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Investigation of Schizophrenia with Human Induced Pluripotent Stem Cells

  • Samuel K. Powell
  • Callan P. O’Shea
  • Sara Rose Shannon
  • Schahram Akbarian
  • Kristen J. BrennandEmail author
Chapter
Part of the Advances in Neurobiology book series (NEUROBIOL, volume 25)

Abstract

Schizophrenia is a chronic and severe neuropsychiatric condition manifested by cognitive, emotional, affective, perceptual, and behavioral abnormalities. Despite decades of research, the biological substrates driving the signs and symptoms of the disorder remain elusive, thus hampering progress in the development of treatments aimed at disease etiologies. The recent emergence of human induced pluripotent stem cell (hiPSC)-based models has provided the field with a highly innovative approach to generate, study, and manipulate living neural tissue derived from patients, making possible the exploration of fundamental roles of genes and early-life stressors in disease-relevant cell types. Here, we begin with a brief overview of the clinical, epidemiological, and genetic aspects of the condition, with a focus on schizophrenia as a neurodevelopmental disorder. We then highlight relevant technical advancements in hiPSC models and assess novel findings attained using hiPSC-based approaches and their implications for disease biology and treatment innovation. We close with a critical appraisal of the developments necessary for both further expanding knowledge of schizophrenia and the translation of new insights into therapeutic innovations.

Keywords

Human induced pluripotent stem cells CRISPR genome engineering Psychiatric genomics Schizophrenia Disease modeling 

References

  1. 1.
    Carpenter Jr., W. T., Strauss, J. S., & Bartko, J. J. (1974). An approach to the diagnosis and understanding of schizophrenia. Introduction. Schizophrenia Bulletin (11), 35–36.  https://doi.org/10.1093/schbul/1.11.35
  2. 2.
    Crow, T. J. (1985). The two-syndrome concept: origins and current status. Schizophrenia Bulletin, 11(3), 471–486.PubMedGoogle Scholar
  3. 3.
    Sartorius, N., Shapiro, R., Kimura, M., & Barrett, K. (1972). WHO international pilot study of schizophrenia. Psychological Medicine, 2(4), 422–425.PubMedGoogle Scholar
  4. 4.
    Strauss, J. S., Carpenter Jr., W. T., & Bartko, J. J. (1974). The diagnosis and understanding of schizophrenia. Summary and conclusions. Schizophrenia Bulletin (11), 70–80.Google Scholar
  5. 5.
    Kay, S. R., Opler, L. A., & Lindenmayer, J. P. (1988). Reliability and validity of the positive and negative syndrome scale for schizophrenics. Psychiatry Research, 23(1), 99–110.PubMedGoogle Scholar
  6. 6.
    Lindenmayer, J. P., Bernstein-Hyman, R., & Grochowski, S. (1994). A new five factor model of schizophrenia. Psychiatric Quarterly, 65(4), 299–322.PubMedGoogle Scholar
  7. 7.
    Wallwork, R. S., Fortgang, R., Hashimoto, R., Weinberger, D. R., & Dickinson, D. (2012). Searching for a consensus five-factor model of the Positive and Negative Syndrome Scale for schizophrenia. Schizophrenia Research, 137(1–3), 246–250.  https://doi.org/10.1016/j.schres.2012.01.031CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: Author.Google Scholar
  9. 9.
    Staehelin, J. E., & Kielholz, P. (1953). Largactil, a new vegetative damping agent in mental disorders. Schweizerische Medizinische Wochenschrift, 83(25), 581–586.PubMedGoogle Scholar
  10. 10.
    Carlsson, A., & Lindqvist, M. (1963). Effect of chlorpromazine or haloperidol on formation of 3methoxytyramine and normetanephrine in mouse brain. Acta Pharmacologica et Toxicologica, 20, 140–144.PubMedGoogle Scholar
  11. 11.
    Creese, I., Burt, D. R., & Snyder, S. H. (1976). Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science, 192(4238), 481–483.PubMedGoogle Scholar
  12. 12.
    Seeman, P., & Lee, T. (1975). Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science, 188(4194), 1217–1219.PubMedGoogle Scholar
  13. 13.
    Borison, R. L., Pathiraja, A. P., Diamond, B. I., & Meibach, R. C. (1992). Risperidone: clinical safety and efficacy in schizophrenia. Psychopharmacology Bulletin, 28(2), 213–218.PubMedGoogle Scholar
  14. 14.
    Jones, P. B., Barnes, T. R., Davies, L., Dunn, G., Lloyd, H., Hayhurst, K. P., et al. (2006). Randomized controlled trial of the effect on quality of life of second- vs first-generation antipsychotic drugs in schizophrenia: cost utility of the latest antipsychotic drugs in schizophrenia study (CUtLASS 1). Archives of General Psychiatry, 63(10), 1079–1087.  https://doi.org/10.1001/archpsyc.63.10.1079CrossRefPubMedGoogle Scholar
  15. 15.
    Lieberman, J. A., Stroup, T. S., McEvoy, J. P., Swartz, M. S., Rosenheck, R. A., Perkins, D. O., et al. (2005). Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. The New England Journal of Medicine, 353(12), 1209–1223.  https://doi.org/10.1056/NEJMoa051688CrossRefPubMedGoogle Scholar
  16. 16.
    Kane, J., Honigfeld, G., Singer, J., & Meltzer, H. (1988). Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Archives of General Psychiatry, 45(9), 789–796.PubMedGoogle Scholar
  17. 17.
    Fusar-Poli, P., Papanastasiou, E., Stahl, D., Rocchetti, M., Carpenter, W., Shergill, S., et al. (2015). Treatments of negative symptoms in schizophrenia: meta-analysis of 168 randomized placebo-controlled trials. Schizophrenia Bulletin, 41(4), 892–899.  https://doi.org/10.1093/schbul/sbu170CrossRefPubMedGoogle Scholar
  18. 18.
    Leucht, S., Cipriani, A., Spineli, L., Mavridis, D., Orey, D., Richter, F., et al. (2013). Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet, 382(9896), 951–962.  https://doi.org/10.1016/S0140-6736(13)60733-3CrossRefPubMedGoogle Scholar
  19. 19.
    Naber, D., & Lambert, M. (2009). The CATIE and CUtLASS studies in schizophrenia: results and implications for clinicians. CNS Drugs, 23(8), 649–659.  https://doi.org/10.2165/00023210-200923080-00002CrossRefPubMedGoogle Scholar
  20. 20.
    Downing, A. M., Kinon, B. J., Millen, B. A., Zhang, L., Liu, L., Morozova, M. A., et al. (2014). A double-blind, placebo-controlled comparator study of LY2140023 monohydrate in patients with schizophrenia. BMC Psychiatry, 14, 351.  https://doi.org/10.1186/s12888-014-0351-3CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Jablensky, A., Sartorius, N., Ernberg, G., Anker, M., Korten, A., Cooper, J. E., et al. (1992). Schizophrenia: manifestations, incidence and course in different cultures. A World Health Organization ten-country study. Psychological Medicine. Monograph Supplement, 20, 1–97.PubMedGoogle Scholar
  22. 22.
    Hjorthoj, C., Sturup, A. E., McGrath, J. J., & Nordentoft, M. (2017). Years of potential life lost and life expectancy in schizophrenia: a systematic review and meta-analysis. Lancet Psychiatry, 4(4), 295–301.  https://doi.org/10.1016/S2215-0366(17)30078-0CrossRefPubMedGoogle Scholar
  23. 23.
    Palmer, B. A., Pankratz, V. S., & Bostwick, J. M. (2005). The lifetime risk of suicide in schizophrenia: a reexamination. Archives of General Psychiatry, 62(3), 247–253.  https://doi.org/10.1001/archpsyc.62.3.247CrossRefPubMedGoogle Scholar
  24. 24.
    Caldwell, C. B., & Gottesman, I. I. (1990). Schizophrenics kill themselves too: a review of risk factors for suicide. Schizophrenia Bulletin, 16(4), 571–589.PubMedGoogle Scholar
  25. 25.
    Phillips, M. R., Yang, G., Li, S., & Li, Y. (2004). Suicide and the unique prevalence pattern of schizophrenia in mainland China: a retrospective observational study. Lancet, 364(9439), 1062–1068.  https://doi.org/10.1016/S0140-6736(04)17061-XCrossRefPubMedGoogle Scholar
  26. 26.
    Brown, S. (1997). Excess mortality of schizophrenia. A meta-analysis. The British Journal of Psychiatry, 171, 502–508.PubMedGoogle Scholar
  27. 27.
    Weinmann, S., Read, J., & Aderhold, V. (2009). Influence of antipsychotics on mortality in schizophrenia: systematic review. Schizophrenia Research, 113(1), 1–11.  https://doi.org/10.1016/j.schres.2009.05.018CrossRefPubMedGoogle Scholar
  28. 28.
    Nielsen, P. R., Laursen, T. M., & Agerbo, E. (2016). Comorbidity of schizophrenia and infection: a population-based cohort study. Social Psychiatry and Psychiatric Epidemiology, 51(12), 1581–1589.  https://doi.org/10.1007/s00127-016-1297-1CrossRefPubMedGoogle Scholar
  29. 29.
    Goff, D. C., Cather, C., Evins, A. E., Henderson, D. C., Freudenreich, O., Copeland, P. M., et al. (2005). Medical morbidity and mortality in schizophrenia: guidelines for psychiatrists. Journal of Clinical Psychiatry, 66(2), 183–194; quiz 147, 273-184.PubMedGoogle Scholar
  30. 30.
    Winklbaur, B., Ebner, N., Sachs, G., Thau, K., & Fischer, G. (2006). Substance abuse in patients with schizophrenia. Dialogues in Clinical Neuroscience, 8(1), 37–43.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Brekke, J. S., Prindle, C., Bae, S. W., & Long, J. D. (2001). Risks for individuals with schizophrenia who are living in the community. Psychiatric Services, 52(10), 1358–1366.  https://doi.org/10.1176/appi.ps.52.10.1358CrossRefPubMedGoogle Scholar
  32. 32.
