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Path from schizophrenia genomics to biology: gene regulation and perturbation in neurons derived from induced pluripotent stem cells and genome editing

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Abstract

Schizophrenia (SZ) is a devastating mental disorder afflicting 1% of the population. Recent genome-wide association studies (GWASs) of SZ have identified >100 risk loci. However, the causal variants/genes and the causal mechanisms remain largely unknown, which hinders the translation of GWAS findings into disease biology and drug targets. Most risk variants are noncoding, thus likely regulate gene expression. A major mechanism of transcriptional regulation is chromatin remodeling, and open chromatin is a versatile predictor of regulatory sequences. MicroRNA-mediated post-transcriptional regulation plays an important role in SZ pathogenesis. Neurons differentiated from patient-specific induced pluripotent stem cells (iPSCs) provide an experimental model to characterize the genetic perturbation of regulatory variants that are often specific to cell type and/or developmental stage. The emerging genome-editing technology enables the creation of isogenic iPSCs and neurons to efficiently characterize the effects of SZ-associated regulatory variants on SZ-relevant molecular and cellular phenotypes involving dopaminergic, glutamatergic, and GABAergic neurotransmissions. SZ GWAS findings equipped with the emerging functional genomics approaches provide an unprecedented opportunity for understanding new disease biology and identifying novel drug targets.

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References

  1. Carlsson A, Lindqvist M. Effect of chlorpromazine or haloperidol on formation of 3methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol (Copenh) 1963, 20: 140–144.

    CAS  Google Scholar 

  2. Shi J, Levinson DF, Duan J, Sanders AR, Zheng Y, Pe’er I, et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 2009, 460: 753–757.

    CAS  PubMed Central  PubMed  Google Scholar 

  3. Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, Sullivan PF, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009, 460: 748–752.

    CAS  PubMed  Google Scholar 

  4. Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D, et al. Common variants conferring risk of schizophrenia. Nature 2009, 460: 744–747.

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Consortium SPG-WASG. Genome-wide association study identifies five new schizophrenia loci. Nat Genet 2011, 43: 969–976.

    Google Scholar 

  6. Ripke S, O’Dushlaine C, Chambert K, Moran JL, Kahler AK, Akterin S, et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet 2013, 45: 1150–1159.

    CAS  PubMed  Google Scholar 

  7. Consortium SWGotPG. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014, 511: 421–427.

    Google Scholar 

  8. Bassett AS, Scherer SW, Brzustowicz LM. Copy number variations in schizophrenia: critical review and new perspectives on concepts of genetics and disease. Am J Psychiatry 2010, 167: 899–914.

    PubMed Central  PubMed  Google Scholar 

  9. Levinson DF, Duan J, Oh S, Wang K, Sanders AR, Shi J, et al. Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. Am J Psychiatry 2011, 168: 302–316.

    PubMed  Google Scholar 

  10. Szatkiewicz JP, O’Dushlaine C, Chen G, Chambert K, Moran JL, Neale BM, et al. Copy number variation in schizophrenia in Sweden. Mol Psychiatry 2014, 19: 762–773.

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Purcell SM, Moran JL, Fromer M, Ruderfer D, Solovieff N, Roussos P, et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature 2014, 506: 185–190.

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Fromer M, Pocklington AJ, Kavanagh DH, Williams HJ, Dwyer S, Gormley P, et al. De novo mutations in schizophrenia implicate synaptic networks. Nature 2014, 506: 179–184.

    CAS  PubMed Central  PubMed  Google Scholar 

  13. Gulsuner S, Walsh T, Watts AC, Lee MK, Thornton AM, Casadei S, et al. Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell 2013, 154: 518–529.

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Brennand KJ, Simone A, Tran N, Gage FH. Modeling psychiatric disorders at the cellular and network levels. Mol Psychiatry 2012, 17: 1239–1253.

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Penzes P, Cahill ME, Jones KA, VanLeeuwen JE, Woolfrey KM. Dendritic spine pathology in neuropsychiatric disorders. Nat Neurosci 2011, 14: 285–293.

