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Kristen Brennand, PhD

Elizabeth Mears and House Jameson Professor of Psychiatry; Co-director, Science Fellows Program

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Kristen Brennand, PhD
Brennand Lab

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Research Summary

My laboratory combines expertise in genetics, neuroscience, and stem cells, in order to identify the mechanisms that underlie brain disease. Our focus lies in resolving the convergence of, and complex interplay between, the many risk variants linked to disease, towards the goal of facilitating the clinical translation of genetic findings.

Extensive Research Description

Each person’s distinct genetic, epigenetic, and environmental risk profile predisposes them to some phenotypes and confers resilience to others. My laboratory seeks to decode highly complex genetic insights into medically actionable information, better connecting the expanding list of genetic loci associated with human disease to pathophysiology. Our goal is to improve diagnostics, predict clinical trajectories, and identify pre-symptomatic points of therapeutic intervention.

Towards this, we employ a functional genomics approach that integrates stem cell models and genome engineering to resolve the impact of patient-specific variants across cell types, genetic backgrounds, and environmental conditions. Individually small risk effects combine to yield much larger impacts in aggregate, but the interactions between the myriad variants remain undetermined. Is there a “tipping point” between health and disease? Can ameliorative early interventions “untip” genetic disease risk? We seek to uncover disease-associated interactions within and between the cell types of the brain, querying the impacts of complex genetic risk within increasingly sophisticated neuronal circuits. Thus, we strive to translate risk “variants to genes”, “genes to pathways”, and “pathways to circuits”, revealing the convergent, additive, and synergistic relationships between risk factors within and between the cell types of the brain.

Even for highly penetrant mutations, a spectrum of phenotypes exist. We hope to understand the genetic, cellular, and environmental contexts that buffer genetic risk, and in doing so, develop interventions to help individuals achieve their greatest phenotypic potential. Thus, the variable penetrance of risk variants can be reframed as phenotypic resilience, evidence of biological “cures” capable of limiting, modifying, or preventing disease in individuals with otherwise high genetic predispositions. Such insights could identify therapeutics tailored to an individual’s specific risk profile, and so springboard the development of novel, personalized approaches to treat disease.

Coauthors

Research Interests

Biological Psychiatry; Neurodegenerative Diseases

Public Health Interests

Genetics, Genomics, Epigenetics

Research Images

Stem cell-derived brain organoid.

