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Stem cell models for context-specific modeling in psychiatric disorders

  • Carina Seah
    Affiliations
    Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, New York, 10029 USA

    Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, 10029 USA

    Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, 10029 USA
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  • Laura M. Huckins
    Correspondence
    Correspondence: and
    Affiliations
    Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, New York, 10029 USA

    Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, 10029 USA

    Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, 10029 USA

    Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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  • Kristen J. Brennand
    Correspondence
    Correspondence: and
    Affiliations
    Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, New York, 10029 USA

    Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, 10029 USA

    Departments of Psychiatry and Genetics, Division of Molecular Psychiatry, Yale University School of Medicine, New Haven CT 06511
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      ABSTRACT

      Genome wide association studies (GWAS) reveal the complex polygenic architecture underlying psychiatric disorder risk, but there is an unmet need to validate causal variants, resolve their target genes(s), and explore their functional impacts to disorder-related mechanisms. Disorder-associated loci regulate transcription of target genes in a cell type- and context-specific manner, which can be measured through expression quantitative trait loci (eQTLs). This review discusses methods and insights from context-specific modeling of genetically- and environmentally-regulated expression (GxE-REX). Human-induced pluripotent stem cell (hiPSC) derived cell type and organoid models have uncovered context-specific psychiatric disorder associations by investigating tissue-, cell type-, sex-, age-, and stressor-specific genetic regulation of expression. Techniques such as massively parallel reporter assays (MPRAs) and pooled CRISPR screens make it possible to functionally fine-map GWAS loci and validate their target genes at scale. Integration of disorder-associated contexts with these patient-specific hiPSC models make it possible to uncover gene by environment interactions mediating disorder risk, which will ultimately improve our ability to diagnose and treat psychiatric disorders.

      KEYWORDS

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      REFERENCES

      1. Pettersson E, Lichtenstein P, Larsson H, Song J, Attention Deficit/Hyperactivity Disorder Working Group of the iPSYCH-Broad-PGC Consortium, Autism Spectrum Disorder Working Group of the iPSYCH-Broad-PGC Consortium, Bipolar Disorder Working Group of the PGC, Eating Disorder Working Group of the PGC, Major Depressive Disorder Working Group of the PGC, Obsessive Compulsive Disorders and Tourette Syndrome Working Group of the PGC, Schizophrenia CLOZUK, Substance Use Disorder Working Group of the PGC, Agrawal A, et al. (2019): Genetic influences on eight psychiatric disorders based on family data of 4 408 646 full and half-siblings, and genetic data of 333 748 cases and controls. Psychol Med 49: 1166–1173.

        • Nievergelt C.M.
        • Maihofer A.X.
        • Klengel T.
        • Atkinson E.G.
        • Chen C.-Y.
        • Choi K.W.
        • et al.
        International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.
        Nat Commun. 2019; 10: 4558
        • Pardiñas A.F.
        • Holmans P.
        • Pocklington A.J.
        • Escott-Price V.
        • Ripke S.
        • Carrera N.
        • et al.
        Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection.
        Nat Genet. 2018; 50: 381-389
        • Howard D.M.
        • Adams M.J.
        • Clarke T.-K.
        • Hafferty J.D.
        • Gibson J.
        • Shirali M.
        • et al.
        Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions.
        Nat Neurosci. 2019; 22: 343-352
        • Grove J.
        • Ripke S.
        • Als T.D.
        • Mattheisen M.
        • Walters R.K.
        • Won H.
        • et al.
        Identification of common genetic risk variants for autism spectrum disorder.
        Nat Genet. 2019; 51: 431-444
        • Maurano M.T.
        • Humbert R.
        • Rynes E.
        • Thurman R.E.
        • Haugen E.
        • Wang H.
        • et al.
        Systematic Localization of Common Disease-Associated Variation in Regulatory DNA.
        Science. 2012; 337: 1190-1195
        • Gamazon E.R.
        • Segrè A.V.
        • van de Bunt M.
        • Wen X.
        • Xi H.S.
        • Hormozdiari F.
        • et al.
        Using an atlas of gene regulation across 44 human tissues to inform complex disease- and trait-associated variation [no. 7].
        Nat Genet. 2018; 50: 956-967
        • Huckins L.M.
        • Dobbyn A.
        • Ruderfer D.M.
        • Hoffman G.
        • Wang W.
        • Pardiñas A.F.
        • et al.
        Gene expression imputation across multiple brain regions provides insights into schizophrenia risk [no. 4].
        Nat Genet. 2019; 51: 659-674
      2. Huckins LM, Dobbyn A, McFadden W, Wang W, Ruderfer DM, Hoffman G, et al. (2017, November 21): Transcriptomic Imputation of Bipolar Disorder and Bipolar subtypes reveals 29 novel associated genes. bioRxiv, p 222786.

      3. Huckins L, Dobbyn A, Thornton L, Eating Disorders Working Group of the PGC, Devlin B, Sieberts S, et al. (2019): 63 - TRANSCRIPTOMIC IMPUTATION ANALYSIS IN ANOREXIA NERVOSA IDENTIFIES BOTH METABOLIC AND PSYCHIATRIC AETIOLOGIES. Eur Neuropsychopharmacol 29: S818.

        • Huckins L.M.
        • Chatzinakos C.
        • Breen M.S.
        • Hartmann J.
        • Klengel T.
        • da Silva Almeida A.C.
        • et al.
        Analysis of Genetically Regulated Gene Expression Identifies a Prefrontal PTSD Gene, SNRNP35, Specific to Military Cohorts.
        Cell Rep. 2020; 31107716
      4. Bryois J, Calini D, Macnair W, Foo L, Urich E, Ortmann W, et al. (2021, October 14): Cell-type specific cis-eQTLs in eight brain cell-types identifies novel risk genes for human brain disorders. medRxiv, p 2021.10.09.21264604.