    Rapoport, J. L., Addington, A. M., Frangou, S., & Psych, M. R. (2005). The neurodevelopmental model of schizophrenia: update 2005. Molecular Psychiatry, 10(5), 434–449.  https://doi.org/10.1038/sj.mp.4001642CrossRefPubMedGoogle Scholar
  33. 33.
    Rapoport, J. L., Giedd, J. N., & Gogtay, N. (2012). Neurodevelopmental model of schizophrenia: update 2012. Molecular Psychiatry, 17(12), 1228–1238.  https://doi.org/10.1038/mp.2012.23CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Stiles, J., & Jernigan, T. L. (2010). The basics of brain development. Neuropsychology Review, 20(4), 327–348.  https://doi.org/10.1007/s11065-010-9148-4CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Muraki, K., & Tanigaki, K. (2015). Neuronal migration abnormalities and its possible implications for schizophrenia. Frontiers in Neuroscience, 9, 74.  https://doi.org/10.3389/fnins.2015.00074CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Schoenfeld, T. J., & Cameron, H. A. (2015). Adult neurogenesis and mental illness. Neuropsychopharmacology, 40(1), 113–128.  https://doi.org/10.1038/npp.2014.230CrossRefPubMedGoogle Scholar
  37. 37.
    Schmidt, M. J., & Mirnics, K. (2015). Neurodevelopment, GABA system dysfunction, and schizophrenia. Neuropsychopharmacology, 40(1), 190–206.  https://doi.org/10.1038/npp.2014.95CrossRefPubMedGoogle Scholar
  38. 38.
    Bartzokis, G. (2002). Schizophrenia: breakdown in the well-regulated lifelong process of brain development and maturation. Neuropsychopharmacology, 27(4), 672–683.  https://doi.org/10.1016/S0893-133X(02)00364-0CrossRefPubMedGoogle Scholar
  39. 39.
    Forsyth, J. K., & Lewis, D. A. (2017). Mapping the consequences of impaired synaptic plasticity in schizophrenia through development: an integrative model for diverse clinical features. Trends in Cognitive Sciences, 21(10), 760–778.  https://doi.org/10.1016/j.tics.2017.06.006CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Hirayasu, Y., Shenton, M. E., Salisbury, D. F., Dickey, C. C., Fischer, I. A., Mazzoni, P., et al. (1998). Lower left temporal lobe MRI volumes in patients with first-episode schizophrenia compared with psychotic patients with first-episode affective disorder and normal subjects. The American Journal of Psychiatry, 155(10), 1384–1391.  https://doi.org/10.1176/ajp.155.10.1384CrossRefPubMedGoogle Scholar
  41. 41.
    Wilke, M., Kaufmann, C., Grabner, A., Putz, B., Wetter, T. C., & Auer, D. P. (2001). Gray matter-changes and correlates of disease severity in schizophrenia: a statistical parametric mapping study. NeuroImage, 13(5), 814–824.  https://doi.org/10.1006/nimg.2001.0751CrossRefPubMedGoogle Scholar
  42. 42.
    Salgado-Pineda, P., Baeza, I., Perez-Gomez, M., Vendrell, P., Junque, C., Bargallo, N., et al. (2003). Sustained attention impairment correlates to gray matter decreases in first episode neuroleptic-naive schizophrenic patients. NeuroImage, 19(2 Pt 1), 365–375.PubMedGoogle Scholar
  43. 43.
    Berge, D., Carmona, S., Rovira, M., Bulbena, A., Salgado, P., & Vilarroya, O. (2011). Gray matter volume deficits and correlation with insight and negative symptoms in first-psychotic-episode subjects. Acta Psychiatrica Scandinavica, 123(6), 431–439.  https://doi.org/10.1111/j.1600-0447.2010.01635.xCrossRefPubMedGoogle Scholar
  44. 44.
    Hirayasu, Y., Tanaka, S., Shenton, M. E., Salisbury, D. F., DeSantis, M. A., Levitt, J. J., et al. (2001). Prefrontal gray matter volume reduction in first episode schizophrenia. Cerebral Cortex, 11(4), 374–381.PubMedGoogle Scholar
  45. 45.
    Paillere-Martinot, M., Caclin, A., Artiges, E., Poline, J. B., Joliot, M., Mallet, L., et al. (2001). Cerebral gray and white matter reductions and clinical correlates in patients with early onset schizophrenia. Schizophrenia Research, 50(1–2), 19–26.PubMedGoogle Scholar
  46. 46.
    Crespo-Facorro, B., Roiz-Santianez, R., Perez-Iglesias, R., Rodriguez-Sanchez, J. M., Mata, I., Tordesillas-Gutierrez, D., et al. (2011). Global and regional cortical thinning in first-episode psychosis patients: relationships with clinical and cognitive features. Psychological Medicine, 41(7), 1449–1460.  https://doi.org/10.1017/S003329171000200XCrossRefPubMedGoogle Scholar
  47. 47.
    Whitford, T. J., Grieve, S. M., Farrow, T. F., Gomes, L., Brennan, J., Harris, A. W., et al. (2006). Progressive grey matter atrophy over the first 2–3 years of illness in first-episode schizophrenia: a tensor-based morphometry study. NeuroImage, 32(2), 511–519.  https://doi.org/10.1016/j.neuroimage.2006.03.041CrossRefPubMedGoogle Scholar
  48. 48.
    Hirayasu, Y., Shenton, M. E., Salisbury, D. F., Kwon, J. S., Wible, C. G., Fischer, I. A., et al. (1999). Subgenual cingulate cortex volume in first-episode psychosis. The American Journal of Psychiatry, 156(7), 1091–1093.  https://doi.org/10.1176/ajp.156.7.1091CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Kasai, K., Shenton, M. E., Salisbury, D. F., Onitsuka, T., Toner, S. K., Yurgelun-Todd, D., et al. (2003). Differences and similarities in insular and temporal pole MRI gray matter volume abnormalities in first-episode schizophrenia and affective psychosis. Archives of General Psychiatry, 60(11), 1069–1077.  https://doi.org/10.1001/archpsyc.60.11.1069CrossRefPubMedGoogle Scholar
  50. 50.
    Rothlisberger, M., Riecher-Rossler, A., Aston, J., Fusar-Poli, P., Radu, E. W., & Borgwardt, S. (2012). Cingulate volume abnormalities in emerging psychosis. Current Pharmaceutical Design, 18(4), 495–504.PubMedGoogle Scholar
  51. 51.
    Liu, J., Pearlson, G., Windemuth, A., Ruano, G., Perrone-Bizzozero, N. I., & Calhoun, V. (2009). Combining fMRI and SNP data to investigate connections between brain function and genetics using parallel ICA. Human Brain Mapping, 30(1), 241–255.  https://doi.org/10.1002/hbm.20508CrossRefPubMedGoogle Scholar
  52. 52.
    Carpenter, D. M., Tang, C. Y., Friedman, J. I., Hof, P. R., Stewart, D. G., Buchsbaum, M. S., et al. (2008). Temporal characteristics of tract-specific anisotropy abnormalities in schizophrenia. Neuroreport, 19(14), 1369–1372.  https://doi.org/10.1097/WNR.0b013e32830abc35CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Karlsgodt, K. H., van Erp, T. G., Poldrack, R. A., Bearden, C. E., Nuechterlein, K. H., & Cannon, T. D. (2008). Diffusion tensor imaging of the superior longitudinal fasciculus and working memory in recent-onset schizophrenia. Biological Psychiatry, 63(5), 512–518.  https://doi.org/10.1016/j.biopsych.2007.06.017CrossRefPubMedGoogle Scholar
  54. 54.
    Perez-Iglesias, R., Tordesillas-Gutierrez, D., Barker, G. J., McGuire, P. K., Roiz-Santianez, R., Mata, I., et al. (2010). White matter defects in first episode psychosis patients: a voxelwise analysis of diffusion tensor imaging. NeuroImage, 49(1), 199–204.  https://doi.org/10.1016/j.neuroimage.2009.07.016CrossRefPubMedGoogle Scholar
  55. 55.
    Ruef, A., Curtis, L., Moy, G., Bessero, S., Badan Ba, M., Lazeyras, F., et al. (2012). Magnetic resonance imaging correlates of first-episode psychosis in young adult male patients: combined analysis of grey and white matter. Journal of Psychiatry & Neuroscience, 37(5), 305–312.  https://doi.org/10.1503/jpn.110057CrossRefGoogle Scholar
  56. 56.
    White, T., Anjum, A., & Schulz, S. C. (2006). The schizophrenia prodrome. The American Journal of Psychiatry, 163(3), 376–380.  https://doi.org/10.1176/appi.ajp.163.3.376CrossRefPubMedGoogle Scholar
  57. 57.
    Yung, A. R., & McGorry, P. D. (1996a). The initial prodrome in psychosis: descriptive and qualitative aspects. The Australian and New Zealand Journal of Psychiatry, 30(5), 587–599.  https://doi.org/10.3109/00048679609062654CrossRefPubMedGoogle Scholar
  58. 58.
    Beiser, M., Erickson, D., Fleming, J. A., & Iacono, W. G. (1993). Establishing the onset of psychotic illness. The American Journal of Psychiatry, 150(9), 1349–1354.  https://doi.org/10.1176/ajp.150.9.1349CrossRefPubMedGoogle Scholar
  59. 59.
    Lencz, T., Cornblatt, B., & Bilder, R. M. (2001). Neurodevelopmental models of schizophrenia: pathophysiologic synthesis and directions for intervention research. Psychopharmacology Bulletin, 35(1), 95–125.PubMedGoogle Scholar
  60. 60.
    Tsuang, M. T., Faraone, S. V., Bingham, S., Young, K., Prabhudesai, S., Haverstock, S. L., et al. (2000). Department of Veterans Affairs Cooperative Studies Program genetic linkage study of schizophrenia: ascertainment methods and sample description. American Journal of Medical Genetics, 96(3), 342–347.PubMedGoogle Scholar
  61. 61.
    Yung, A. R., & McGorry, P. D. (1996b). The prodromal phase of first-episode psychosis: past and current conceptualizations. Schizophrenia Bulletin, 22(2), 353–370.PubMedGoogle Scholar
  62. 62.