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Brennand KJ, Gage FH. Concise review: the promise of human induced pluripotent stem cell-based studies of schizophrenia. Stem Cells 2011, 29: 1915–1922.

    CAS  PubMed Central  PubMed  Google Scholar 

  17. Rapoport JL, Giedd JN, Blumenthal J, Hamburger S, Jeffries N, Fernandez T, et al. Progressive cortical change during adolescence in childhood-onset schizophrenia. A longitudinal magnetic resonance imaging study. Arch Gen Psychiatry 1999, 56: 649–654.

    CAS  PubMed  Google Scholar 

  18. Goghari VM, Rehm K, Carter CS, MacDonald AW, 3rd. Regionally specific cortical thinning and gray matter abnormalities in the healthy relatives of schizophrenia patients. Cereb Cortex 2007, 17: 415–424.

    PubMed  Google Scholar 

  19. Lewis DA, Gonzalez-Burgos G. Neuroplasticity of neocortical circuits in schizophrenia. Neuropsychopharmacology 2008, 33: 141–165.

    PubMed  Google Scholar 

  20. Harris KM. Structure, development, and plasticity of dendritic spines. Curr Opin Neurobiol 1999, 9: 343–348.

    CAS  PubMed  Google Scholar 

  21. Prasad KM, Goradia D, Eack S, Rajagopalan M, Nutche J, Magge T, et al. Cortical surface characteristics among offspring of schizophrenia subjects. Schizophr Res 2010, 116: 143–151.

    PubMed Central  PubMed  Google Scholar 

  22. Harms MP, Wang L, Campanella C, Aldridge K, Moffitt AJ, Kuelper J, et al. Structural abnormalities in gyri of the prefrontal cortex in individuals with schizophrenia and their unaffected siblings. Br J Psychiatry 2010, 196: 150–157.

    PubMed Central  PubMed  Google Scholar 

  23. Karlsgodt KH, Sun D, Jimenez AM, Lutkenhoff ES, Willhite R, van Erp TG, et al. Developmental disruptions in neural connectivity in the pathophysiology of schizophrenia. Dev Psychopathol 2008, 20: 1297–1327.

    PubMed  Google Scholar 

  24. Kushima I, Nakamura Y, Aleksic B, Ikeda M, Ito Y, Shiino T, et al. Resequencing and association analysis of the KALRN and EPHB1 genes and their contribution to schizophrenia susceptibility. Schizophr Bull 2012, 38: 552–560.

    PubMed Central  PubMed  Google Scholar 

  25. Hill JJ, Hashimoto T, Lewis DA. Molecular mechanisms contributing to dendritic spine alterations in the prefrontal cortex of subjects with schizophrenia. Mol Psychiatry 2006, 11: 557–566.

    CAS  PubMed  Google Scholar 

  26. Sebat J, Levy DL, McCarthy SE. Rare structural variants in schizophrenia: one disorder, multiple mutations; one mutation, multiple disorders. Trends Genet 2009, 25: 528–535.

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Myers RA, Casals F, Gauthier J, Hamdan FF, Keebler J, Boyko AR, et al. A population genetic approach to mapping neurological disorder genes using deep resequencing. PLoS Genet 2011, 7: e1001318.

    CAS  PubMed Central  PubMed  Google Scholar 

  28. King MC, Wilson AC. Evolution at two levels in humans and chimpanzees. Science 1975, 188: 107–116.

    CAS  PubMed  Google Scholar 

  29. Duan J, Sanders AR, Gejman PV. Genome-wide approaches to schizophrenia. Brain Res Bull 2010, 83: 93–102.

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Duan J, Wainwright MS, Comeron JM, Saitou N, Sanders AR, Gelernter J, et al. Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. Hum Mol Genet 2003, 12: 205–216.

    CAS  PubMed  Google Scholar 

  31. Duan J, Shi J, Ge X, Dolken L, Moy W, He D, et al. Genomewide survey of interindividual differences of RNA stability in human lymphoblastoid cell lines. Sci Rep 2013, 3: 1318.

