophreniaYoung Adult
2024
209 Transcriptomic Analysis of the Post-mortem Brain in Intracranial Atherosclerosis Implicates Interferon Signaling
Seah C, Devarajan A, Jurczyszak D, Chakka A, Huckins L, Brennand K, Girgenti M. 209 Transcriptomic Analysis of the Post-mortem Brain in Intracranial Atherosclerosis Implicates Interferon Signaling. Neurosurgery 2024, 70: 55-56. DOI: 10.1227/neu.0000000000002809_209.Peer-Reviewed Original ResearchIntracranial atherosclerotic stenosisIntracranial arteriesInterferon-inducible genesInterferon signalingPeripheral atherosclerosisCerebral atherosclerosisExpression of interferon-inducible genesGlial cellsSymptomatic intracranial atherosclerotic stenosisInduced pluripotent stem cellsPost-mortem brainsWorsened functional outcomesHuman induced pluripotent stem cellsUpregulation of interferon inducible genesCause of ischemic strokePluripotent stem cellsRisk of atherosclerosisLipid-rich plaquesRisk factor managementClinical outcomesPoor prognosisExcitatory neuronsIncreased morbidityHistopathological profileFunctional outcomes
2022
Reduced LYNX1 expression in transcriptome of human iPSC-derived neural progenitors modeling fragile X syndrome
Talvio K, Minkeviciene R, Townsley K, Achuta V, Huckins L, Corcoran P, Brennand K, Castrén M. Reduced LYNX1 expression in transcriptome of human iPSC-derived neural progenitors modeling fragile X syndrome. Frontiers In Cell And Developmental Biology 2022, 10: 1034679. PMID: 36506088, PMCID: PMC9731341, DOI: 10.3389/fcell.2022.1034679.Peer-Reviewed Original ResearchInduced pluripotent stem cellsFragile X syndromeHuman induced pluripotent stem cellsNeural progenitorsX syndromeEarly gene expression changesGene expression changesPatient-derived induced pluripotent stem cellsTriplet repeat instabilityFunctional enrichment analysisHuman neural progenitorsPluripotent stem cellsRNA splicingPhenotypic variationIntellectual disability syndromeEnrichment analysisExpression changesRepeat instabilityMolecular mechanismsProtein resultsGrowth factor pathwaysInsulin-like growth factor (IGF) pathwayAltered expressionStem cellsTranscriptomeChromatin 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 role
2021
Chapter 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
Massively parallel techniques for cataloguing the regulome of the human brain
Townsley KG, Brennand KJ, Huckins LM. Massively parallel techniques for cataloguing the regulome of the human brain. Nature Neuroscience 2020, 23: 1509-1521. PMID: 33199899, PMCID: PMC8018778, DOI: 10.1038/s41593-020-00740-1.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsRegulatory elementsTarget genesParallel reporter assaysPutative regulatory elementsNon-coding regionsDisease-associated lociSpecific expression patternsCandidate risk lociPluripotent stem cellsHigh-throughput assaysRelevant molecular pathwaysTranscriptional responseRegulatory architectureRisk lociExpression patternsReporter assaysComplex brain disordersMolecular pathwaysRegulomeStem cellsRisk architectureGenetic riskGenesLociGenetic diagnosisPluripotent Stem Cells May Unlock How Genetic Variants Result in Mental Disorders
Powell S, Yu A, Katz C, Brennand K. Pluripotent Stem Cells May Unlock How Genetic Variants Result in Mental Disorders. Psychiatric News 2020, 55 DOI: 10.1176/appi.pn.2020.7b14.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsIntegration of CRISPR-engineering and hiPSC-based models of psychiatric genomics