        • Cuomo A.S.E.
        • Seaton D.D.
        • McCarthy D.J.
        • Martinez I.
        • Bonder M.J.
        • Garcia-Bernardo J.
        • et al.
        Single-cell RNA-sequencing of differentiating iPS cells reveals dynamic genetic effects on gene expression.
        Nat Commun. 2020; 11: 810
        • Hollander J.A.
        • Cory-Slechta D.A.
        • Jacka F.N.
        • Szabo S.T.
        • Guilarte T.R.
        • Bilbo S.D.
        • et al.
        Beyond the looking glass: recent advances in understanding the impact of environmental exposures on neuropsychiatric disease [no. 7].
        Neuropsychopharmacology. 2020; 45: 1086-1096
        • Townsley K.G.
        • Brennand K.J.
        • Huckins L.M.
        Massively parallel techniques for cataloguing the regulome of the human brain.
        Nat Neurosci. 2020; : 1-13
        • Cano-Gamez E.
        • Trynka G.
        From GWAS to Function: Using Functional Genomics to Identify the Mechanisms Underlying Complex Diseases.
        Front Genet. 2020; 11 (Retrieved April 21, 2022, from)
        • Zhu Z.
        • Zhang F.
        • Hu H.
        • Bakshi A.
        • Robinson M.R.
        • Powell J.E.
        • et al.
        Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets [no. 5].
        Nat Genet. 2016; 48: 481-487
        • Highland H.M.
        • Wojcik G.L.
        • Graff M.
        • Nishimura K.K.
        • Hodonsky C.J.
        • Baldassari A.R.
        • et al.
        Predicted gene expression in ancestrally diverse populations leads to discovery of susceptibility loci for lifestyle and cardiometabolic traits.
        Am J Hum Genet. 2022; 109: 669-679
        • Fu J.
        • Wolfs M.G.M.
        • Deelen P.
        • Westra H.-J.
        • Fehrmann R.S.N.
        • Meerman GJ te
        • et al.
        Unraveling the Regulatory Mechanisms Underlying Tissue-Dependent Genetic Variation of Gene Expression.
        PLOS Genet. 2012; 8e1002431
        • Neavin D.
        • Nguyen Q.
        • Daniszewski M.S.
        • Liang H.H.
        • Chiu H.S.
        • Wee Y.K.
        • et al.
        Single cell eQTL analysis identifies cell type-specific genetic control of gene expression in fibroblasts and reprogrammed induced pluripotent stem cells.
        Genome Biol. 2021; 22: 76
        • Hoffman G.E.
        • Ma Y.
        • Montgomery K.S.
        • Bendl J.
        • Jaiswal M.K.
        • Kozlenkov A.
        • et al.
        Sex Differences in the Human Brain Transcriptome of Cases With Schizophrenia.
        Biol Psychiatry. 2022; 91: 92-101
        • Jonkers I.H.
        • Wijmenga C.
        Context-specific effects of genetic variants associated with autoimmune disease.
        Hum Mol Genet. 2017; 26: R185-R192
      5. Young H, Cote A, Huckins LM (2022): Chapter 14 - Integration with systems biology approaches and -omics data to characterize risk variation. In: Tsermpini EE, Alda M, Patrinos GP, editors. Psychiatric Genomics. Academic Press, pp 289–315.

        • Lonsdale J.
        • Thomas J.
        • Salvatore M.
        • Phillips R.
        • Lo E.
        • Shad S.
        • et al.
        The Genotype-Tissue Expression (GTEx) project.
        Nat Genet. 2013; 45: 580-585
        • Yao D.W.
        • O’Connor L.J.
        • Price A.L.
        • Gusev A.
        Quantifying genetic effects on disease mediated by assayed gene expression levels.
        Nat Genet. 2020; 52: 626-633
        • Peters J.E.
        • Lyons P.A.
        • Lee J.C.
        • Richard A.C.
        • Fortune M.D.
        • Newcombe P.J.
        • et al.
        Insight into Genotype-Phenotype Associations through eQTL Mapping in Multiple Cell Types in Health and Immune-Mediated Disease.
        PLOS Genet. 2016; 12e1005908
        • Young A.M.
        • Kumasaka N.
        • Calvert F.
        • Hammond T.R.
        • Knights A.
        • Panousis N.
        • et al.
        A map of transcriptional heterogeneity and regulatory variation in human microglia.
        Nat Genet. 2021; 53: 861-868
      6. Kosoy R, Fullard JF, Zeng B, Bendl J, Dong P, Rahman S, et al. (2021, October 18): Genetics of the human microglia regulome refines Alzheimer’s disease risk loci. medRxiv, p 2021.10.17.21264910.

        • Ramikie T.S.
        • Ressler K.J.
        Mechanisms of Sex Differences in Fear and Posttraumatic Stress Disorder.
        Biol Psychiatry. 2018; 83: 876-885
        • Abel K.M.
        • Drake R.
        • Goldstein J.M.
        Sex differences in schizophrenia.
        Int Rev Psychiatry Abingdon Engl. 2010; 22: 417-428
        • Oliva M.
        • Muñoz-Aguirre M.
        • Kim-Hellmuth S.
        • Wucher V.
        • Gewirtz A.D.H.
        • Cotter D.J.
        • et al.
        The impact of sex on gene expression across human tissues.
        Science. 2020; 369eaba3066
        • Yao C.
        • Joehanes R.
        • Johnson A.D.
        • Huan T.
        • Esko T.
        • Ying S.
        • et al.
        Sex- and age-interacting eQTLs in human complex diseases.
        Hum Mol Genet. 2014; 23 (–1956): 1947
        • Zorn J.V.
        • Schür R.R.
        • Boks M.P.
        • Kahn R.S.
        • Joëls M.
        • Vinkers C.H.
        Cortisol stress reactivity across psychiatric disorders: A systematic review and meta-analysis.
        Psychoneuroendocrinology. 2017; 77: 25-36
        • Smoller J.W.
        The Genetics of Stress-Related Disorders: PTSD, Depression, and Anxiety Disorders.
        Neuropsychopharmacology. 2016; 41: 297-319
        • Arloth J.
        • Bogdan R.
        • Weber P.
        • Frishman G.
        • Menke A.
        • Wagner K.V.
        • et al.
        Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders.
        Neuron. 2015; 86: 1189-1202
      7. Moore SR, Halldorsdottir T, Martins J, Lucae S, Müller-Myhsok B, Müller NS, et al. (2021): Sex Differences in the Genetic Regulation of the Blood Transcriptome Response to Glucocorticoid Receptor Activation. p 2020.10.19.20213983.