    PubMed Central  PubMed  Google Scholar 

  32. Shi S, Leites C, He D, Schwartz D, Moy W, Shi J, et al. MicroRNA-9 and microRNA-326 regulate human dopamine D2 receptor expression and the microRNA-mediated expression regulation is altered by a genetic variant. J Biol Chem 2014, 289: 13434–13444.

    CAS  PubMed  Google Scholar 

  33. Cookson W, Liang L, Abecasis G, Moffatt M, Lathrop M. Mapping complex disease traits with global gene expression. Nat Rev Genet 2009, 10: 184–194.

    CAS  PubMed  Google Scholar 

  34. He X, Fuller CK, Song Y, Meng Q, Zhang B, Yang X, et al. Sherlock: detecting gene-disease associations by matching patterns of expression QTL and GWAS. Am J Hum Genet 2013, 92: 667–680.

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Richards AL, Jones L, Moskvina V, Kirov G, Gejman PV, Levinson DF, et al. Schizophrenia susceptibility alleles are enriched for alleles that affect gene expression in adult human brain. Mol Psychiatry 2012, 17: 193–201.

    CAS  PubMed  Google Scholar 

  36. Lipska BK, Deep-Soboslay A, Weickert CS, Hyde TM, Martin CE, Herman MM, et al. Critical factors in gene expression in postmortem human brain: Focus on studies in schizophrenia. Biol Psychiatry 2006, 60: 650–658.

    CAS  PubMed  Google Scholar 

  37. Nica AC, Ongen H, Irminger JC, Bosco D, Berney T, Antonarakis SE, et al. Cell-type, allelic, and genetic signatures in the human pancreatic beta cell transcriptome. Genome Res 2013, 23: 1554–1562.

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Civelek M, Lusis AJ. Systems genetics approaches to understand complex traits. Nat Rev Genet 2014, 15: 34–48.

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Paul DS, Soranzo N, Beck S. Functional interpretation of non-coding sequence variation: concepts and challenges. Bioessays 2014, 36: 191–199.

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Kellis M, Wold B, Snyder MP, Bernstein BE, Kundaje A, Marinov GK, et al. Defining functional DNA elements in the human genome. Proc Natl Acad Sci U S A 2014, 111: 6131–6138.

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Thurman RE, Rynes E, Humbert R, Vierstra J, Maurano MT, Haugen E, et al. The accessible chromatin landscape of the human genome. Nature 2012, 489: 75–82.

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Bernstein BE, Stamatoyannopoulos JA, Costello JF, Ren B, Milosavljevic A, Meissner A, et al. The NIH Roadmap Epigenomics Mapping Consortium. Nat Biotechnol 2010, 28: 1045–1048.

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Dunham I, Kundaje A, Aldred SF, Collins PJ, Davis CA, Doyle F, et al. An integrated encyclopedia of DNA elements in the human genome. Nature 2012, 489: 57–74.

    CAS  Google Scholar 

  44. Ritchie GR, Dunham I, Zeggini E, Flicek P. Functional annotation of noncoding sequence variants. Nat Methods 2014, 11: 294–296.

    CAS  PubMed  Google Scholar 

  45. Kornberg RD, Thomas JO. Chromatin structure; oligomers of the histones. Science 1974, 184: 865–868.

    CAS  PubMed  Google Scholar 

  46. Voss TC, Hager GL. Dynamic regulation of transcriptional states by chromatin and transcription factors. Nat Rev Genet 2014, 15: 69–81.

    CAS  PubMed  Google Scholar 

  47. Furey TS, Sethupathy P. Genetics. Genetics driving epigenetics. Science 2013, 342: 705–706.

    CAS  PubMed  Google Scholar 

  48. Stower H. Gene regulation: from genetic variation to phenotype via chromatin. Nat Rev Genet 2013, 14: 824.

    CAS  PubMed  Google Scholar 

  49. Kilpinen H, Waszak SM, Gschwind AR, Raghav SK, Witwicki RM, Orioli A, et al. Coordinated effects of sequence variation on DNA binding, chromatin structure, and transcription. Science 2013, 342: 744–747.