    Cornblatt, B., Lencz, T., & Obuchowski, M. (2002). The schizophrenia prodrome: treatment and high-risk perspectives. Schizophrenia Research, 54(1–2), 177–186.PubMedGoogle Scholar
  63. 63.
    Cornblatt, B., Obuchowski, M., Roberts, S., Pollack, S., & Erlenmeyer-Kimling, L. (1999). Cognitive and behavioral precursors of schizophrenia. Development and Psychopathology, 11(3), 487–508.PubMedGoogle Scholar
  64. 64.
    Lappin, J. M., Dazzan, P., Morgan, K., Morgan, C., Chitnis, X., Suckling, J., et al. (2007). Duration of prodromal phase and severity of volumetric abnormalities in first-episode psychosis. The British Journal of Psychiatry. Supplement, 51, s123–s127.  https://doi.org/10.1192/bjp.191.51.s123CrossRefPubMedGoogle Scholar
  65. 65.
    Fusar-Poli, P., Tantardini, M., De Simone, S., Ramella-Cravaro, V., Oliver, D., Kingdon, J., et al. (2017). Deconstructing vulnerability for psychosis: meta-analysis of environmental risk factors for psychosis in subjects at ultra high-risk. European Psychiatry, 40, 65–75.  https://doi.org/10.1016/j.eurpsy.2016.09.003CrossRefPubMedGoogle Scholar
  66. 66.
    Clarke, M. C., Tanskanen, A., Huttunen, M., Leon, D. A., Murray, R. M., Jones, P. B., et al. (2011). Increased risk of schizophrenia from additive interaction between infant motor developmental delay and obstetric complications: evidence from a population-based longitudinal study. The American Journal of Psychiatry, 168(12), 1295–1302.  https://doi.org/10.1176/appi.ajp.2011.11010011CrossRefPubMedGoogle Scholar
  67. 67.
    Jones, P., Rodgers, B., Murray, R., & Marmot, M. (1994). Child development risk factors for adult schizophrenia in the British 1946 birth cohort. Lancet, 344(8934), 1398–1402.PubMedGoogle Scholar
  68. 68.
    Kremen, W. S., Buka, S. L., Seidman, L. J., Goldstein, J. M., Koren, D., & Tsuang, M. T. (1998). IQ decline during childhood and adult psychotic symptoms in a community sample: a 19-year longitudinal study. The American Journal of Psychiatry, 155(5), 672–677.  https://doi.org/10.1176/ajp.155.5.672CrossRefPubMedGoogle Scholar
  69. 69.
    Wood, S. J., Pantelis, C., Proffitt, T., Phillips, L. J., Stuart, G. W., Buchanan, J. A., et al. (2003). Spatial working memory ability is a marker of risk-for-psychosis. Psychological Medicine, 33(7), 1239–1247.PubMedGoogle Scholar
  70. 70.
    Brewer, W. J., Francey, S. M., Wood, S. J., Jackson, H. J., Pantelis, C., Phillips, L. J., et al. (2005). Memory impairments identified in people at ultra-high risk for psychosis who later develop first-episode psychosis. The American Journal of Psychiatry, 162(1), 71–78.  https://doi.org/10.1176/appi.ajp.162.1.71CrossRefPubMedGoogle Scholar
  71. 71.
    Dickson, H., Laurens, K. R., Cullen, A. E., & Hodgins, S. (2012). Meta-analyses of cognitive and motor function in youth aged 16 years and younger who subsequently develop schizophrenia. Psychological Medicine, 42(4), 743–755.  https://doi.org/10.1017/S0033291711001693CrossRefPubMedGoogle Scholar
  72. 72.
    Erlenmeyer-Kimling, L., Rock, D., Roberts, S. A., Janal, M., Kestenbaum, C., Cornblatt, B., et al. (2000). Attention, memory, and motor skills as childhood predictors of schizophrenia-related psychoses: the New York High-Risk Project. The American Journal of Psychiatry, 157(9), 1416–1422.  https://doi.org/10.1176/appi.ajp.157.9.1416CrossRefPubMedGoogle Scholar
  73. 73.
    Done, D. J., Crow, T. J., Johnstone, E. C., & Sacker, A. (1994). Childhood antecedents of schizophrenia and affective illness: social adjustment at ages 7 and 11. BMJ, 309(6956), 699–703.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Davidson, M., Reichenberg, A., Rabinowitz, J., Weiser, M., Kaplan, Z., & Mark, M. (1999). Behavioral and intellectual markers for schizophrenia in apparently healthy male adolescents. The American Journal of Psychiatry, 156(9), 1328–1335.  https://doi.org/10.1176/ajp.156.9.1328CrossRefPubMedGoogle Scholar
  75. 75.
    Klosterkotter, J., Hellmich, M., Steinmeyer, E. M., & Schultze-Lutter, F. (2001). Diagnosing schizophrenia in the initial prodromal phase. Archives of General Psychiatry, 58(2), 158–164.PubMedGoogle Scholar
  76. 76.
    Pantelis, C., Velakoulis, D., McGorry, P. D., Wood, S. J., Suckling, J., Phillips, L. J., et al. (2003). Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison. Lancet, 361(9354), 281–288.  https://doi.org/10.1016/S0140-6736(03)12323-9CrossRefPubMedGoogle Scholar
  77. 77.
    Borgwardt, S. J., McGuire, P. K., Aston, J., Berger, G., Dazzan, P., Gschwandtner, U., et al. (2007). Structural brain abnormalities in individuals with an at-risk mental state who later develop psychosis. The British Journal of Psychiatry. Supplement, 51, s69–s75.  https://doi.org/10.1192/bjp.191.51.s69CrossRefPubMedGoogle Scholar
  78. 78.
    Fornito, A., Yung, A. R., Wood, S. J., Phillips, L. J., Nelson, B., Cotton, S., et al. (2008). Anatomic abnormalities of the anterior cingulate cortex before psychosis onset: an MRI study of ultra-high-risk individuals. Biological Psychiatry, 64(9), 758–765.  https://doi.org/10.1016/j.biopsych.2008.05.032CrossRefPubMedGoogle Scholar
  79. 79.
    Takahashi, T., Wood, S. J., Soulsby, B., Kawasaki, Y., McGorry, P. D., Suzuki, M., et al. (2009a). An MRI study of the superior temporal subregions in first-episode patients with various psychotic disorders. Schizophrenia Research, 113(2–3), 158–166.  https://doi.org/10.1016/j.schres.2009.06.016CrossRefPubMedGoogle Scholar
  80. 80.
    Takahashi, T., Wood, S. J., Yung, A. R., Phillips, L. J., Soulsby, B., McGorry, P. D., et al. (2009b). Insular cortex gray matter changes in individuals at ultra-high-risk of developing psychosis. Schizophrenia Research, 111(1–3), 94–102.  https://doi.org/10.1016/j.schres.2009.03.024CrossRefPubMedGoogle Scholar
  81. 81.
    Mechelli, A., Riecher-Rossler, A., Meisenzahl, E. M., Tognin, S., Wood, S. J., Borgwardt, S. J., et al. (2011). Neuroanatomical abnormalities that predate the onset of psychosis: a multicenter study. Archives of General Psychiatry, 68(5), 489–495.  https://doi.org/10.1001/archgenpsychiatry.2011.42CrossRefPubMedGoogle Scholar
  82. 82.
    Fusar-Poli, P., Broome, M. R., Woolley, J. B., Johns, L. C., Tabraham, P., Bramon, E., et al. (2011). Altered brain function directly related to structural abnormalities in people at ultra high risk of psychosis: longitudinal VBM-fMRI study. Journal of Psychiatric Research, 45(2), 190–198.  https://doi.org/10.1016/j.jpsychires.2010.05.012CrossRefPubMedGoogle Scholar
  83. 83.
    Jung, W. H., Kim, J. S., Jang, J. H., Choi, J. S., Jung, M. H., Park, J. Y., et al. (2011). Cortical thickness reduction in individuals at ultra-high-risk for psychosis. Schizophrenia Bulletin, 37(4), 839–849.  https://doi.org/10.1093/schbul/sbp151CrossRefPubMedGoogle Scholar
  84. 84.
    Gilmore, J. H., Kang, C., Evans, D. D., Wolfe, H. M., Smith, J. K., Lieberman, J. A., et al. (2010a). Prenatal and neonatal brain structure and white matter maturation in children at high risk for schizophrenia. The American Journal of Psychiatry, 167(9), 1083–1091.  https://doi.org/10.1176/appi.ajp.2010.09101492CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Gilmore, J. H., Schmitt, J. E., Knickmeyer, R. C., Smith, J. K., Lin, W., Styner, M., et al. (2010b). Genetic and environmental contributions to neonatal brain structure: A twin study. Human Brain Mapping, 31(8), 1174–1182.  https://doi.org/10.1002/hbm.20926CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Walterfang, M., McGuire, P. K., Yung, A. R., Phillips, L. J., Velakoulis, D., Wood, S. J., et al. (2008). White matter volume changes in people who develop psychosis. The British Journal of Psychiatry, 193(3), 210–215.  https://doi.org/10.1192/bjp.bp.107.043463CrossRefPubMedGoogle Scholar
  87. 87.
    Bloemen, O. J., de Koning, M. B., Schmitz, N., Nieman, D. H., Becker, H. E., de Haan, L., et al. (2010). White-matter markers for psychosis in a prospective ultra-high-risk cohort. Psychological Medicine, 40(8), 1297–1304.  https://doi.org/10.1017/S0033291709991711CrossRefPubMedGoogle Scholar
  88. 88.
    Brown, A. S. (2006). Prenatal infection as a risk factor for schizophrenia. Schizophrenia Bulletin, 32(2), 200–202.  https://doi.org/10.1093/schbul/sbj052CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Brown, A. S. (2012). Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism. Developmental Neurobiology, 72(10), 1272–1276.  https://doi.org/10.1002/dneu.22024CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Cannon, M., Jones, P. B., & Murray, R. M. (2002). Obstetric complications and schizophrenia: historical and meta-analytic review. The American Journal of Psychiatry, 159(7), 1080–1092.  https://doi.org/10.1176/appi.ajp.159.7.1080CrossRefPubMedGoogle Scholar
  91. 91.
