2022
Stem Cell Models for Context-Specific Modeling in Psychiatric Disorders
Seah C, Huckins L, Brennand K. Stem Cell Models for Context-Specific Modeling in Psychiatric Disorders. Biological Psychiatry 2022, 93: 642-650. PMID: 36658083, DOI: 10.1016/j.biopsych.2022.09.033.Peer-Reviewed Original ResearchConceptsStem cell modelCell typesTarget genesGenome-wide association study (GWAS) lociExpression quantitative trait lociGenome-wide association studiesParallel reporter assaysQuantitative trait lociStem cell-derived cell typesPluripotent stem cell modelsComplex polygenic architectureContext-specific mannerPsychiatric disorder riskTrait lociRegulates transcriptionStudy lociGenetic regulationPolygenic architectureCRISPR screensCell modelCausal variantsRegulated expressionPatient-specific humanReporter assaysAssociation studiesPopulation-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 samples
2021
Using the dCas9-KRAB system to repress gene expression in hiPSC-derived NGN2 neurons
Li A, Cartwright S, Yu A, Ho SM, Schrode N, Deans PJM, Matos MR, Garcia MF, Townsley KG, Zhang B, Brennand KJ. Using the dCas9-KRAB system to repress gene expression in hiPSC-derived NGN2 neurons. STAR Protocols 2021, 2: 100580. PMID: 34151300, PMCID: PMC8188621, DOI: 10.1016/j.xpro.2021.100580.Peer-Reviewed Original ResearchConceptsCRISPR inhibitionGene expressionDCas9-KRAB systemEndogenous gene expressionMultiple target genesGene repressionGene activationTarget genesGene manipulationFusion proteinComplete detailsPluripotent stemExpressionGlutamatergic neuronsRepressionGenesPhenotypicProteinStemNeuronsActivationBrain diseasesInhibition
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 diagnosisA 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