    CAS  PubMed  Google Scholar 

  50. Kasowski M, Kyriazopoulou-Panagiotopoulou S, Grubert F, Zaugg JB, Kundaje A, Liu Y, et al. Extensive variation in chromatin states across humans. Science 2013, 342: 750–752.

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Degner JF, Pai AA, Pique-Regi R, Veyrieras JB, Gaffney DJ, Pickrell JK, et al. DNase I sensitivity QTLs are a major determinant of human expression variation. Nature 2012, 482: 390–394.

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Shi J, Marconett CN, Duan J, Hyland PL, Li P, Wang Z, et al. Characterizing the genetic basis of methylome diversity in histologically normal human lung tissue. Nat Commun 2014, 5: 3365.

    PubMed Central  PubMed  Google Scholar 

  53. Maurano MT, Humbert R, Rynes E, Thurman RE, Haugen E, Wang H, et al. Systematic localization of common disease-associated variation in regulatory DNA. Science 2012, 337: 1190–1195.

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Maurano MT, Wang H, Kutyavin T, Stamatoyannopoulos JA. Widespread site-dependent buffering of human regulatory polymorphism. PLoS Genet 2012, 8: e1002599.

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Holt CE, Schuman EM. The central dogma decentralized: new perspectives on RNA function and local translation in neurons. Neuron 2013, 80: 648–657.

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Santini E, Huynh TN, MacAskill AF, Carter AG, Pierre P, Ruggero D, et al. Exaggerated translation causes synaptic and behavioural aberrations associated with autism. Nature 2013, 493: 411–415.

    CAS  PubMed Central  PubMed  Google Scholar 

  57. Gkogkas CG, Khoutorsky A, Ran I, Rampakakis E, Nevarko T, Weatherill DB, et al. Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature 2013, 493: 371–377.

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Miura P, Shenker S, Andreu-Agullo C, Westholm JO, Lai EC. Widespread and extensive lengthening of 3′ UTRs in the mammalian brain. Genome Res 2013, 23: 812–825.

    CAS  PubMed Central  PubMed  Google Scholar 

  59. Moreno JA, Halliday M, Molloy C, Radford H, Verity N, Axten JM, et al. Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci Transl Med 2013, 5: 206ra138.

    PubMed  Google Scholar 

  60. Im HI, Kenny PJ. MicroRNAs in neuronal function and dysfunction. Trends Neurosci 2012, 35: 325–334.

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Guarnieri DJ, DiLeone RJ. MicroRNAs: a new class of gene regulators. Ann Med 2008, 40: 197–208.

    CAS  PubMed  Google Scholar 

  62. Karayiorgou M, Simon TJ, Gogos JA. 22q11.2 microdeletions: linking DNA structural variation to brain dysfunction and schizophrenia. Nat Rev Neurosci 2010, 11: 402–416.

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Xu B, Hsu PK, Stark KL, Karayiorgou M, Gogos JA. Derepression of a neuronal inhibitor due to miRNA dysregulation in a schizophrenia-related microdeletion. Cell 2013, 152: 262–275.

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Earls LR, Fricke RG, Yu J, Berry RB, Baldwin LT, Zakharenko SS. Age-dependent microRNA control of synaptic plasticity in 22q11 deletion syndrome and schizophrenia. J Neurosci 2012, 32: 14132–14144.

    CAS  PubMed Central  PubMed  Google Scholar 

  65. Earls LR, Bayazitov IT, Fricke RG, Berry RB, Illingworth E, Mittleman G, et al. Dysregulation of presynaptic calcium and synaptic plasticity in a mouse model of 22q11 deletion syndrome. J Neurosci 2010, 30: 15843–15855.

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Lee SH, DeCandia TR, Ripke S, Yang J, Sullivan PF, Goddard ME, et al. Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs. Nat Genet 2012, 44: 247–250.

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Weng R, Cohen SM. Drosophila miR-124 regulates neuroblast proliferation through its target anachronism. Development 2012, 139: 1427–1434.

    CAS  PubMed  Google Scholar 

  68. Yu JY, Chung KH, Deo M, Thompson RC, Turner DL. MicroRNA miR-124 regulates neurite outgrowth during neuronal differentiation. Exp Cell Res 2008, 314: 2618–2633.