        • Jin M.J.
        • Jeon H.
        • Hyun M.H.
        • Lee S.-H.
        Influence of childhood trauma and brain-derived neurotrophic factor Val66Met polymorphism on posttraumatic stress symptoms and cortical thickness.
        Sci Rep. 2019; 9: 6028
        • Hosang G.M.
        • Shiles C.
        • Tansey K.E.
        • McGuffin P.
        • Uher R.
        Interaction between stress and the BDNFVal66Met polymorphism in depression: a systematic review and meta-analysis.
        BMC Med. 2014; 12: 7
        • Hosang G.M.
        • Uher R.
        • Keers R.
        • Cohen-Woods S.
        • Craig I.
        • Korszun A.
        • et al.
        Stressful life events and the brain-derived neurotrophic factor gene in bipolar disorder.
        J Affect Disord. 2010; 125: 345-349
        • Alemany S.
        • Arias B.
        • Aguilera M.
        • Villa H.
        • Moya J.
        • Ibáñez M.I.
        • et al.
        Childhood abuse, the BDNF-Val66Met polymorphism and adult psychotic-like experiences.
        Br J Psychiatry. 2011; 199: 38-42
        • Balliu B.
        • Carcamo-Orive I.
        • Gloudemans M.J.
        • Nachun D.C.
        • Durrant M.G.
        • Gazal S.
        • et al.
        An integrated approach to identify environmental modulators of genetic risk factors for complex traits.
        Am J Hum Genet. 2021; 108: 1866-1879
        • Zhernakova D.V.
        • Deelen P.
        • Vermaat M.
        • van Iterson M.
        • van Galen M.
        • Arindrarto W.
        • et al.
        Identification of context-dependent expression quantitative trait loci in whole blood [no. 1].
        Nat Genet. 2017; 49: 139-145
        • Mu Z.
        • Wei W.
        • Fair B.
        • Miao J.
        • Zhu P.
        • Li Y.I.
        The impact of cell type and context-dependent regulatory variants on human immune traits.
        Genome Biol. 2021; 22: 122
        • Huan T.
        • Joehanes R.
        • Song C.
        • Peng F.
        • Guo Y.
        • Mendelson M.
        • et al.
        Genome-wide identification of DNA methylation QTLs in whole blood highlights pathways for cardiovascular disease [no. 1].
        Nat Commun. 2019; 10: 4267
        • Keele G.R.
        • Quach B.C.
        • Israel J.W.
        • Chappell G.A.
        • Lewis L.
        • Safi A.
        • et al.
        Integrative QTL analysis of gene expression and chromatin accessibility identifies multi-tissue patterns of genetic regulation.
        PLOS Genet. 2020; 16e1008537
        • Knowles D.A.
        • Davis J.R.
        • Edgington H.
        • Raj A.
        • Favé M.-J.
        • Zhu X.
        • et al.
        Allele-specific expression reveals interactions between genetic variation and environment [no. 7].
        Nat Methods. 2017; 14: 699-702
        • Ng B.
        • White C.C.
        • Klein H.-U.
        • Sieberts S.K.
        • McCabe C.
        • Patrick E.
        • et al.
        An xQTL map integrates the genetic architecture of the human brain’s transcriptome and epigenome [no. 10].
        Nat Neurosci. 2017; 20: 1418-1426
        • Vaucher J.
        • Keating B.J.
        • Lasserre A.M.
        • Gan W.
        • Lyall D.M.
        • Ward J.
        • et al.
        Cannabis use and risk of schizophrenia: a Mendelian randomization study.
        Mol Psychiatry. 2018; 23: 1287-1292
        • Heilbron K.
        • Jensen M.P.
        • Bandres-Ciga S.
        • Fontanillas P.
        • Blauwendraat C.
        • Nalls M.A.
        • et al.
        Unhealthy Behaviours and Risk of Parkinson’s Disease: A Mendelian Randomisation Study.
        J Park Dis. 2021; 11 (–1993): 1981
        • Yang H.
        • Liu D.
        • Zhao C.
        • Feng B.
        • Lu W.
        • Yang X.
        • et al.
        Mendelian randomization integrating GWAS and eQTL data revealed genes pleiotropically associated with major depressive disorder [no. 1].
        Transl Psychiatry. 2021; 11: 1-9
        • Liu D.
        • Wang Y.
        • Jing H.
        • Meng Q.
        • Yang J.
        Mendelian randomization integrating GWAS and mQTL data identified novel pleiotropic DNA methylation loci for neuropathology of Alzheimer’s disease.
        Neurobiol Aging. 2021; 97: 18-27
        • Jareborg N.
        • Birney E.
        • Durbin R.
        Comparative Analysis of Noncoding Regions of 77 Orthologous Mouse and Human Gene Pairs.
        Genome Res. 1999; 9: 815-824
        • Aguet F.
        • Brown A.A.
        • Castel S.E.
        • Davis J.R.
        • He Y.
        • Jo B.
        • et al.
        Genetic effects on gene expression across human tissues.
        Nature. 2017; 550: 204-213
        • Wen Z.
        • Nguyen H.N.
        • Guo Z.
        • Lalli M.A.
        • Wang X.
        • Su Y.
        • et al.
        Synaptic dysregulation in a human iPS cell model of mental disorders [no. 7527].
        Nature. 2014; 515: 414-418
        • Canals I.
        • Ginisty A.
        • Quist E.
        • Timmerman R.
        • Fritze J.
        • Miskinyte G.
        • et al.
        Rapid and efficient induction of functional astrocytes from human pluripotent stem cells.
        Nat Methods. 2018; 15: 693-696
        • McQuade A.
        • Coburn M.
        • Tu C.H.
        • Hasselmann J.
        • Davtyan H.
        • Blurton-Jones M.
        Development and validation of a simplified method to generate human microglia from pluripotent stem cells.
        Mol Neurodegener. 2018; 13: 67
        • Zhang Y.
        • Pak C.
        • Han Y.
        • Ahlenius H.
        • Zhang Z.
        • Chanda S.
        • et al.
        Rapid single-step induction of functional neurons from human pluripotent stem cells.
        Neuron. 2013; 78: 785-798
        • Yang N.
        • Chanda S.