    Picker, J. D., & Coyle, J. T. (2005). Do maternal folate and homocysteine levels play a role in neurodevelopmental processes that increase risk for schizophrenia? Harvard Review of Psychiatry, 13(4), 197–205.  https://doi.org/10.1080/10673220500243372CrossRefPubMedGoogle Scholar
  92. 92.
    Roseboom, T. J., Painter, R. C., van Abeelen, A. F., Veenendaal, M. V., & de Rooij, S. R. (2011). Hungry in the womb: what are the consequences? Lessons from the Dutch famine. Maturitas, 70(2), 141–145.  https://doi.org/10.1016/j.maturitas.2011.06.017CrossRefPubMedGoogle Scholar
  93. 93.
    Knud Larsen, J., Bendsen, B. B., Foldager, L., & Munk-Jorgensen, P. (2010). Prematurity and low birth weight as risk factors for the development of affective disorder, especially depression and schizophrenia: a register study. Acta Neuropsychiatrica, 22(6), 284–291.  https://doi.org/10.1111/j.1601-5215.2010.00498.xCrossRefPubMedGoogle Scholar
  94. 94.
    Rifkin, L., Lewis, S., Jones, P., Toone, B., & Murray, R. (1994). Low birth weight and schizophrenia. The British Journal of Psychiatry, 165(3), 357–362.PubMedGoogle Scholar
  95. 95.
    Wahlbeck, K., Forsen, T., Osmond, C., Barker, D. J., & Eriksson, J. G. (2001). Association of schizophrenia with low maternal body mass index, small size at birth, and thinness during childhood. Archives of General Psychiatry, 58(1), 48–52.PubMedGoogle Scholar
  96. 96.
    Torniainen, M., Wegelius, A., Tuulio-Henriksson, A., Lonnqvist, J., & Suvisaari, J. (2013). Both low birthweight and high birthweight are associated with cognitive impairment in persons with schizophrenia and their first-degree relatives. Psychological Medicine, 43(11), 2361–2367.  https://doi.org/10.1017/S0033291713000032CrossRefPubMedGoogle Scholar
  97. 97.
    Moilanen, K., Jokelainen, J., Jones, P. B., Hartikainen, A. L., Jarvelin, M. R., & Isohanni, M. (2010). Deviant intrauterine growth and risk of schizophrenia: a 34-year follow-up of the Northern Finland 1966 Birth Cohort. Schizophrenia Research, 124(1–3), 223–230.  https://doi.org/10.1016/j.schres.2010.09.006CrossRefPubMedGoogle Scholar
  98. 98.
    Davies, G., Welham, J., Chant, D., Torrey, E. F., & McGrath, J. (2003). A systematic review and meta-analysis of Northern Hemisphere season of birth studies in schizophrenia. Schizophrenia Bulletin, 29(3), 587–593.PubMedGoogle Scholar
  99. 99.
    Frissen, A., Lieverse, R., Drukker, M., van Winkel, R., Delespaul, P., & Investigators, G. (2015). Childhood trauma and childhood urbanicity in relation to psychotic disorder. Social Psychiatry and Psychiatric Epidemiology, 50(10), 1481–1488.  https://doi.org/10.1007/s00127-015-1049-7CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Lataster, J., Myin-Germeys, I., Lieb, R., Wittchen, H. U., & van Os, J. (2012). Adversity and psychosis: a 10-year prospective study investigating synergism between early and recent adversity in psychosis. Acta Psychiatrica Scandinavica, 125(5), 388–399.  https://doi.org/10.1111/j.1600-0447.2011.01805.xCrossRefPubMedGoogle Scholar
  101. 101.
    Marconi, A., Di Forti, M., Lewis, C. M., Murray, R. M., & Vassos, E. (2016). Meta-analysis of the association between the level of cannabis use and risk of psychosis. Schizophrenia Bulletin, 42(5), 1262–1269.  https://doi.org/10.1093/schbul/sbw003CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Moore, T. H., Zammit, S., Lingford-Hughes, A., Barnes, T. R., Jones, P. B., Burke, M., et al. (2007). Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet, 370(9584), 319–328.  https://doi.org/10.1016/S0140-6736(07)61162-3CrossRefPubMedGoogle Scholar
  103. 103.
    Heinz, A., Deserno, L., & Reininghaus, U. (2013). Urbanicity, social adversity and psychosis. World Psychiatry, 12(3), 187–197.  https://doi.org/10.1002/wps.20056CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Lichtenstein, P., Yip, B. H., Bjork, C., Pawitan, Y., Cannon, T. D., Sullivan, P. F., et al. (2009). Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet, 373(9659), 234–239.  https://doi.org/10.1016/S0140-6736(09)60072-6CrossRefPubMedGoogle Scholar
  105. 105.
    Lichtenstein, P., Bjork, C., Hultman, C. M., Scolnick, E., Sklar, P., & Sullivan, P. F. (2006). Recurrence risks for schizophrenia in a Swedish national cohort. Psychological Medicine, 36(10), 1417–1425.  https://doi.org/10.1017/S0033291706008385CrossRefPubMedGoogle Scholar
  106. 106.
    Cardno, A. G., & Gottesman, I. I. (2000). Twin studies of schizophrenia: from bow-and-arrow concordances to star wars Mx and functional genomics. American Journal of Medical Genetics, 97(1), 12–17.PubMedGoogle Scholar
  107. 107.
    Hilker, R., Helenius, D., Fagerlund, B., Skytthe, A., Christensen, K., Werge, T. M., et al. (2018). Heritability of schizophrenia and schizophrenia spectrum based on the Nationwide Danish Twin Register. Biological Psychiatry, 83(6), 492–498.  https://doi.org/10.1016/j.biopsych.2017.08.017CrossRefPubMedGoogle Scholar
  108. 108.
    Sullivan, P. F., Agrawal, A., Bulik, C. M., Andreassen, O. A., Borglum, A. D., Breen, G., et al. (2018). Psychiatric genomics: an update and an agenda. The American Journal of Psychiatry, 175(1), 15–27.  https://doi.org/10.1176/appi.ajp.2017.17030283CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Power, R. A., Kyaga, S., Uher, R., MacCabe, J. H., Langstrom, N., Landen, M., et al. (2013). Fecundity of patients with schizophrenia, autism, bipolar disorder, depression, anorexia nervosa, or substance abuse vs their unaffected siblings. JAMA Psychiatry, 70(1), 22–30.  https://doi.org/10.1001/jamapsychiatry.2013.268CrossRefPubMedGoogle Scholar
  110. 110.
    Gershon, E. S., Alliey-Rodriguez, N., & Liu, C. (2011). After GWAS: searching for genetic risk for schizophrenia and bipolar disorder. The American Journal of Psychiatry, 168(3), 253–256.  https://doi.org/10.1176/appi.ajp.2010.10091340CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Malaspina, D., Brown, A., Goetz, D., Alia-Klein, N., Harkavy-Friedman, J., Harlap, S., et al. (2002). Schizophrenia risk and paternal age: a potential role for de novo mutations in schizophrenia vulnerability genes. CNS Spectrums, 7(1), 26–29.PubMedGoogle Scholar
  112. 112.
    Kong, A., Frigge, M. L., Masson, G., Besenbacher, S., Sulem, P., Magnusson, G., et al. (2012). Rate of de novo mutations and the importance of father's age to disease risk. Nature, 488(7412), 471–475.  https://doi.org/10.1038/nature11396CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Gulsuner, S., Walsh, T., Watts, A. C., Lee, M. K., Thornton, A. M., Casadei, S., et al. (2013). Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell, 154(3), 518–529.  https://doi.org/10.1016/j.cell.2013.06.049CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Xu, B., Ionita-Laza, I., Roos, J. L., Boone, B., Woodrick, S., Sun, Y., et al. (2012). De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia. Nature Genetics, 44(12), 1365–1369.  https://doi.org/10.1038/ng.2446CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Fromer, M., Pocklington, A. J., Kavanagh, D. H., Williams, H. J., Dwyer, S., Gormley, P., et al. (2014). De novo mutations in schizophrenia implicate synaptic networks. Nature, 506(7487), 179–184.  https://doi.org/10.1038/nature12929CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Awadalla, P., Gauthier, J., Myers, R. A., Casals, F., Hamdan, F. F., Griffing, A. R., et al. (2010). Direct measure of the de novo mutation rate in autism and schizophrenia cohorts. American Journal of Human Genetics, 87(3), 316–324.  https://doi.org/10.1016/j.ajhg.2010.07.019CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Girard, S. L., Gauthier, J., Noreau, A., Xiong, L., Zhou, S., Jouan, L., et al. (2011). Increased exonic de novo mutation rate in individuals with schizophrenia. Nature Genetics, 43(9), 860–863.  https://doi.org/10.1038/ng.886CrossRefPubMedGoogle Scholar
  118. 118.
    Purcell, S. M., Moran, J. L., Fromer, M., Ruderfer, D., Solovieff, N., Roussos, P., et al. (2014). A polygenic burden of rare disruptive mutations in schizophrenia. Nature, 506(7487), 185–190.  https://doi.org/10.1038/nature12975CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Genovese, G., Fromer, M., Stahl, E. A., Ruderfer, D. M., Chambert, K., Landen, M., et al. (2016). Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia. Nature Neuroscience, 19(11), 1433–1441.  https://doi.org/10.1038/nn.4402CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Genovese G., Fromer M., Stahl E. A., Ruderfer D. M., Chambert K., Landén M., et al. (2016) Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia. Nature Neuroscience 19(11):1433–1441Google Scholar
  121. 121.
    Szatkiewicz, J. P., O'Dushlaine, C., Chen, G., Chambert, K., Moran, J. L., Neale, B. M., et al. (2014). Copy number variation in schizophrenia in Sweden. Molecular Psychiatry, 19(7), 762–773.  https://doi.org/10.1038/mp.2014.40CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Rees, E., Kirov, G., O'Donovan, M. C., & Owen, M. J. (2012). De novo mutation in schizophrenia. Schizophrenia Bulletin, 38(3), 377–381.  https://doi.org/10.1093/schbul/sbs047CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Marshall, C. R., Howrigan, D. P., Merico, D., Thiruvahindrapuram, B., Wu, W., Greer, D. S., et al. (2017). Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nature Genetics, 49(1), 27–35.  https://doi.org/10.1038/ng.3725CrossRefPubMedGoogle Scholar
  124. 124.