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Sun K, Westholm JO, Tsurudome K, Hagen JW, Lu Y, Kohwi M, et al. Neurophysiological defects and neuronal gene deregulation in Drosophila mir-124 mutants. PLoS Genet 2012, 8: e1002515.

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Rajasethupathy P, Fiumara F, Sheridan R, Betel D, Puthanveettil SV, Russo JJ, et al. Characterization of small RNAs in aplysia reveals a role for miR-124 in constraining synaptic plasticity through CREB. Neuron 2009, 63: 803–817.

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Fischbach SJ, Carew TJ. MicroRNAs in memory processing. Neuron 2009, 63: 714–716.

    CAS  PubMed  Google Scholar 

  72. Yoo AS, Staahl BT, Chen L, Crabtree GR. MicroRNA-mediated switching of chromatin-remodelling complexes in neural development. Nature 2009, 460: 642–646.

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Cheng LC, Pastrana E, Tavazoie M, Doetsch F. miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche. Nat Neurosci 2009, 12: 399–408.

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Wayman GA, Davare M, Ando H, Fortin D, Varlamova O, Cheng HY, et al. An activity-regulated microRNA controls dendritic plasticity by down-regulating p250GAP. Proc Natl Acad Sci U S A 2008, 105: 9093–9098.

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Magill ST, Cambronne XA, Luikart BW, Lioy DT, Leighton BH, Westbrook GL, et al. microRNA-132 regulates dendritic growth and arborization of newborn neurons in the adult hippocampus. Proc Natl Acad Sci U S A 2010, 107: 20382–20387.

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Sun G, Ye P, Murai K, Lang MF, Li S, Zhang H, et al. miR-137 forms a regulatory loop with nuclear receptor TLX and LSD1 in neural stem cells. Nat Commun 2011, 2: 529.

    PubMed Central  PubMed  Google Scholar 

  77. Silber J, Lim DA, Petritsch C, Persson AI, Maunakea AK, Yu M, et al. miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med 2008, 6: 14.

    PubMed Central  PubMed  Google Scholar 

  78. Smrt RD, Szulwach KE, Pfeiffer RL, Li X, Guo W, Pathania M, et al. MicroRNA miR-137 regulates neuronal maturation by targeting ubiquitin ligase mind bomb-1. Stem Cells 2010, 28: 1060–1070.

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Szulwach KE, Li X, Smrt RD, Li Y, Luo Y, Lin L, et al. Cross talk between microRNA and epigenetic regulation in adult neurogenesis. J Cell Biol 2010, 189: 127–141.

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Volvert ML, Rogister F, Moonen G, Malgrange B, Nguyen L. MicroRNAs tune cerebral cortical neurogenesis. Cell Death Differ 2012, 19: 1573–1581.

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Miller BH, Zeier Z, Xi L, Lanz TA, Deng S, Strathmann J, et al. MicroRNA-132 dysregulation in schizophrenia has implications for both neurodevelopment and adult brain function. Proc Natl Acad Sci U S A 2012, 109: 3125–3130.

    CAS  PubMed Central  PubMed  Google Scholar 

  82. Kim AH, Reimers M, Maher B, Williamson V, McMichael O, McClay JL, et al. MicroRNA expression profiling in the prefrontal cortex of individuals affected with schizophrenia and bipolar disorders. Schizophr Res 2010, 124: 183–191.

    PubMed  Google Scholar 

  83. Brennand KJ, Simone A, Jou J, Gelboin-Burkhart C, Tran N, Sangar S, et al. Modelling schizophrenia using human induced pluripotent stem cells. Nature 2011, 473: 221–225.

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Shi Y, Kirwan P, Smith J, Robinson HP, Livesey FJ. Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses. Nat Neurosci 2012, 15: 477–486, S471.

    CAS  PubMed  Google Scholar 

  85. Pasca SP, Portmann T, Voineagu I, Yazawa M, Shcheglovitov A, Pasca AM, et al. Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat Med 2011, 17: 1657–1662.