        • Marro S.
        • Ng Y.-H.
        • Janas J.A.
        • Haag D.
        • et al.
        Generation of pure GABAergic neurons by transcription factor programming [no. 6].
        Nat Methods. 2017; 14: 621-628
        • Powell S.K.
        • O’Shea C.
        • Townsley K.
        • Prytkova I.
        • Dobrindt K.
        • Elahi R.
        • et al.
        Induction of dopaminergic neurons for neuronal subtype-specific modeling of psychiatric disease risk.
        Mol Psychiatry. 2021; : 1-13
        • Lu J.
        • Zhong X.
        • Liu H.
        • Hao L.
        • Huang C.T.-L.
        • Sherafat M.A.
        • et al.
        Generation of serotonin neurons from human pluripotent stem cells.
        Nat Biotechnol. 2016; 34: 89-94
        • Hoffman G.E.
        • Hartley B.J.
        • Flaherty E.
        • Ladran I.
        • Gochman P.
        • Ruderfer D.M.
        • et al.
        Transcriptional signatures of schizophrenia in hiPSC-derived NPCs and neurons are concordant with post-mortem adult brains [no. 1].
        Nat Commun. 2017; 8: 2225
        • Chen H.M.
        • DeLong C.J.
        • Bame M.
        • Rajapakse I.
        • Herron T.J.
        • McInnis M.G.
        • O’Shea K.S.
        Transcripts involved in calcium signaling and telencephalic neuronal fate are altered in induced pluripotent stem cells from bipolar disorder patients.
        Transl Psychiatry. 2014; 4: e375
        • Vadodaria K.C.
        • Ji Y.
        • Skime M.
        • Paquola A.
        • Nelson T.
        • Hall-Flavin D.
        • et al.
        Serotonin-induced hyperactivity in SSRI-resistant major depressive disorder patient-derived neurons [no. 6].
        Mol Psychiatry. 2019; 24: 795-807
        • Volkow N.D.
        • Wise R.A.
        • Baler R.
        The dopamine motive system: implications for drug and food addiction [no. 12].
        Nat Rev Neurosci. 2017; 18: 741-752
        • Vierbuchen T.
        • Ostermeier A.
        • Pang Z.P.
        • Kokubu Y.
        • Südhof T.C.
        • Wernig M.
        Direct conversion of fibroblasts to functional neurons by defined factors.
        Nature. 2010; 463: 1035-1041
        • Tanabe K.
        • Ang C.E.
        • Chanda S.
        • Olmos V.H.
        • Haag D.
        • Levinson D.F.
        • et al.
        Transdifferentiation of human adult peripheral blood T cells into neurons.
        Proc Natl Acad Sci U S A. 2018; 115: 6470-6475
        • Huh C.J.
        • Zhang B.
        • Victor M.B.
        • Dahiya S.
        • Batista L.F.
        • Horvath S.
        • Yoo A.S.
        Maintenance of age in human neurons generated by microRNA-based neuronal conversion of fibroblasts.
        eLife. 2016; 5e18648
        • Grath A.
        • Dai G.
        Direct cell reprogramming for tissue engineering and regenerative medicine.
        J Biol Eng. 2019; 13: 14
        • Pfisterer U.
        • Kirkeby A.
        • Torper O.
        • Wood J.
        • Nelander J.
        • Dufour A.
        • et al.
        Direct conversion of human fibroblasts to dopaminergic neurons.
        Proc Natl Acad Sci U S A. 2011; 108: 10343-10348
        • Dong X.
        • Li X.
        • Chang T.-W.
        • Scherzer C.R.
        • Weiss S.T.
        • Qiu W.
        powerEQTL: an R package and shiny application for sample size and power calculation of bulk tissue and single-cell eQTL analysis.
        Bioinformatics. 2021; 37: 4269-4271
        • Schrode N.
        • Ho S.-M.
        • Yamamuro K.
        • Dobbyn A.
        • Huckins L.
        • Matos M.R.
        • et al.
        Synergistic effects of common schizophrenia risk variants.
        Nat Genet. 2019; 51: 1475-1485
        • DeBoever C.
        • Li H.
        • Jakubosky D.
        • Benaglio P.
        • Reyna J.
        • Olson K.M.
        • et al.
        Large-Scale Profiling Reveals the Influence of Genetic Variation on Gene Expression in Human Induced Pluripotent Stem Cells.
        Cell Stem Cell. 2017; 20 (e7): 533-546
        • Hoffman G.E.
        • Bendl J.
        • Voloudakis G.
        • Montgomery K.S.
        • Sloofman L.
        • Wang Y.-C.
        • et al.
        CommonMind Consortium provides transcriptomic and epigenomic data for Schizophrenia and Bipolar Disorder.
        Sci Data. 2019; 6: 180
        • Mitchell J.M.
        • Nemesh J.
        • Ghosh S.
        • Handsaker R.E.
        • Mello C.J.
        • Meyer D.
        • et al.
        Mapping Genetic Effects on Cellular Phenotypes with “Cell Villages.
        Genetics. 2020; https://doi.org/10.1101/2020.06.29.174383
        • Di Lullo E.
        • Kriegstein A.R.
        The use of brain organoids to investigate neural development and disease [no. 10].
        Nat Rev Neurosci. 2017; 18: 573-584
        • Quadrato G.
        • Nguyen T.
        • Macosko E.Z.
        • Sherwood J.L.
        • Min Yang S.
        • Berger D.R.
        • et al.
        Cell diversity and network dynamics in photosensitive human brain organoids.
        Nature. 2017; 545: 48-53
        • Madhavan M.
        • Nevin Z.S.
        • Shick H.E.
        • Garrison E.
        • Clarkson-Paredes C.
        • Karl M.
        • et al.
        Induction of myelinating oligodendrocytes in human cortical spheroids [no. 9].
        Nat Methods. 2018; 15: 700-706
        • Camp J.G.
        • Badsha F.
        • Florio M.
        • Kanton S.
        • Gerber T.
        • Wilsch-Bräuninger M.
        • et al.
        Human cerebral organoids recapitulate gene expression programs of fetal neocortex development.
        Proc Natl Acad Sci U S A. 2015; 112: 15672-15677
        • Luo C.
        • Lancaster M.A.
        • Castanon R.
        • Nery J.R.
        • Knoblich J.A.
        • Ecker J.R.