    Schneider, M., Debbane, M., Bassett, A. S., Chow, E. W., Fung, W. L., van den Bree, M., et al. (2014). Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome: results from the International Consortium on Brain and Behavior in 22q11.2 deletion syndrome. The American Journal of Psychiatry, 171(6), 627–639.  https://doi.org/10.1176/appi.ajp.2013.13070864CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Van, L., Boot, E., & Bassett, A. S. (2017). Update on the 22q11.2 deletion syndrome and its relevance to schizophrenia. Current Opinion in Psychiatry, 30(3), 191–196.  https://doi.org/10.1097/YCO.0000000000000324CrossRefPubMedGoogle Scholar
  126. 126.
    Bergen, S. E., Ploner, A., Howrigan, D., CNV Analysis Group and the Schizophrenia Working Group of the Psychiatric Genomics Consortium, O’Donovan, M. C., Smoller, J. W., et al. (2018). Joint contributions of rare copy number variants and common SNPs to risk for schizophrenia. Am J Psychiatry, 176, 29.  https://doi.org/10.1176/appi.ajp.2018.17040467CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Tansey, K. E., Rees, E., Linden, D. E., Ripke, S., Chambert, K. D., Moran, J. L., et al. (2016). Common alleles contribute to schizophrenia in CNV carriers. Molecular Psychiatry, 21(8), 1153.  https://doi.org/10.1038/mp.2015.170CrossRefPubMedGoogle Scholar
  128. 128.
    Gottesman, I. I., & Shields, J. (1967). A polygenic theory of schizophrenia. Proceedings of the National Academy of Sciences of the United States of America, 58(1), 199–205.PubMedPubMedCentralGoogle Scholar
  129. 129.
    Shi, J., Levinson, D. F., Duan, J., Sanders, A. R., Zheng, Y., Pe'er, I., et al. (2009). Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature, 460(7256), 753–757.  https://doi.org/10.1038/nature08192CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    International Schizophrenia Consortium, Purcell, S. M., Wray, N. R., Stone, J. L., Visscher, P. M., O'Donovan, M. C., et al. (2009). Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature, 460(7256), 748–752.  https://doi.org/10.1038/nature08185CrossRefPubMedCentralGoogle Scholar
  131. 131.
    O'Donovan, M. C., Craddock, N., Norton, N., Williams, H., Peirce, T., Moskvina, V., et al. (2008). Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nature Genetics, 40(9), 1053–1055.  https://doi.org/10.1038/ng.201CrossRefPubMedGoogle Scholar
  132. 132.
    Stefansson, H., Ophoff, R. A., Steinberg, S., Andreassen, O. A., Cichon, S., Rujescu, D., et al. (2009). Common variants conferring risk of schizophrenia. Nature, 460(7256), 744–747.  https://doi.org/10.1038/nature08186CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium, Ripke, S., Sanders, A. R., Kendler, K. S., Levinson, D. F., Sklar, P., et al. (2011). Genome-wide association study identifies five new schizophrenia loci. Nature Genetics, 43(10), 969–976.  https://doi.org/10.1038/ng.940CrossRefGoogle Scholar
  134. 134.
    Ripke, S., O'Dushlaine, C., Chambert, K., Moran, J. L., Kahler, A. K., Akterin, S., et al. (2013). Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nature Genetics, 45(10), 1150–1159.  https://doi.org/10.1038/ng.2742CrossRefPubMedPubMedCentralGoogle Scholar
  135. 135.
    Schmitt, A., Malchow, B., Hasan, A., & Falkai, P. (2014). The impact of environmental factors in severe psychiatric disorders. Frontiers in Neuroscience, 8, 19.  https://doi.org/10.3389/fnins.2014.00019CrossRefPubMedPubMedCentralGoogle Scholar
  136. 136.
    Pardinas, A. F., Holmans, P., Pocklington, A. J., Escott-Price, V., Ripke, S., Carrera, N., et al. (2018). Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nature Genetics, 50(3), 381–389.  https://doi.org/10.1038/s41588-018-0059-2CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    Schizophrenia Working Group of the Psychiatric Genomics Consortium. (2014). Biological insights from 108 schizophrenia-associated genetic loci. Nature, 511(7510), 421–427.  https://doi.org/10.1038/nature13595CrossRefPubMedCentralGoogle Scholar
  138. 138.
    Li, Z., Chen, J., Yu, H., He, L., Xu, Y., Zhang, D., et al. (2017). Genome-wide association analysis identifies 30 new susceptibility loci for schizophrenia. Nature Genetics, 49(11), 1576–1583.  https://doi.org/10.1038/ng.3973CrossRefPubMedGoogle Scholar
  139. 139.
    Shi, Y., Li, Z., Xu, Q., Wang, T., Li, T., Shen, J., et al. (2011). Common variants on 8p12 and 1q24.2 confer risk of schizophrenia. Nature Genetics, 43(12), 1224–1227.  https://doi.org/10.1038/ng.980CrossRefPubMedPubMedCentralGoogle Scholar
  140. 140.
    GTEx Consortium, Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group, Statistical Methods groups—Analysis Working Group, Enhancing GTEx (eGTEx) groups, NIH Common Fund, NIH/NCI, et al. (2017). Genetic effects on gene expression across human tissues. Nature, 550(7675), 204–213.  https://doi.org/10.1038/nature24277CrossRefPubMedCentralGoogle Scholar
  141. 141.
    Maurano, M. T., Humbert, R., Rynes, E., Thurman, R. E., Haugen, E., Wang, H., et al. (2012). Systematic localization of common disease-associated variation in regulatory DNA. Science, 337(6099), 1190–1195.  https://doi.org/10.1126/science.1222794CrossRefPubMedPubMedCentralGoogle Scholar
  142. 142.
    Albert, F. W., & Kruglyak, L. (2015). The role of regulatory variation in complex traits and disease. Nature Reviews Genetics, 16(4), 197–212.  https://doi.org/10.1038/nrg3891CrossRefPubMedGoogle Scholar
  143. 143.
    Ng, B., White, C. C., Klein, H. U., Sieberts, S. K., McCabe, C., Patrick, E., et al. (2017). An xQTL map integrates the genetic architecture of the human brain’s transcriptome and epigenome. Nature Neuroscience, 20(10), 1418–1426.  https://doi.org/10.1038/nn.4632CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Gandal, M. J., Zhang, P., Hadjimichael, E., Walker, R. L., Chen, C., Liu, S., et al. (2018). Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. Science, 362(6420).  https://doi.org/10.1126/science.aat8127
  145. 145.
    Rajarajan, P., Gil, S. E., Brennand, K. J., & Akbarian, S. (2016). Spatial genome organization and cognition. Nature Reviews Neuroscience, 17(11), 681–691.  https://doi.org/10.1038/nrn.2016.124CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Richards, A. L., Jones, L., Moskvina, V., Kirov, G., Gejman, P. V., Levinson, D. F., et al. (2012). Schizophrenia susceptibility alleles are enriched for alleles that affect gene expression in adult human brain. Molecular Psychiatry, 17(2), 193–201.  https://doi.org/10.1038/mp.2011.11CrossRefPubMedGoogle Scholar
  147. 147.
    Fromer, M., Roussos, P., Sieberts, S. K., Johnson, J. S., Kavanagh, D. H., Perumal, T. M., et al. (2016). Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nature Neuroscience, 19(11), 1442–1453.  https://doi.org/10.1038/nn.4399CrossRefPubMedPubMedCentralGoogle Scholar
  148. 148.
    de la Torre-Ubieta, L., Stein, J. L., Won, H., Opland, C. K., Liang, D., Lu, D., et al. (2018). The dynamic landscape of open chromatin during human cortical neurogenesis. Cell2, 172(1–2), 289–304, e218.  https://doi.org/10.1016/j.cell.2017.12.014CrossRefGoogle Scholar
  149. 149.
    Jaffe, A. E., Straub, R. E., Shin, J. H., Tao, R., Gao, Y., Collado-Torres, L., et al. (2018). Developmental and genetic regulation of the human cortex transcriptome illuminate schizophrenia pathogenesis. Nature Neuroscience, 21(8), 1117–1125.  https://doi.org/10.1038/s41593-018-0197-yCrossRefPubMedPubMedCentralGoogle Scholar
  150. 150.
    Zhang, Y. E., Landback, P., Vibranovski, M. D., & Long, M. (2011). Accelerated recruitment of new brain development genes into the human genome. PLoS Biology, 9(10), e1001179.  https://doi.org/10.1371/journal.pbio.1001179CrossRefPubMedPubMedCentralGoogle Scholar
  151. 151.
    Akbarian, S., Bunney Jr., W. E., Potkin, S. G., Wigal, S. B., Hagman, J. O., Sandman, C. A., et al. (1993). Altered distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase cells in frontal lobe of schizophrenics implies disturbances of cortical development. Archives of General Psychiatry, 50(3), 169–177.PubMedGoogle Scholar
  152. 152.
    Jakob, H., & Beckmann, H. (1986). Prenatal developmental disturbances in the limbic allocortex in schizophrenics. Journal of Neural Transmission, 65(3–4), 303–326.PubMedGoogle Scholar
  153. 153.
    Fung, S. J., Webster, M. J., Sivagnanasundaram, S., Duncan, C., Elashoff, M., & Weickert, C. S. (2010). Expression of interneuron markers in the dorsolateral prefrontal cortex of the developing human and in schizophrenia. The American Journal of Psychiatry, 167(12), 1479–1488.  https://doi.org/10.1176/appi.ajp.2010.09060784CrossRefPubMedGoogle Scholar
  154. 154.
    Hyde, T. M., Lipska, B. K., Ali, T., Mathew, S. V., Law, A. J., Metitiri, O. E., et al. (2011). Expression of GABA signaling molecules KCC2, NKCC1, and GAD1 in cortical development and schizophrenia. The Journal of Neuroscience, 31(30), 11088–11095.  https://doi.org/10.1523/JNEUROSCI.1234-11.2011CrossRefPubMedPubMedCentralGoogle Scholar
  155. 155.