    CAS  PubMed Central  PubMed  Google Scholar 

  86. Kriks S, Shim JW, Piao J, Ganat YM, Wakeman DR, Xie Z, et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature 2011, 480: 547–551.

    CAS  PubMed Central  PubMed  Google Scholar 

  87. Vaccarino FM, Stevens HE, Kocabas A, Palejev D, Szekely A, Grigorenko EL, et al. Induced pluripotent stem cells: a new tool to confront the challenge of neuropsychiatric disorders. Neuropharmacology 2011, 60: 1355–1363.

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Brennand K, Savas JN, Kim Y, Tran N, Simone A, Hashimoto-Torii K, et al. Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Mol Psychiatry 2014.

    Google Scholar 

  89. Carlson GC, Talbot K, Halene TB, Gandal MJ, Kazi HA, Schlosser L, et al. Dysbindin-1 mutant mice implicate reduced fast-phasic inhibition as a final common disease mechanism in schizophrenia. Proc Natl Acad Sci U S A 2011, 108: E962–970.

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Dong Z, Peng J, Guo S. Stable Gene Silencing in Zebrafish with Spatiotemporally Targetable RNA Interference. Genetics 2013.

    Google Scholar 

  91. Jeong JY, Einhorn Z, Mercurio S, Lee S, Lau B, Mione M, et al. Neurogenin1 is a determinant of zebrafish basal forebrain dopaminergic neurons and is regulated by the conserved zinc finger protein Tof/Fezl. Proc Natl Acad Sci U S A 2006, 103: 5143–5148.

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Johnson MB, Kawasawa YI, Mason CE, Krsnik Z, Coppola G, Bogdanovic D, et al. Functional and evolutionary insights into human brain development through global transcriptome analysis. Neuron 2009, 62: 494–509.

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Shen Y, Yue F, McCleary DF, Ye Z, Edsall L, Kuan S, et al. A map of the cis-regulatory sequences in the mouse genome. Nature 2012, 488: 116–120.

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Brennand KJ, Landek-Salgado MA, Sawa A. Modeling Heterogeneous Patients With a Clinical Diagnosis of Schizophrenia With Induced Pluripotent Stem Cells. Biol Psychiatry 2014, 75: 936–944.

    PubMed  Google Scholar 

  95. Seki T, Yuasa S, Fukuda K. Generation of induced pluripotent stem cells from a small amount of human peripheral blood using a combination of activated T cells and Sendai virus. Nat Protoc 2012, 7: 718–728.

    CAS  PubMed  Google Scholar 

  96. Muller FJ, Schuldt BM, Williams R, Mason D, Altun G, Papapetrou EP, et al. A bioinformatic assay for pluripotency in human cells. Nat Methods 2011, 8: 315–317.

    PubMed Central  PubMed  Google Scholar 

  97. Lister R, Pelizzola M, Kida YS, Hawkins RD, Nery JR, Hon G, et al. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 2011, 471: 68–73.

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Gore A, Li Z, Fung HL, Young JE, Agarwal S, Antosiewicz-Bourget J, et al. Somatic coding mutations in human induced pluripotent stem cells. Nature 2011, 471: 63–67.

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Hussein SM, Batada NN, Vuoristo S, Ching RW, Autio R, Narva E, et al. Copy number variation and selection during reprogramming to pluripotency. Nature 2011, 471: 58–62.

    CAS  PubMed  Google Scholar 

  100. Wright R, Rethelyi JM, Gage FH. Enhancing induced pluripotent stem cell models of schizophrenia. JAMA Psychiatry 2014, 71: 334–335.

    PubMed  Google Scholar 

  101. Nakazawa K, Zsiros V, Jiang Z, Nakao K, Kolata S, Zhang S, et al. GABAergic interneuron origin of schizophrenia pathophysiology. Neuropharmacology 2012, 62: 1574–1583.

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Nicholas CR, Chen J, Tang Y, Southwell DG, Chalmers N, Vogt D, et al. Functional maturation of hPSC-derived forebrain interneurons requires an extended timeline and mimics human neural development. Cell Stem Cell 2013, 12: 573–586.