        Cerebral Organoids Recapitulate Epigenomic Signatures of the Human Fetal Brain.
        Cell Rep. 2016; 17: 3369-3384
        • Lancaster M.A.
        • Renner M.
        • Martin C.-A.
        • Wenzel D.
        • Bicknell L.S.
        • Hurles M.E.
        • et al.
        Cerebral organoids model human brain development and microcephaly.
        Nature. 2013; 501: 373-379
        • Sidhaye J.
        • Knoblich J.A.
        Brain organoids: an ensemble of bioassays to investigate human neurodevelopment and disease [no. 1].
        Cell Death Differ. 2021; 28: 52-67
        • Xiang Y.
        • Tanaka Y.
        • Cakir B.
        • Patterson B.
        • Kim K.-Y.
        • Sun P.
        • et al.
        hESC-Derived Thalamic Organoids Form Reciprocal Projections When Fused with Cortical Organoids.
        Cell Stem Cell. 2019; 24 (e7): 487-497
        • Qian X.
        • Jacob F.
        • Song M.M.
        • Nguyen H.N.
        • Song H.
        • Ming G.-L.
        Generation of human brain region-specific organoids using a miniaturized spinning bioreactor.
        Nat Protoc. 2018; 13: 565-580
        • Muguruma K.
        • Nishiyama A.
        • Kawakami H.
        • Hashimoto K.
        • Sasai Y.
        Self-organization of polarized cerebellar tissue in 3D culture of human pluripotent stem cells.
        Cell Rep. 2015; 10: 537-550
        • Jo J.
        • Xiao Y.
        • Sun A.X.
        • Cukuroglu E.
        • Tran H.-D.
        • Göke J.
        • et al.
        Midbrain-like Organoids from Human Pluripotent Stem Cells Contain Functional Dopaminergic and Neuromelanin-Producing Neurons.
        Cell Stem Cell. 2016; 19: 248-257
        • Gong Q.
        • Puthusseryppady V.
        • Dai J.
        • He M.
        • Xu X.
        • Shi Y.
        • et al.
        Dysconnectivity of the medio-dorsal thalamic nucleus in drug-naïve first episode schizophrenia: diagnosis-specific or trans-diagnostic effect? [no. 1].
        Transl Psychiatry. 2019; 9: 1-9
        • Anand A.
        • Li Y.
        • Wang Y.
        • Wu J.
        • Gao S.
        • Bukhari L.
        • et al.
        Activity and Connectivity of Brain Mood Regulating Circuit in Depression: A Functional Magnetic Resonance Study.
        Biol Psychiatry. 2005; 57: 1079-1088
        • Yin Y.
        • Jin C.
        • Hu X.
        • Duan L.
        • Li Z.
        • Song M.
        • et al.
        Altered resting-state functional connectivity of thalamus in earthquake-induced posttraumatic stress disorder: A functional magnetic resonance imaging study.
        Brain Res. 2011; 1411: 98-107
        • Smits L.M.
        • Reinhardt L.
        • Reinhardt P.
        • Glatza M.
        • Monzel A.S.
        • Stanslowsky N.
        • et al.
        Modeling Parkinson’s disease in midbrain-like organoids [no. 1].
        Npj Park Dis. 2019; 5: 1-8
        • Xu R.
        • Brawner A.T.
        • Li S.
        • Liu J.-J.
        • Kim H.
        • Xue H.
        • et al.
        OLIG2 Drives Abnormal Neurodevelopmental Phenotypes in Human iPSC-Based Organoid and Chimeric Mouse Models of Down Syndrome.
        Cell Stem Cell. 2019; 24 (e8): 908-926
        • Mariani J.
        • Coppola G.
        • Zhang P.
        • Abyzov A.
        • Provini L.
        • Tomasini L.
        • et al.
        FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders.
        Cell. 2015; 162: 375-390
        • Notaras M.
        • Lodhi A.
        • Dündar F.
        • Collier P.
        • Sayles N.M.
        • Tilgner H.
        • et al.
        Schizophrenia is defined by cell-specific neuropathology and multiple neurodevelopmental mechanisms in patient-derived cerebral organoids.
        Mol Psychiatry. 2021; : 1-19
        • Miura Y.
        • Li M.-Y.
        • Revah O.
        • Yoon S.-J.
        • Narazaki G.
        • Pașca S.P.
        Engineering brain assembloids to interrogate human neural circuits.
        Nat Protoc. 2022; 17: 15-35
        • Dang J.
        • Tiwari S.K.
        • Lichinchi G.
        • Qin Y.
        • Patil V.S.
        • Eroshkin A.M.
        • Rana T.M.
        Zika Virus Depletes Neural Progenitors in Human Cerebral Organoids through Activation of the Innate Immune Receptor TLR3.
        Cell Stem Cell. 2016; 19: 258-265
        • Xu M.
        • Lee E.M.
        • Wen Z.
        • Cheng Y.
        • Huang W.-K.
        • Qian X.
        • et al.
        Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen.
        Nat Med. 2016; 22: 1101-1107
        • Pașca A.M.
        • Park J.-Y.
        • Shin H.-W.
        • Qi Q.
        • Revah O.
        • Krasnoff R.
        • et al.
        Human 3D cellular model of hypoxic brain injury of prematurity.
        Nat Med. 2019; 25: 784-791
        • Khan T.A.
        • Revah O.
        • Gordon A.
        • Yoon S.-J.
        • Krawisz A.K.
        • Goold C.
        • et al.
        Neuronal defects in a human cellular model of 22q11.2 deletion syndrome [no. 12].
        Nat Med. 2020; 26 (–1898): 1888
        • Ormel P.R.
        • Vieira de Sá R.
        • van Bodegraven E.J.
        • Karst H.
        • Harschnitz O.
        • Sneeboer M.A.M.
        • et al.
        Microglia innately develop within cerebral organoids [no. 1].
        Nat Commun. 2018; 9: 4167
        • Cruceanu C.
        • Dony L.
        • Krontira A.C.
        • Fischer D.S.
        • Roeh S.
        • Di Giaimo R.
        • et al.
        Cell-Type-Specific Impact of Glucocorticoid Receptor Activation on the Developing Brain: A Cerebral Organoid Study.
        Am J Psychiatry appiajp202121010095. 2021;
      8. Narazaki G, Miura Y, Pavlov SD, Thete MV, Roth JG, Shin S, et al. (2022, March 18): Biocompatible polymers for scalable production of human neural organoids. bioRxiv, p 2022.03.18.484949.