Matos MR, Ho SM, Schrode N, Brennand KJ. Integration of CRISPR-engineering and hiPSC-based models of psychiatric genomics. Molecular And Cellular Neuroscience 2020, 107: 103532. PMID: 32712198, PMCID: PMC7484226, DOI: 10.1016/j.mcn.2020.103532.Peer-Reviewed Original ResearchConceptsPenetrant rare variantsDisease-associated variantsNeuronal cell typesPluripotent stem cellsGenomic engineeringFunctional characterizationComplex geneticsCRISPR engineeringCRISPR technologyIsogenic comparisonsPsychiatric genomicsCell typesGenetic variantsStem cellsIndividual variantsCommon variantsPolygenic disorderRare variantsVariantsComplex interplayGenomicsGenetic riskPleiotropyCRISPRGeneticsTranscriptional signatures of participant-derived neural progenitor cells and neurons implicate altered Wnt signaling in Phelan-McDermid syndrome and autism
Breen MS, Browne A, Hoffman GE, Stathopoulos S, Brennand K, Buxbaum JD, Drapeau E. Transcriptional signatures of participant-derived neural progenitor cells and neurons implicate altered Wnt signaling in Phelan-McDermid syndrome and autism. Molecular Autism 2020, 11: 53. PMID: 32560742, PMCID: PMC7304190, DOI: 10.1186/s13229-020-00355-0.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAutistic DisorderChildChild, PreschoolChromosome DeletionChromosome DisordersChromosomes, Human, Pair 22FemaleGene Expression ProfilingGene Expression RegulationHumansInduced Pluripotent Stem CellsMaleNeural Stem CellsNeuronsReproducibility of ResultsWnt Signaling PathwayConceptsNeural progenitor cellsTranscriptional signatureGene co-expression network analysisHiPSC-NPCsCo-expression network analysisIndependent biological samplesHiPSC-derived neural cellsProgenitor cellsPostsynaptic density genesDistinct transcriptional signaturesGenetic risk lociHuman-induced pluripotent stem cellsPluripotent stem cellsPotassium channel activityProtein translationSpecific neurobiological pathwaysTranscriptional differencesEmbryonic developmentLoss of SHANK3Risk lociHiPSC neuronsMorphological phenotypesWnt pathwayGenesHiPSC clonesCell Type-Specific In Vitro Gene Expression Profiling of Stem Cell-Derived Neural Models
Gregory JA, Hoelzli E, Abdelaal R, Braine C, Cuevas M, Halpern M, Barretto N, Schrode N, Akbalik G, Kang K, Cheng E, Bowles K, Lotz S, Goderie S, Karch CM, Temple S, Goate A, Brennand KJ, Phatnani H. Cell Type-Specific In Vitro Gene Expression Profiling of Stem Cell-Derived Neural Models. Cells 2020, 9: 1406. PMID: 32516938, PMCID: PMC7349756, DOI: 10.3390/cells9061406.Peer-Reviewed Original ResearchConceptsCell type-restricted expressionDisease-associated interactionsGene expression profilingHiPSC-derived motor neuronsHuman-induced pluripotent stem cellsPluripotent stem cellsCell-type specific perturbationsImmortalized cell linesRibosomal proteinsGenomic studiesExpression profilingMolecular mechanismsOff-target RNAMouse tissuesCell typesStem cellsPrimary mouse astrocytesExperimental replicatesCell linesMixed speciesMouse astrocytesExpressionMotor neuronsRiboTagCellsModeling 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 diagnosisVariantsASCL1- and DLX2-induced GABAergic neurons from hiPSC-derived NPCs
Barretto N, Zhang H, Powell SK, Fernando MB, Zhang S, Flaherty EK, Ho SM, Slesinger PA, Duan J, Brennand KJ. ASCL1- and DLX2-induced GABAergic neurons from hiPSC-derived NPCs. Journal Of Neuroscience Methods 2020, 334: 108548. PMID: 32065989, PMCID: PMC7426253, DOI: 10.1016/j.jneumeth.2019.108548.Peer-Reviewed Original ResearchNeural progenitor cellsHiPSC-NPCsSomatic cell reprogrammingGABAergic neuronsHiPSC-derived neural progenitor cellsDifferentiation of hiPSCsDistinct transcriptional profilesPluripotent stem cellsCell reprogrammingPatient-derived cellsElectrophysiological maturityFunctional GABAergic neuronsTranscriptional profilesNeuronal inductionStem cellsProgenitor cellsLentiviral overexpressionPure populationsDlx2Study of diseasesAscl1HiPSCsNeuronal populationsInduction protocolCell sourceIntegrating CRISPR Engineering and hiPSC-Derived 2D Disease Modeling Systems