    CAS  PubMed Central  PubMed  Google Scholar 

  103. Soldner F, Jaenisch R. Medicine. iPSC disease modeling. Science 2012, 338: 1155–1156.

    PubMed  Google Scholar 

  104. 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.

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Soldner F, Laganiere J, Cheng AW, Hockemeyer D, Gao Q, Alagappan R, et al. Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations. Cell 2011, 146: 318–331.

    CAS  PubMed Central  PubMed  Google Scholar 

  106. Hockemeyer D, Wang H, Kiani S, Lai CS, Gao Q, Cassady JP, et al. Genetic engineering of human pluripotent cells using TALE nucleases. Nat Biotechnol 2011, 29: 731–734.

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Sanjana NE, Cong L, Zhou Y, Cunniff MM, Feng G, Zhang F. A transcription activator-like effector toolbox for genome engineering. Nat Protoc 2012, 7: 171–192.

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Ding Q, Lee YK, Schaefer EA, Peters DT, Veres A, Kim K, et al. A TALEN genome-editing system for generating human stem cell-based disease models. Cell Stem Cell 2013, 12: 238–251.

    CAS  PubMed Central  PubMed  Google Scholar 

  109. Reyon D, Tsai SQ, Khayter C, Foden JA, Sander JD, Joung JK. FLASH assembly of TALENs for high-throughput genome editing. Nat Biotechnol 2012, 30: 460–465.

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Joung JK, Sander JD. TALENs: a widely applicable technology for targeted genome editing. Nat Rev Mol Cell Biol 2012, 14: 49–55.

    PubMed Central  PubMed  Google Scholar 

  111. Bedell VM, Wang Y, Campbell JM, Poshusta TL, Starker CG, Krug RG, 2nd, et al. In vivo genome editing using a high-efficiency TALEN system. Nature 2012, 491: 114–118.

    CAS  PubMed Central  PubMed  Google Scholar 

  112. Schmid-Burgk JL, Schmidt T, Kaiser V, Honing K, Hornung V. A ligation-independent cloning technique for high-throughput assembly of transcription activator-like effector genes. Nat Biotechnol 2012, 31: 76–81.

    Google Scholar 

  113. Choi SM, Kim Y, Shim JS, Park JT, Wang RH, Leach SD, et al. Efficient drug screening and gene correction for treating liver disease using patient-specific stem cells. Hepatology 2013.

    Google Scholar 

  114. Mali P, Yang L, Esvelt KM, Aach J, Guell M, DiCarlo JE, et al. RNA-guided human genome engineering via Cas9. Science 2013, 339: 823–826.

    CAS  PubMed Central  PubMed  Google Scholar 

  115. Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, et al. Multiplex genome engineering using CRISPR/Cas systems. Science 2013, 339: 819–823.

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Wang H, Yang H, Shivalila CS, Dawlaty MM, Cheng AW, Zhang F, et al. One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell 2013, 153: 910–918.

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Fu Y, Foden JA, Khayter C, Maeder ML, Reyon D, Joung JK, et al. High-frequency off-target mutagenesis induced by CRISPR-Cas nucleases in human cells. Nat Biotechnol 2013, 31: 822–826.

    CAS  PubMed Central  PubMed  Google Scholar 

  118. Sander JD, Joung JK. CRISPR-Cas systems for editing, regulating and targeting genomes. Nat Biotechnol 2014, 32: 347–355.

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Shalem O, Sanjana NE, Hartenian E, Shi X, Scott DA, Mikkelsen TS, et al. Genome-scale CRISPR-Cas9 knockout screening in human cells. Science 2014, 343: 84–87.

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F. Genome engineering using the CRISPR-Cas9 system. Nat Protoc 2013, 8: 2281–2308.

    CAS  PubMed Central  PubMed  Google Scholar 

  121. Ran FA, Hsu PD, Lin CY, Gootenberg JS, Konermann S, Trevino AE, et al. Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity. Cell 2013, 154: 1380–1389.