    Horváth S., Janka Z., Mirnics K., (2011) Analyzing Schizophrenia by DNA Microarrays. Biological Psychiatry 69(2):157–162Google Scholar
  156. 156.
    Torkamani, A., Dean, B., Schork, N. J., & Thomas, E. A. (2010). Coexpression network analysis of neural tissue reveals perturbations in developmental processes in schizophrenia. Genome Research, 20(4), 403–412.  https://doi.org/10.1101/gr.101956.109CrossRefPubMedPubMedCentralGoogle Scholar
  157. 157.
    Mistry, M., Gillis, J., & Pavlidis, P. (2013a). Genome-wide expression profiling of schizophrenia using a large combined cohort. Molecular Psychiatry, 18(2), 215–225.  https://doi.org/10.1038/mp.2011.172CrossRefPubMedGoogle Scholar
  158. 158.
    Mistry, M., Gillis, J., & Pavlidis, P. (2013b). Meta-analysis of gene coexpression networks in the post-mortem prefrontal cortex of patients with schizophrenia and unaffected controls. BMC Neuroscience, 14, 105.  https://doi.org/10.1186/1471-2202-14-105CrossRefPubMedPubMedCentralGoogle Scholar
  159. 159.
    Finucane, H. K., Reshef, Y. A., Anttila, V., Slowikowski, K., Gusev, A., Byrnes, A., et al. (2018). Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types. Nature Genetics, 50(4), 621–629.  https://doi.org/10.1038/s41588-018-0081-4CrossRefPubMedPubMedCentralGoogle Scholar
  160. 160.
    Gusev, A., Mancuso, N., Won, H., Kousi, M., Finucane, H. K., Reshef, Y., et al. (2018). Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights. Nature Genetics, 50(4), 538–548.  https://doi.org/10.1038/s41588-018-0092-1CrossRefPubMedPubMedCentralGoogle Scholar
  161. 161.
    Skene, N. G., Bryois, J., Bakken, T. E., Breen, G., Crowley, J. J., Gaspar, H. A., et al. (2018). Genetic identification of brain cell types underlying schizophrenia. Nature Genetics, 50(6), 825–833.  https://doi.org/10.1038/s41588-018-0129-5CrossRefPubMedPubMedCentralGoogle Scholar
  162. 162.
    Roussos, P., Katsel, P., Davis, K. L., Siever, L. J., & Haroutunian, V. (2012). A system-level transcriptomic analysis of schizophrenia using postmortem brain tissue samples. Archives of General Psychiatry, 69(12), 1205–1213.  https://doi.org/10.1001/archgenpsychiatry.2012.704CrossRefPubMedGoogle Scholar
  163. 163.
    Radulescu, E., Jaffe, A. E., Straub, R. E., Chen, Q., Shin, J. H., Hyde, T. M., et al. (2018). Identification and prioritization of gene sets associated with schizophrenia risk by co-expression network analysis in human brain. Molecular Psychiatry.  https://doi.org/10.1038/s41380-018-0304-1
  164. 164.
    Gusev, A., Ko, A., Shi, H., Bhatia, G., Chung, W., Penninx, B. W., et al. (2016). Integrative approaches for large-scale transcriptome-wide association studies. Nature Genetics, 48(3), 245–252.  https://doi.org/10.1038/ng.3506CrossRefPubMedPubMedCentralGoogle Scholar
  165. 165.
    Huckins L. M., Dobbyn A., Ruderfer D. M., Hoffman G., Wang W., Pardiñas A. F., et al. (2019) Gene expression imputation across multiple brain regions provides insights into schizophrenia risk. Nature Genetics 51(4):659–674Google Scholar
  166. 166.
    The Network, O'Dushlaine, C., Rossin, L., Lee, P. H., Duncan, L., Parikshak, N. N., et al. (2015). Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways. Nature Neuroscience, 18, 199.  https://doi.org/10.1038/nn.3922. https://www.nature.com/articles/nn.3922#supplementary-informationCrossRefGoogle Scholar
  167. 167.
    Trynka, G., Sandor, C., Han, B., Xu, H., Stranger, B. E., Liu, X. S., et al. (2013). Chromatin marks identify critical cell types for fine mapping complex trait variants. Nature Genetics, 45(2), 124–130.  https://doi.org/10.1038/ng.2504CrossRefPubMedGoogle Scholar
  168. 168.
    Roussos, P., Mitchell, A. C., Voloudakis, G., Fullard, J. F., Pothula, V. M., Tsang, J., et al. (2014). A role for noncoding variation in schizophrenia. Cell Reports, 9(4), 1417–1429.  https://doi.org/10.1016/j.celrep.2014.10.015CrossRefPubMedPubMedCentralGoogle Scholar
  169. 169.
    Psych, E. C., Akbarian, S., Liu, C., Knowles, J. A., Vaccarino, F. M., Farnham, P. J., et al. (2015). The PsychENCODE project. Nature Neuroscience, 18(12), 1707–1712.  https://doi.org/10.1038/nn.4156CrossRefGoogle Scholar
  170. 170.
    Girdhar, K., Hoffman, G. E., Jiang, Y., Brown, L., Kundakovic, M., Hauberg, M. E., et al. (2018). Cell-specific histone modification maps in the human frontal lobe link schizophrenia risk to the neuronal epigenome. Nature Neuroscience, 21(8), 1126–1136.  https://doi.org/10.1038/s41593-018-0187-0CrossRefPubMedPubMedCentralGoogle Scholar
  171. 171.
    Jaffe, A. E., Gao, Y., Deep-Soboslay, A., Tao, R., Hyde, T. M., Weinberger, D. R., et al. (2016). Mapping DNA methylation across development, genotype and schizophrenia in the human frontal cortex. Nature Neuroscience, 19(1), 40–47.  https://doi.org/10.1038/nn.4181CrossRefPubMedGoogle Scholar
  172. 172.
    Schulz, H., Ruppert, A. K., Herms, S., Wolf, C., Mirza-Schreiber, N., Stegle, O., et al. (2017). Genome-wide mapping of genetic determinants influencing DNA methylation and gene expression in human hippocampus. Nature Communications, 8(1), 1511.  https://doi.org/10.1038/s41467-017-01818-4CrossRefPubMedPubMedCentralGoogle Scholar
  173. 173.
    Dobbyn, A., Huckins, L. M., Boocock, J., Sloofman, L. G., Glicksberg, B. S., Giambartolomei, C., et al. (2018). Landscape of conditional eQTL in dorsolateral prefrontal cortex and co-localization with schizophrenia GWAS. American Journal of Human Genetics, 102(6), 1169–1184.  https://doi.org/10.1016/j.ajhg.2018.04.011CrossRefPubMedPubMedCentralGoogle Scholar
  174. 174.
    Rajarajan, P., Borrman, T., Liao, W., Schrode, N., Flaherty, E., Casino, C., et al. (2018a). Neuron-specific signatures in the chromosomal connectome associated with schizophrenia risk. Science, 362(6420), eaat4311.  https://doi.org/10.1126/science.aat4311CrossRefPubMedPubMedCentralGoogle Scholar
  175. 175.
    Bharadwaj, R., Jiang, Y., Mao, W., Jakovcevski, M., Dincer, A., Krueger, W., et al. (2013). Conserved chromosome 2q31 conformations are associated with transcriptional regulation of GAD1 GABA synthesis enzyme and altered in prefrontal cortex of subjects with schizophrenia. The Journal of Neuroscience, 33(29), 11839–11851.  https://doi.org/10.1523/JNEUROSCI.1252-13.2013CrossRefPubMedPubMedCentralGoogle Scholar
  176. 176.
    Bharadwaj, R., Peter, C. J., Jiang, Y., Roussos, P., Vogel-Ciernia, A., Shen, E. Y., et al. (2014). Conserved higher-order chromatin regulates NMDA receptor gene expression and cognition. Neuron, 84(5), 997–1008.  https://doi.org/10.1016/j.neuron.2014.10.032CrossRefPubMedPubMedCentralGoogle Scholar
  177. 177.
    Bryois, J., Garrett, M. E., Song, L., Safi, A., Giusti-Rodriguez, P., Johnson, G. D., et al. (2018). Evaluation of chromatin accessibility in prefrontal cortex of individuals with schizophrenia. Nature Communications, 9(1), 3121.  https://doi.org/10.1038/s41467-018-05379-yCrossRefPubMedPubMedCentralGoogle Scholar
  178. 178.
    Fullard, J. F., Giambartolomei, C., Hauberg, M. E., Xu, K., Voloudakis, G., Shao, Z., et al. (2017). Open chromatin profiling of human postmortem brain infers functional roles for non-coding schizophrenia loci. Human Molecular Genetics, 26(10), 1942–1951.  https://doi.org/10.1093/hmg/ddx103CrossRefPubMedPubMedCentralGoogle Scholar
  179. 179.
    Fullard, J. F., Hauberg, M. E., Bendl, J., Egervari, G., Cirnaru, M. D., Reach, S. M., et al. (2018). An atlas of chromatin accessibility in the adult human brain. Genome Research, 28(8), 1243–1252.  https://doi.org/10.1101/gr.232488.117CrossRefPubMedPubMedCentralGoogle Scholar
  180. 180.
    Won, H., de la Torre-Ubieta, L., Stein, J. L., Parikshak, N. N., Huang, J., Opland, C. K., et al. (2016). Chromosome conformation elucidates regulatory relationships in developing human brain. Nature, 538(7626), 523–527.  https://doi.org/10.1038/nature19847CrossRefPubMedPubMedCentralGoogle Scholar
  181. 181.
    Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663–676.  https://doi.org/10.1016/j.cell.2006.07.024CrossRefPubMedPubMedCentralGoogle Scholar
  182. 182.
    Narsinh, K. H., Plews, J., & Wu, J. C. (2011). Comparison of human induced pluripotent and embryonic stem cells: fraternal or identical twins? Molecular Therapy, 19(4), 635–638.  https://doi.org/10.1038/mt.2011.41CrossRefPubMedPubMedCentralGoogle Scholar
  183. 183.