        • Avila Cobos F.
        • Alquicira-Hernandez J.
        • Powell J.E.
        • Mestdagh P.
        • De Preter K.
        Benchmarking of cell type deconvolution pipelines for transcriptomics data [no. 1].
        Nat Commun. 2020; 11: 5650
        • Inoue F.
        • Kreimer A.
        • Ashuach T.
        • Ahituv N.
        • Yosef N.
        Identification and Massively Parallel Characterization of Regulatory Elements Driving Neural Induction.
        Cell Stem Cell. 2019; 25 (e10): 713-727
        • Uebbing S.
        • Gockley J.
        • Reilly S.K.
        • Kocher A.A.
        • Geller E.
        • Gandotra N.
        • et al.
        Massively parallel discovery of human-specific substitutions that alter enhancer activity.
        Proc Natl Acad Sci U S A. 2021; 118e2007049118
        • Albert F.W.
        • Kruglyak L.
        The role of regulatory variation in complex traits and disease.
        Nat Rev Genet. 2015; 16: 197-212
        • Kreimer A.
        • Ashuach T.
        • Inoue F.
        • Khodaverdian A.
        • Deng C.
        • Yosef N.
        • Ahituv N.
        Massively parallel reporter perturbation assays uncover temporal regulatory architecture during neural differentiation [no. 1].
        Nat Commun. 2022; 13: 1504
        • Nott A.
        • Holtman I.R.
        • Coufal N.G.
        • Schlachetzki J.C.M.
        • Yu M.
        • Hu R.
        • et al.
        Brain cell type-specific enhancer-promoter interactome maps and disease-risk association.
        Science. 2019; 366: 1134-1139
        • Tewhey R.
        • Kotliar D.
        • Park D.S.
        • Liu B.
        • Winnicki S.
        • Reilly S.K.
        • et al.
        Direct Identification of Hundreds of Expression-Modulating Variants using a Multiplexed Reporter Assay.
        Cell. 2016; 165: 1519-1529
        • Komor A.C.
        • Kim Y.B.
        • Packer M.S.
        • Zuris J.A.
        • Liu D.R.
        Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage.
        Nature. 2016; 533: 420-424
        • Anzalone A.V.
        • Randolph P.B.
        • Davis J.R.
        • Sousa A.A.
        • Koblan L.W.
        • Levy J.M.
        • et al.
        Search-and-replace genome editing without double-strand breaks or donor DNA.
        Nature. 2019; 576: 149-157
        • Larson M.H.
        • Gilbert L.A.
        • Wang X.
        • Lim W.A.
        • Weissman J.S.
        • Qi L.S.
        CRISPR interference (CRISPRi) for sequence-specific control of gene expression.
        Nat Protoc. 2013; 8: 2180-2196
        • Hilton I.B.
        • D’Ippolito A.M.
        • Vockley C.M.
        • Thakore P.I.
        • Crawford G.E.
        • Reddy T.E.
        • Gersbach C.A.
        Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers.
        Nat Biotechnol. 2015; 33: 510-517
        • Xie S.
        • Duan J.
        • Li B.
        • Zhou P.
        • Hon G.C.
        Multiplexed Engineering and Analysis of Combinatorial Enhancer Activity in Single Cells.
        Mol Cell. 2017; 66 (e5): 285-299
        • Fulco C.P.
        • Nasser J.
        • Jones T.R.
        • Munson G.
        • Bergman D.T.
        • Subramanian V.
        • et al.
        Activity-by-contact model of enhancer-promoter regulation from thousands of CRISPR perturbations.
        Nat Genet. 2019; 51: 1664-1669
        • Tian R.
        • Abarientos A.
        • Hong J.
        • Hashemi S.H.
        • Yan R.
        • Dräger N.
        • et al.
        Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis [no. 7].
        Nat Neurosci. 2021; 24: 1020-1034
        • Sanchez C.G.
        • Acker C.M.
        • Gray A.
        • Varadarajan M.
        • Song C.
        • Cochran N.R.
        • et al.
        Genome-wide CRISPR screen identifies protein pathways modulating tau protein levels in neurons [no. 1].
        Commun Biol. 2021; 4: 1-14
        • Shi J.
        • Wang E.
        • Milazzo J.P.
        • Wang Z.
        • Kinney J.B.
        • Vakoc C.R.
        Discovery of cancer drug targets by CRISPR-Cas9 screening of protein domains.
        Nat Biotechnol. 2015; 33: 661-667
        • Maranville J.C.
        • Luca F.
        • Richards A.L.
        • Wen X.
        • Witonsky D.B.
        • Baxter S.
        • et al.
        Interactions between Glucocorticoid Treatment and Cis-Regulatory Polymorphisms Contribute to Cellular Response Phenotypes.
        PLOS Genet. 2011; 7e1002162
        • Lee M.N.
        • Ye C.
        • Villani A.-C.
        • Raj T.
        • Li W.
        • Eisenhaure T.M.
        • et al.
        Common genetic variants modulate pathogen-sensing responses in human dendritic cells.
        Science. 2014; 3431246980
        • Ye C.J.
        • Feng T.
        • Kwon H.-K.
        • Raj T.
        • Wilson M.T.
        • Asinovski N.
        • et al.
        Intersection of population variation and autoimmunity genetics in human T cell activation.
        Science. 2014; 3451254665
        • Fairfax B.P.
        • Humburg P.
        • Makino S.
        • Naranbhai V.
        • Wong D.
        • Lau E.
        • et al.
        Innate immune activity conditions the effect of regulatory variants upon monocyte gene expression.
        Science. 2014; 3431246949
        • Quach H.
        • Rotival M.
        • Pothlichet J.
        • Loh Y.-H.E.
        • Dannemann M.
        • Zidane N.
        • et al.
        Genetic Adaptation and Neandertal Admixture Shaped the Immune System of Human Populations.
        Cell. 2016; 167 (e17): 643-656
        • Kim-Hellmuth S.
        • Bechheim M.
        • Pütz B.
        • Mohammadi P.
        • Nédélec Y.
        • Giangreco N.
        • et al.
        Genetic regulatory effects modified by immune activation contribute to autoimmune disease associations.
        Nat Commun. 2017; 8: 266
      9. Alasoo K, Rodrigues J, Danesh J, Freitag DF, Paul DS, Gaffney DJ (2019): Genetic effects on promoter usage are highly context-specific and contribute to complex traits ((S. Parker & M. I. McCarthy, editors)). eLife 8: e41673.