    CAS  PubMed  Google Scholar 

  122. MacArthur DG, Manolio TA, Dimmock DP, Rehm HL, Shendure J, Abecasis GR, et al. Guidelines for investigating causality of sequence variants in human disease. Nature 2014, 508: 469–476.

    CAS  PubMed Central  PubMed  Google Scholar 

  123. Merkle FT, Eggan K. Modeling human disease with pluripotent stem cells: from genome association to function. Cell Stem Cell 2013, 12: 656–668.

    CAS  PubMed  Google Scholar 

  124. Musunuru K, Strong A, Frank-Kamenetsky M, Lee NE, Ahfeldt T, Sachs KV, et al. From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature 2010, 466: 714–719.

    CAS  PubMed Central  PubMed  Google Scholar 

  125. Bauer DE, Kamran SC, Lessard S, Xu J, Fujiwara Y, Lin C, et al. An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Science 2013, 342: 253–257.

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Corradin O, Saiakhova A, Akhtar-Zaidi B, Myeroff L, Willis J, Cowper-Sallari R, et al. Combinatorial effects of multiple enhancer variants in linkage disequilibrium dictate levels of gene expression to confer susceptibility to common traits. Genome Res 2014, 24: 1–13.

    CAS  PubMed Central  PubMed  Google Scholar 

  127. Miller CL, Haas U, Diaz R, Leeper NJ, Kundu RK, Patlolla B, et al. Coronary heart disease-associated variation in TCF21 disrupts a miR-224 binding site and miRNA-mediated regulation. PLoS Genet 2014, 10: e1004263.

    PubMed Central  PubMed  Google Scholar 

  128. Spieler D, Kaffe M, Knauf F, Bessa J, Tena JJ, Giesert F, et al. Restless legs syndrome-associated intronic common variant in Meis1 alters enhancer function in the developing telencephalon. Genome Res 2014, 24: 592–603.

    CAS  PubMed Central  PubMed  Google Scholar 

  129. Kulzer JR, Stitzel ML, Morken MA, Huyghe JR, Fuchsberger C, Kuusisto J, et al. A common functional regulatory variant at a type 2 diabetes locus upregulates ARAP1 expression in the pancreatic beta cell. Am J Hum Genet 2014, 94: 186–197.

    CAS  PubMed Central  PubMed  Google Scholar 

  130. Buenrostro JD, Giresi PG, Zaba LC, Chang HY, Greenleaf WJ. Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat Methods 2013, 10: 1213–1218.

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Patwardhan RP, Hiatt JB, Witten DM, Kim MJ, Smith RP, May D, et al. Massively parallel functional dissection of mammalian enhancers in vivo. Nat Biotechnol 2012, 30: 265–270.

    CAS  PubMed Central  PubMed  Google Scholar 

  132. Melnikov A, Murugan A, Zhang X, Tesileanu T, Wang L, Rogov P, et al. Systematic dissection and optimization of inducible enhancers in human cells using a massively parallel reporter assay. Nat Biotechnol 2012, 30: 271–277.

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Gonzalez F, Zhu Z, Shi ZD, Lelli K, Verma N, Li QV, et al. An iCRISPR platform for rapid, multiplexable, and inducible genome editing in human pluripotent stem cells. Cell Stem Cell 2014, 15: 215–226.

    CAS  PubMed  Google Scholar 

  134. Huang ZJ, Zeng H. Genetic approaches to neural circuits in the mouse. Annu Rev Neurosci 2013, 36: 183–215.

    CAS  PubMed  Google Scholar 

  135. Oh SW, Harris JA, Ng L, Winslow B, Cain N, Mihalas S, et al. A mesoscale connectome of the mouse brain. Nature 2014, 508: 207–214.

    CAS  PubMed  Google Scholar 

  136. Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, et al. Cerebral organoids model human brain development and microcephaly. Nature 2013, 501: 373–379.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL, USA

    Jubao Duan

  2. Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL, USA

    Jubao Duan

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Duan, J. Path from schizophrenia genomics to biology: gene regulation and perturbation in neurons derived from induced pluripotent stem cells and genome editing. Neurosci. Bull. 31, 113–127 (2015). https://doi.org/10.1007/s12264-014-1488-2

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