Selected Publications

  • 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 2021, 89: 65-75. PMID: 33131715, PMCID: PMC7718420, DOI: 10.1016/j.biopsych.2020.06.033.
  • Transformative Network Modeling of Multi-omics Data Reveals Detailed Circuits, Key Regulators, and Potential Therapeutics for Alzheimer's Disease.Wang M, Li A, Sekiya M, Beckmann ND, Quan X, Schrode N, Fernando MB, Yu A, Zhu L, Cao J, Lyu L, Horgusluoglu E, Wang Q, Guo L, Wang YS, Neff R, Song WM, Wang E, Shen Q, Zhou X, Ming C, Ho SM, Vatansever S, Kaniskan HÜ, Jin J, Zhou MM, Ando K, Ho L, Slesinger PA, Yue Z, Zhu J, Katsel P, Gandy S, Ehrlich ME, Fossati V, Noggle S, Cai D, Haroutunian V, Iijima KM, Schadt E, Brennand KJ, Zhang B. Transformative Network Modeling of Multi-omics Data Reveals Detailed Circuits, Key Regulators, and Potential Therapeutics for Alzheimer's Disease. Neuron 2021, 109: 257-272.e14. PMID: 33238137, PMCID: PMC7855384, DOI: 10.1016/j.neuron.2020.11.002.
  • 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, DOI: 10.1038/s41593-020-00740-1.
  • Integration 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 Neurosciences 2020, 107: 103532. PMID: 32712198, PMCID: PMC7484226, DOI: 10.1016/j.mcn.2020.103532.
  • Transcriptional 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.
  • Cell 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 PMID: 32516938, PMCID: PMC7349756, DOI: 10.3390/cells9061406.
  • If there is not one cure for schizophrenia, there may be many.Seah C, Brennand KJ. If there is not one cure for schizophrenia, there may be many. NPJ Schizophrenia 2020, 6: 11. PMID: 32313122, PMCID: PMC7170875, DOI: 10.1038/s41537-020-0101-0.
  • Sex-Specific Role for the Long Non-coding RNA LINC00473 in Depression.Issler O, van der Zee YY, Ramakrishnan A, Wang J, Tan C, Loh YE, Purushothaman I, Walker DM, Lorsch ZS, Hamilton PJ, Peña CJ, Flaherty E, Hartley BJ, Torres-Berrío A, Parise EM, Kronman H, Duffy JE, Estill MS, Calipari ES, Labonté B, Neve RL, Tamminga CA, Brennand KJ, Dong Y, Shen L, Nestler EJ. Sex-Specific Role for the Long Non-coding RNA LINC00473 in Depression. Neuron 2020, 106: 912-926.e5. PMID: 32304628, PMCID: PMC7305959, DOI: 10.1016/j.neuron.2020.03.023.
  • Modeling 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, DOI: 10.1038/s41588-020-0596-3.
  • A 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.
  • ASCL1- 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.
  • Integrating 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. The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience 2020, 40: 1176-1185. PMID: 32024766, PMCID: PMC7002154, DOI: 10.1523/JNEUROSCI.0518-19.2019.
  • A psychiatric disease-related circular RNA controls synaptic gene expression and cognition.Zimmerman AJ, Hafez AK, Amoah SK, Rodriguez BA, Dell'Orco M, Lozano E, Hartley BJ, Alural B, Lalonde J, Chander P, Webster MJ, Perlis RH, Brennand KJ, Haggarty SJ, Weick J, Perrone-Bizzozero N, Brigman JL, Mellios N. A psychiatric disease-related circular RNA controls synaptic gene expression and cognition. Molecular Psychiatry 2020, 25: 2712-2727. PMID: 31988434, PMCID: PMC7577899, DOI: 10.1038/s41380-020-0653-4.
  • Investigation of Schizophrenia with Human Induced Pluripotent Stem Cells.Powell SK, O'Shea CP, Shannon SR, Akbarian S, Brennand KJ. Investigation of Schizophrenia with Human Induced Pluripotent Stem Cells. Advances In Neurobiology 2020, 25: 155-206. PMID: 32578147, DOI: 10.1007/978-3-030-45493-7_6.
  • 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 2020, 217: 26-36. PMID: 31277978, PMCID: PMC6939156, DOI: 10.1016/j.schres.2019.06.017.
  • Neuronal 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.
  • 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.
  • Differential transcriptional response following glucocorticoid activation in cultured blood immune cells: a novel approach to PTSD biomarker development.Breen MS, Bierer LM, Daskalakis NP, Bader HN, Makotkine I, Chattopadhyay M, Xu C, Buxbaum Grice A, Tocheva AS, Flory JD, Buxbaum JD, Meaney MJ, Brennand K, Yehuda R. Differential transcriptional response following glucocorticoid activation in cultured blood immune cells: a novel approach to PTSD biomarker development. Translational Psychiatry 2019, 9: 201. PMID: 31434874, PMCID: PMC6704073, DOI: 10.1038/s41398-019-0539-x.
  • Examining the relationship between astrocyte dysfunction and neurodegeneration in ALS using hiPSCs.Halpern M, Brennand KJ, Gregory J. Examining the relationship between astrocyte dysfunction and neurodegeneration in ALS using hiPSCs. Neurobiology Of Disease 2019, 132: 104562. PMID: 31381978, PMCID: PMC6834907, DOI: 10.1016/j.nbd.2019.104562.
  • Spatial genome exploration in the context of cognitive and neurological disease.Rajarajan P, Borrman T, Liao W, Espeso-Gil S, Chandrasekaran S, Jiang Y, Weng Z, Brennand KJ, Akbarian S. Spatial genome exploration in the context of cognitive and neurological disease. Current Opinion In Neurobiology 2019, 59: 112-119. PMID: 31255842, PMCID: PMC6889018, DOI: 10.1016/j.conb.2019.05.007.
  • Leveraging Human Induced Pluripotent Stem Cell-Based Models Provides Biological Context to Genome-wide Association Study Findings.Brennand KJ. Leveraging Human Induced Pluripotent Stem Cell-Based Models Provides Biological Context to Genome-wide Association Study Findings. Biological Psychiatry 2019, 85: 532-533. PMID: 30871689, DOI: 10.1016/j.biopsych.2019.01.021.
  • Type 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.
  • New considerations for hiPSC-based models of neuropsychiatric disorders.Hoffman GE, Schrode N, Flaherty E, Brennand KJ. New considerations for hiPSC-based models of neuropsychiatric disorders. Molecular Psychiatry 2019, 24: 49-66. PMID: 29483625, PMCID: PMC6109625, DOI: 10.1038/s41380-018-0029-1.
  • Neuron-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 (New York, N.Y.) 2018, 362 PMID: 30545851, PMCID: PMC6408958, DOI: 10.1126/science.aat4311.
  • 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.
  • THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders.Guennewig B, Bitar M, Obiorah I, Hanks J, O'Brien EA, 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.
  • Modeling Neuropsychiatric and Neurodegenerative Diseases With Induced Pluripotent Stem Cells.LaMarca EA, Powell SK, Akbarian S, Brennand KJ. Modeling Neuropsychiatric and Neurodegenerative Diseases With Induced Pluripotent Stem Cells. Frontiers In Pediatrics 2018, 6: 82. PMID: 29666786, PMCID: PMC5891587, DOI: 10.3389/fped.2018.00082.
  • Mapping regulatory variants in hiPSC models.Hoffman GE, Brennand KJ. Mapping regulatory variants in hiPSC models. Nature Genetics 2018, 50: 1-2. PMID: 29273803, DOI: 10.1038/s41588-017-0017-4.
  • Transcriptional signatures of schizophrenia in hiPSC-derived NPCs and neurons are concordant with post-mortem adult brains.Hoffman GE, Hartley BJ, Flaherty E, Ladran I, Gochman P, Ruderfer DM, Stahl EA, Rapoport J, Sklar P, Brennand KJ. Transcriptional signatures of schizophrenia in hiPSC-derived NPCs and neurons are concordant with post-mortem adult brains. Nature Communications 2017, 8: 2225. PMID: 29263384, PMCID: PMC5738408, DOI: 10.1038/s41467-017-02330-5.
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