    Hoffman, G. E., Schrode, N., Flaherty, E., & Brennand, K. J. (2018). New considerations for hiPSC-based models of neuropsychiatric disorders. Molecular Psychiatry, 24, 49.  https://doi.org/10.1038/s41380-018-0029-1CrossRefPubMedPubMedCentralGoogle Scholar
  184. 184.
    Laurent, L. C., Ulitsky, I., Slavin, I., Tran, H., Schork, A., Morey, R., et al. (2011). Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture. Cell Stem Cell, 8(1), 106–118.  https://doi.org/10.1016/j.stem.2010.12.003CrossRefPubMedPubMedCentralGoogle Scholar
  185. 185.
    Lister, R., Pelizzola, M., Kida, Y. S., Hawkins, R. D., Nery, J. R., Hon, G., et al. (2011). Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature, 471(7336), 68–73.  https://doi.org/10.1038/nature09798CrossRefPubMedPubMedCentralGoogle Scholar
  186. 186.
    Julia, T. C. W., Carvalho, C. M. B., Yuan, B., Gu, S., Altheimer, A. N., McCarthy, S., et al. (2017). Divergent levels of marker chromosomes in an hiPSC-based model of psychosis. Stem Cell Reports, 8(3), 519–528.  https://doi.org/10.1016/j.stemcr.2017.01.010CrossRefGoogle Scholar
  187. 187.
    Grochowski, C. M., Gu, S., Yuan, B., Tcw, J., Brennand, K. J., Sebat, J., et al. (2018). Marker chromosome genomic structure and temporal origin implicate a chromoanasynthesis event in a family with pleiotropic psychiatric phenotypes. Human Mutation, 39(7), 939–946.  https://doi.org/10.1002/humu.23537CrossRefPubMedPubMedCentralGoogle Scholar
  188. 188.
    Kyttala, A., Moraghebi, R., Valensisi, C., Kettunen, J., Andrus, C., Pasumarthy, K. K., et al. (2016). Genetic variability overrides the impact of parental cell type and determines iPSC Differentiation Potential. Stem Cell Reports, 6(2), 200–212.  https://doi.org/10.1016/j.stemcr.2015.12.009CrossRefPubMedPubMedCentralGoogle Scholar
  189. 189.
    Hoffman, G. E., Hartley, B. J., Flaherty, E., Ladran, I., Gochman, P., Ruderfer, D. M., et al. (2017). Transcriptional signatures of schizophrenia in hiPSC-derived NPCs and neurons are concordant with post-mortem adult brains. Nature Communications, 8(1), 2225.  https://doi.org/10.1038/s41467-017-02330-5CrossRefPubMedPubMedCentralGoogle Scholar
  190. 190.
    Nehme, R., Zuccaro, E., Ghosh, S. D., Li, C., Sherwood, J. L., Pietilainen, O., et al. (2018). Combining NGN2 Programming with developmental patterning generates human excitatory neurons with NMDAR-mediated synaptic transmission. Cell Reports, 23(8), 2509–2523.  https://doi.org/10.1016/j.celrep.2018.04.066CrossRefPubMedPubMedCentralGoogle Scholar
  191. 191.
    Mertens, J., Marchetto, M. C., Bardy, C., & Gage, F. H. (2016). Evaluating cell reprogramming, differentiation and conversion technologies in neuroscience. Nature Reviews Neuroscience, 17(7), 424–437.  https://doi.org/10.1038/nrn.2016.46CrossRefPubMedPubMedCentralGoogle Scholar
  192. 192.
    Chambers, S. M., Fasano, C. A., Papapetrou, E. P., Tomishima, M., Sadelain, M., & Studer, L. (2009). Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nature Biotechnology, 27(3), 275–280.  https://doi.org/10.1038/nbt.1529CrossRefPubMedPubMedCentralGoogle Scholar
  193. 193.
    Marchetto, M. C., Carromeu, C., Acab, A., Yu, D., Yeo, G. W., Mu, Y., et al. (2010). A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell, 143(4), 527–539.  https://doi.org/10.1016/j.cell.2010.10.016CrossRefPubMedPubMedCentralGoogle Scholar
  194. 194.
    Maroof, A. M., Keros, S., Tyson, J. A., Ying, S. W., Ganat, Y. M., Merkle, F. T., et al. (2013). Directed differentiation and functional maturation of cortical interneurons from human embryonic stem cells. Cell Stem Cell, 12(5), 559–572.  https://doi.org/10.1016/j.stem.2013.04.008CrossRefPubMedPubMedCentralGoogle Scholar
  195. 195.
    Kriks, S., Shim, J. W., Piao, J., Ganat, Y. M., Wakeman, D. R., Xie, Z., et al. (2011). Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease. Nature, 480(7378), 547–551.  https://doi.org/10.1038/nature10648CrossRefPubMedPubMedCentralGoogle Scholar
  196. 196.
    Lu J., Zhong X., Liu H., Hao L., Tzu-Ling Huang C., Sherafat M. A., et al. (2016) Generation of serotonin neurons from human pluripotent stem cells. Nature Biotechnology 34(1):89–94Google Scholar
  197. 197.
    Yu, D. X., Di Giorgio, F. P., Yao, J., Marchetto, M. C., Brennand, K., Wright, R., et al. (2014). Modeling hippocampal neurogenesis using human pluripotent stem cells. Stem Cell Reports, 2(3), 295–310.  https://doi.org/10.1016/j.stemcr.2014.01.009CrossRefPubMedPubMedCentralGoogle Scholar
  198. 198.
    Sarkar, A., Mei, A., Paquola, A. C. M., Stern, S., Bardy, C., Klug, J. R., et al. (2018). Efficient generation of CA3 neurons from human pluripotent stem cells enables modeling of hippocampal connectivity in vitro. Cell Stem Cell, 22(5), 684–697. e689.  https://doi.org/10.1016/j.stem.2018.04.009CrossRefPubMedPubMedCentralGoogle Scholar
  199. 199.
    Qi, Y., Zhang, X. J., Renier, N., Wu, Z., Atkin, T., Sun, Z., et al. (2017). Combined small-molecule inhibition accelerates the derivation of functional cortical neurons from human pluripotent stem cells. Nature Biotechnology, 35(2), 154–163.  https://doi.org/10.1038/nbt.3777CrossRefPubMedPubMedCentralGoogle Scholar
  200. 200.
    Schwartzentruber, J., Foskolou, S., Kilpinen, H., Rodrigues, J., Alasoo, K., Knights, A. J., et al. (2018). Molecular and functional variation in iPSC-derived sensory neurons. Nature Genetics, 50(1), 54–61.  https://doi.org/10.1038/s41588-017-0005-8CrossRefPubMedGoogle Scholar
  201. 201.
    Kuijlaars, J., Oyelami, T., Diels, A., Rohrbacher, J., Versweyveld, S., Meneghello, G., et al. (2016). Sustained synchronized neuronal network activity in a human astrocyte co-culture system. Scientific Reports, 6, 36529.  https://doi.org/10.1038/srep36529CrossRefPubMedPubMedCentralGoogle Scholar
  202. 202.
    Gunhanlar, N., Shpak, G., van der Kroeg, M., Gouty-Colomer, L. A., Munshi, S. T., Lendemeijer, B., et al. (2018). A simplified protocol for differentiation of electrophysiologically mature neuronal networks from human induced pluripotent stem cells. Molecular Psychiatry, 23(5), 1336–1344.  https://doi.org/10.1038/mp.2017.56CrossRefPubMedGoogle Scholar
  203. 203.
    Vierbuchen, T., Ostermeier, A., Pang, Z. P., Kokubu, Y., Sudhof, T. C., & Wernig, M. (2010). Direct conversion of fibroblasts to functional neurons by defined factors. Nature, 463(7284), 1035–1041.  https://doi.org/10.1038/nature08797CrossRefPubMedPubMedCentralGoogle Scholar
  204. 204.
    Pang, Z. P., Yang, N., Vierbuchen, T., Ostermeier, A., Fuentes, D. R., Yang, T. Q., et al. (2011). Induction of human neuronal cells by defined transcription factors. Nature, 476(7359), 220–223.  https://doi.org/10.1038/nature10202CrossRefPubMedPubMedCentralGoogle Scholar
  205. 205.
    Zhang, Y., Pak, C., Han, Y., Ahlenius, H., Zhang, Z., Chanda, S., et al. (2013). Rapid single-step induction of functional neurons from human pluripotent stem cells. Neuron, 78(5), 785–798.  https://doi.org/10.1016/j.neuron.2013.05.029CrossRefPubMedPubMedCentralGoogle Scholar
  206. 206.
    Ho, S. M., Hartley, B. J., Tcw, J., Beaumont, M., Stafford, K., Slesinger, P. A., et al. (2016). Rapid Ngn2-induction of excitatory neurons from hiPSC-derived neural progenitor cells. Methods, 101, 113–124.  https://doi.org/10.1016/j.ymeth.2015.11.019CrossRefPubMedGoogle Scholar
  207. 207.
    Colasante, G., Lignani, G., Rubio, A., Medrihan, L., Yekhlef, L., Sessa, A., et al. (2015). Rapid conversion of fibroblasts into functional forebrain GABAergic interneurons by direct genetic reprogramming. Cell Stem Cell, 17(6), 719–734.  https://doi.org/10.1016/j.stem.2015.09.002CrossRefPubMedGoogle Scholar
  208. 208.
    Sun, A. X., Yuan, Q., Tan, S., Xiao, Y., Wang, D., Khoo, A. T., et al. (2016). Direct induction and functional maturation of forebrain GABAergic neurons from human pluripotent stem cells. Cell Reports, 16(7), 1942–1953.  https://doi.org/10.1016/j.celrep.2016.07.035CrossRefPubMedGoogle Scholar
  209. 209.
    Yang, N., Chanda, S., Marro, S., Ng, Y. H., Janas, J. A., Haag, D., et al. (2017). Generation of pure GABAergic neurons by transcription factor programming. Nature Methods, 14(6), 621–628.  https://doi.org/10.1038/nmeth.4291CrossRefPubMedPubMedCentralGoogle Scholar
  210. 210.