      10. Knowles DA, Burrows CK, Blischak JD, Patterson KM, Serie DJ, Norton N, et al. (2018): Determining the genetic basis of anthracycline-cardiotoxicity by molecular response QTL mapping in induced cardiomyocytes ((G. McVean, editor)). eLife 7: e33480.

        • Manry J.
        • Nédélec Y.
        • Fava V.M.
        • Cobat A.
        • Orlova M.
        • Thuc N.V.
        • et al.
        Deciphering the genetic control of gene expression following Mycobacterium leprae antigen stimulation.
        PLoS Genet. 2017; 13e1006952
        • Çalışkan M.
        • Baker S.W.
        • Gilad Y.
        • Ober C.
        Host genetic variation influences gene expression response to rhinovirus infection.
        PLoS Genet. 2015; 11e1005111
        • Mangravite L.M.
        • Engelhardt B.E.
        • Medina M.W.
        • Smith J.D.
        • Brown C.D.
        • Chasman D.I.
        • et al.
        A statin-dependent QTL for GATM expression is associated with statin-induced myopathy.
        Nature. 2013; 502: 377-380
        • Skene N.G.
        • Bryois J.
        • Bakken T.E.
        • Breen G.
        • Crowley J.J.
        • Gaspar H.A.
        • et al.
        Genetic identification of brain cell types underlying schizophrenia [no. 6].
        Nat Genet. 2018; 50: 825-833
        • Nakazawa K.
        • Zsiros V.
        • Jiang Z.
        • Nakao K.
        • Kolata S.
        • Zhang S.
        • Belforte J.E.
        GABAergic interneuron origin of schizophrenia pathophysiology.
        Neuropharmacology. 2012; 62: 1574-1583
        • Steullet P.
        • Cabungcal J.-H.
        • Bukhari S.A.
        • Ardelt M.I.
        • Pantazopoulos H.
        • Hamati F.
        • et al.
        The thalamic reticular nucleus in schizophrenia and bipolar disorder: role of parvalbumin-expressing neuron networks and oxidative stress [no. 10].
        Mol Psychiatry. 2018; 23: 2057-2065
        • Hauberg M.E.
        • Creus-Muncunill J.
        • Bendl J.
        • Kozlenkov A.
        • Zeng B.
        • Corwin C.
        • et al.
        Common schizophrenia risk variants are enriched in open chromatin regions of human glutamatergic neurons [no. 1].
        Nat Commun. 2020; 11: 5581
        • Marconi A.
        • Di Forti M.
        • Lewis C.M.
        • Murray R.M.
        • Vassos E.
        Meta-analysis of the Association Between the Level of Cannabis Use and Risk of Psychosis.
        Schizophr Bull. 2016; 42: 1262-1269
        • Hoseth E.Z.
        • Ueland T.
        • Dieset I.
        • Birnbaum R.
        • Shin J.H.
        • Kleinman J.E.
        • et al.
        A Study of TNF Pathway Activation in Schizophrenia and Bipolar Disorder in Plasma and Brain Tissue.
        Schizophr Bull. 2017; 43: 881-890
        • Borovcanin M.M.
        • Jovanovic I.
        • Radosavljevic G.
        • Pantic J.
        • Minic Janicijevic S.
        • Arsenijevic N.
        • Lukic M.L.
        Interleukin-6 in Schizophrenia—Is There a Therapeutic Relevance?.
        Front Psychiatry. 2017; 8: 221
        • Bagalkote H.
        • Pang D.
        • Jones P.B.
        Maternal Influenza and Schizophrenia in the Offspring.
        Int J Ment Health. 2000; 29: 3-21
        • Akkouh I.A.
        • Hribkova H.
        • Grabiec M.
        • Budinska E.
        • Szabo A.
        • Kasparek T.
        • et al.
        Derivation and Molecular Characterization of a Morphological Subpopulation of Human iPSC Astrocytes Reveal a Potential Role in Schizophrenia and Clozapine Response.
        Schizophr Bull. 2022; 48: 190-198
      11. Watkins CC, Sawa A, Pomper MG (2014): Glia and immune cell signaling in bipolar disorder: insights from neuropharmacology and molecular imaging to clinical application [no. 1]. Transl Psychiatry 4: e350–e350.