Rehbach K, Fernando MB, Brennand KJ. Integrating CRISPR Engineering and hiPSC-Derived 2D Disease Modeling Systems. Journal Of Neuroscience 2020, 40: 1176-1185. PMID: 32024766, PMCID: PMC7002154, DOI: 10.1523/jneurosci.0518-19.2019.Peer-Reviewed Original ResearchConceptsHuman induced pluripotent stem cellsMajor brain cell typesDual Perspectives CompanionBrain cell typesNeuronal maturityPsychiatric disordersHuman neuronsDisease riskStudy designBrain organoidsIntradonor variabilityDisease modelsHuman neurodevelopmentInduced pluripotent stem cellsNeural differentiationDiseaseStem cellsCell typesPluripotent stem cellsHuman diseasesEfficient neural differentiationInduction strategyPatient-specific cellsDisease modelingCells
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 effectsType I interferon response impairs differentiation potential of pluripotent stem cells
Eggenberger J, Blanco-Melo D, Panis M, Brennand KJ, tenOever BR. Type I interferon response impairs differentiation potential of pluripotent stem cells. Proceedings Of The National Academy Of Sciences Of The United States Of America 2019, 116: 1384-1393. PMID: 30606801, PMCID: PMC6347712, DOI: 10.1073/pnas.1812449116.Peer-Reviewed Original Research
2018
Expression-based drug screening of neural progenitor cells from individuals with schizophrenia
Readhead B, Hartley BJ, Eastwood BJ, Collier DA, Evans D, Farias R, He C, Hoffman G, Sklar P, Dudley JT, Schadt EE, Savić R, Brennand KJ. Expression-based drug screening of neural progenitor cells from individuals with schizophrenia. Nature Communications 2018, 9: 4412. PMID: 30356048, PMCID: PMC6200740, DOI: 10.1038/s41467-018-06515-4.Peer-Reviewed Original ResearchConceptsNeural progenitor cellsHiPSC neural progenitor cellsCell typesCancer cell linesGene expression differencesProgenitor cellsDisease-associated genesPatient-specific platformPluripotent stem cellsTranscriptional responseExpression differencesTranscriptional signatureTranscriptomic signaturesStem cellsCell linesDependent mannerDrug discoveryDrug screeningCellsNeuropsychiatric disordersSchizophreniaBest treatmentDrugsDiscoveryGenesTHC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders
Guennewig B, Bitar M, Obiorah I, Hanks J, O’Brien E, Kaczorowski DC, Hurd YL, Roussos P, Brennand KJ, Barry G. THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Translational Psychiatry 2018, 8: 89. PMID: 29691375, PMCID: PMC5915454, DOI: 10.1038/s41398-018-0137-3.Peer-Reviewed Original ResearchConceptsHuman-induced pluripotent stem cellsPluripotent stem cellsHuman iPSC neuronsTranscriptional responseTranscriptomic analysisRNA transcriptomic analysisHuman neural cellsIPSC-neuronsMolecular pathwaysNeuropsychiatric disordersStem cellsNeural cellsDiagnosis-specific differencesGenesTHC exposureNeuronal depolarizationTHC administrationChronic exposureCannabis useNeuronsΔ9-tetrahydrocannabinolStrong associationSignificant alterationsCellsDynamic changesModeling the Brain in the Culture Dish: Advancements and Applications of Induced Pluripotent Stem‐Cell‐Derived Neurons
Chandrasekaran S, Rajarajan P, Akbarian S, Brennand K. Modeling the Brain in the Culture Dish: Advancements and Applications of Induced Pluripotent Stem‐Cell‐Derived Neurons. 2018, 119-157. DOI: 10.1002/9781119283249.ch6.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsHuman induced pluripotent stem cellsInduced pluripotent stem cell-derived neuronsPluripotent stem cell-derived neuronsStem cell-derived neuronsZika virus epidemicPathophysiological mechanismsNeurological diseasesInduction protocolNeuropsychiatric diseasesCerebral organoidsTranslational benefitsVirus epidemicDrug testingDisease treatmentInduced pluripotent stem cellsDiseaseNeuronsStem cellsOptimization of differentiationPluripotent stem cellsSpecific subsetNeuroscience researchCulture dishesTransplantationBrain