        • Mertens J.
        • Wang Q.-W.
        • Kim Y.
        • Yu D.X.
        • Pham S.
        • Yang B.
        • et al.
        Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder.
        Nature. 2015; 527: 95-99
        • Howard D.
        • Negraes P.
        • Voineskos A.N.
        • Kaplan A.S.
        • Muotri A.R.
        • Duvvuri V.
        • French L.
        Molecular neuroanatomy of anorexia nervosa [no. 1].
        Sci Rep. 2020; 1011411
        • Hayakawa K.
        • Sakamoto Y.
        • Kanie O.
        • Ohtake A.
        • Daikoku S.
        • Ito Y.
        • Shiota K.
        Reactivation of hyperglycemia-induced hypocretin (HCRT) gene silencing by N-acetyl-d-mannosamine in the orexin neurons derived from human iPS cells.
        Epigenetics. 2017; 12: 764-778
      12. Negraes PD, Cugola FR, Herai RH, Trujillo CA, Cristino AS, Chailangkarn T, et al. (2017): Modeling anorexia nervosa: transcriptional insights from human iPSC-derived neurons [no. 3]. Transl Psychiatry 7: e1060–e1060.

        • Tagami T.
        • Satoh N.
        • Usui T.
        • Yamada K.
        • Shimatsu A.
        • Kuzuya H.
        Adiponectin in Anorexia Nervosa and Bulimia Nervosa.
        J Clin Endocrinol Metab. 2004; 89: 1833-1837
        • Nisar S.
        • Bhat A.A.
        • Masoodi T.
        • Hashem S.
        • Akhtar S.
        • Ali T.A.
        • et al.
        Genetics of glutamate and its receptors in autism spectrum disorder.
        Mol Psychiatry. 2022; : 1-13
        • Guan J.
        • Wang Y.
        • Lin Y.
        • Yin Q.
        • Zhuang Y.
        • Ji G.
        Cell Type-Specific Predictive Models Perform Prioritization of Genes and Gene Sets Associated With Autism.
        Front Genet. 2021; 11 (Retrieved April 29, 2022, from)
        • Crider A.
        • Pillai A.
        Estrogen Signaling as a Therapeutic Target in Neurodevelopmental Disorders.
        J Pharmacol Exp Ther. 2017; 360: 48-58
        • Bernaerts S.
        • Boets B.
        • Bosmans G.
        • Steyaert J.
        • Alaerts K.
        Behavioral effects of multiple-dose oxytocin treatment in autism: a randomized, placebo-controlled trial with long-term follow-up.
        Mol Autism. 2020; 11: 6
        • Wang J.
        • Cheng Y.
        • Wang X.
        • Hellard E.R.
        • Ma T.
        • Gil H.
        • et al.
        Alcohol Elicits Functional and Structural Plasticity Selectively in Dopamine D1 Receptor-Expressing Neurons of the Dorsomedial Striatum.
        J Neurosci. 2015; 35: 11634-11643
        • Ben Hamida S.
        • Boulos L.-J.
        • McNicholas M.
        • Charbogne P.
        • Kieffer B.L.
        Mu opioid receptors in GABAergic neurons of the forebrain promote alcohol reward and drinking.
        Addict Biol. 2019; 24: 28-39
        • Adermark L.
        • Bowers M.S.
        Disentangling the Role of Astrocytes in Alcohol Use Disorder.
        Alcohol Clin Exp Res. 2016; 40: 1802-1816
        • Rao P.S.S.
        • Bell R.L.
        • Engleman E.A.
        • Sari Y.
        Targeting glutamate uptake to treat alcohol use disorders.
        Front Neurosci. 2015; 9 (Retrieved April 29, 2022, from)