    Caiazzo, M., Dell'Anno, M. T., Dvoretskova, E., Lazarevic, D., Taverna, S., Leo, D., et al. (2011). Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature, 476(7359), 224–227.  https://doi.org/10.1038/nature10284CrossRefPubMedGoogle Scholar
  211. 211.
    Theka, I., Caiazzo, M., Dvoretskova, E., Leo, D., Ungaro, F., Curreli, S., et al. (2013). Rapid generation of functional dopaminergic neurons from human induced pluripotent stem cells through a single-step procedure using cell lineage transcription factors. Stem Cells Translational Medicine, 2(6), 473–479.  https://doi.org/10.5966/sctm.2012-0133CrossRefPubMedPubMedCentralGoogle Scholar
  212. 212.
    Lu, J., Zhong, X., Liu, H., Hao, L., Huang, C. T., Sherafat, M. A., et al. (2016). Generation of serotonin neurons from human pluripotent stem cells. Nature Biotechnology, 34(1), 89–94.  https://doi.org/10.1038/nbt.3435CrossRefPubMedGoogle Scholar
  213. 213.
    Vadodaria, K. C., Mertens, J., Paquola, A., Bardy, C., Li, X., Jappelli, R., et al. (2016). Generation of functional human serotonergic neurons from fibroblasts. Molecular Psychiatry, 21(1), 49–61.  https://doi.org/10.1038/mp.2015.161CrossRefPubMedGoogle Scholar
  214. 214.
    Brennand, K. J., Simone, A., Jou, J., Gelboin-Burkhart, C., Tran, N., Sangar, S., et al. (2011). Modelling schizophrenia using human induced pluripotent stem cells. Nature, 473(7346), 221–225.  https://doi.org/10.1038/nature09915CrossRefPubMedPubMedCentralGoogle Scholar
  215. 215.
    Hook, V., Brennand, K. J., Kim, Y., Toneff, T., Funkelstein, L., Lee, K. C., et al. (2014). Human iPSC neurons display activity-dependent neurotransmitter secretion: aberrant catecholamine levels in schizophrenia neurons. Stem Cell Reports, 3(4), 531–538.  https://doi.org/10.1016/j.stemcr.2014.08.001CrossRefPubMedPubMedCentralGoogle Scholar
  216. 216.
    Robicsek, O., Karry, R., Petit, I., Salman-Kesner, N., Muller, F. J., Klein, E., et al. (2013). Abnormal neuronal differentiation and mitochondrial dysfunction in hair follicle-derived induced pluripotent stem cells of schizophrenia patients. Molecular Psychiatry, 18(10), 1067–1076.  https://doi.org/10.1038/mp.2013.67CrossRefPubMedGoogle Scholar
  217. 217.
    Xu, J., Hartley, B. J., Kurup, P., Phillips, A., Topol, A., Xu, M., et al. (2018). Inhibition of STEP61 ameliorates deficits in mouse and hiPSC-based schizophrenia models. Molecular Psychiatry, 23(2), 271–281.  https://doi.org/10.1038/mp.2016.163CrossRefPubMedGoogle Scholar
  218. 218.
    Carty, N. C., Xu, J., Kurup, P., Brouillette, J., Goebel-Goody, S. M., Austin, D. R., et al. (2012). The tyrosine phosphatase STEP: implications in schizophrenia and the molecular mechanism underlying antipsychotic medications. Translational Psychiatry, 2, e137.  https://doi.org/10.1038/tp.2012.63CrossRefPubMedPubMedCentralGoogle Scholar
  219. 219.
    Brennand, K., Savas, J. N., Kim, Y., Tran, N., Simone, A., Hashimoto-Torii, K., et al. (2015). Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Molecular Psychiatry, 20(3), 361–368.  https://doi.org/10.1038/mp.2014.22CrossRefPubMedGoogle Scholar
  220. 220.
    Topol, A., English, J. A., Flaherty, E., Rajarajan, P., Hartley, B. J., Gupta, S., et al. (2015a). Increased abundance of translation machinery in stem cell-derived neural progenitor cells from four schizophrenia patients. Translational Psychiatry, 5, e662.  https://doi.org/10.1038/tp.2015.118CrossRefPubMedPubMedCentralGoogle Scholar
  221. 221.
    Topol, A., Zhu, S., Tran, N., Simone, A., Fang, G., & Brennand, K. J. (2015b). Altered WNT signaling in human induced pluripotent stem cell neural progenitor cells derived from four schizophrenia patients. Biological Psychiatry, 78(6), e29–e34.  https://doi.org/10.1016/j.biopsych.2014.12.028CrossRefPubMedPubMedCentralGoogle Scholar
  222. 222.
    Casas, B. S., Vitoria, G., do Costa, M. N., Madeiro da Costa, R., Trindade, P., Maciel, R., et al. (2018). hiPSC-derived neural stem cells from patients with schizophrenia induce an impaired angiogenesis. Translational Psychiatry, 8(1), 48.  https://doi.org/10.1038/s41398-018-0095-9CrossRefPubMedPubMedCentralGoogle Scholar
  223. 223.
    Hino, M., Kunii, Y., Matsumoto, J., Wada, A., Nagaoka, A., Niwa, S., et al. (2016). Decreased VEGFR2 expression and increased phosphorylated Akt1 in the prefrontal cortex of individuals with schizophrenia. Journal of Psychiatric Research, 82, 100–108.  https://doi.org/10.1016/j.jpsychires.2016.07.018CrossRefPubMedGoogle Scholar
  224. 224.
    Lee, B. H., Hong, J. P., Hwang, J. A., Ham, B. J., Na, K. S., Kim, W. J., et al. (2015). Alterations in plasma vascular endothelial growth factor levels in patients with schizophrenia before and after treatment. Psychiatry Research, 228(1), 95–99.  https://doi.org/10.1016/j.psychres.2015.04.020CrossRefPubMedGoogle Scholar
  225. 225.
    Lopes, R., Soares, R., Coelho, R., & Figueiredo-Braga, M. (2015). Angiogenesis in the pathophysiology of schizophrenia - a comprehensive review and a conceptual hypothesis. Life Sciences, 128, 79–93.  https://doi.org/10.1016/j.lfs.2015.02.010CrossRefPubMedGoogle Scholar
  226. 226.
    Gonzalez, D. M., Gregory, J., & Brennand, K. J. (2017). The importance of non-neuronal cell types in hiPSC-based disease modeling and drug screening. Frontiers in Cell and Development Biology, 5, 117.  https://doi.org/10.3389/fcell.2017.00117CrossRefGoogle Scholar
  227. 227.
    Ben-Shachar, D. (2002). Mitochondrial dysfunction in schizophrenia: a possible linkage to dopamine. Journal of Neurochemistry, 83(6), 1241–1251.PubMedGoogle Scholar
  228. 228.
    Prabakaran, S., Swatton, J. E., Ryan, M. M., Huffaker, S. J., Huang, J. T., Griffin, J. L., et al. (2004). Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress. Molecular Psychiatry, 9(7), 684–697, 643.  https://doi.org/10.1038/sj.mp.4001511CrossRefPubMedGoogle Scholar
  229. 229.
    Uguz, A. C., Demirci, K., & Espino, J. (2016). The importance of melatonin and mitochondria interaction in mood disorders and schizophrenia: a current assessment. Current Medicinal Chemistry, 23(20), 2146–2158.PubMedGoogle Scholar
  230. 230.
    Paulsen Bda, S., de Moraes Maciel, R., Galina, A., Souza da Silveira, M., dos Santos Souza, C., Drummond, H., et al. (2012). Altered oxygen metabolism associated to neurogenesis of induced pluripotent stem cells derived from a schizophrenic patient. Cell Transplantation, 21(7), 1547–1559.  https://doi.org/10.3727/096368911X600957CrossRefPubMedGoogle Scholar
  231. 231.
    Robicsek, O., Ene, H. M., Karry, R., Ytzhaki, O., Asor, E., McPhie, D., et al. (2018). Isolated mitochondria transfer improves neuronal differentiation of schizophrenia-derived induced pluripotent stem cells and rescues deficits in a rat model of the disorder. Schizophrenia Bulletin, 44(2), 432–442.  https://doi.org/10.1093/schbul/sbx077CrossRefPubMedGoogle Scholar
  232. 232.
    Caputo, V., Ciolfi, A., Macri, S., & Pizzuti, A. (2015). The emerging role of MicroRNA in schizophrenia. CNS & Neurological Disorders Drug Targets, 14(2), 208–221.Google Scholar
  233. 233.
    Shi, S., Leites, C., He, D., Schwartz, D., Moy, W., Shi, J., et al. (2014). MicroRNA-9 and microRNA-326 regulate human dopamine D2 receptor expression, and the microRNA-mediated expression regulation is altered by a genetic variant. The Journal of Biological Chemistry, 289(19), 13434–13444.  https://doi.org/10.1074/jbc.M113.535203CrossRefPubMedPubMedCentralGoogle Scholar
  234. 234.
    Han, J., Kim, H. J., Schafer, S. T., Paquola, A., Clemenson, G. D., Toda, T., et al. (2016). Functional implications of miR-19 in the migration of newborn neurons in the adult brain. Neuron, 91(1), 79–89.  https://doi.org/10.1016/j.neuron.2016.05.034CrossRefPubMedGoogle Scholar
  235. 235.
    Topol, A., Zhu, S., Hartley, B. J., English, J., Hauberg, M. E., Tran, N., et al. (2016). Dysregulation of miRNA-9 in a subset of schizophrenia patient-derived neural progenitor cells. Cell Reports, 15(5), 1024–1036.  https://doi.org/10.1016/j.celrep.2016.03.090CrossRefPubMedPubMedCentralGoogle Scholar
  236. 236.
    Hauberg, M. E., Roussos, P., Grove, J., Borglum, A. D., Mattheisen, M., & Schizophrenia Working Group of the Psychiatric Genomics Consortium. (2016). Analyzing the role of MicroRNAs in schizophrenia in the context of common genetic risk variants. JAMA Psychiatry, 73(4), 369–377.  https://doi.org/10.1001/jamapsychiatry.2015.3018CrossRefPubMedPubMedCentralGoogle Scholar
  237. 237.
    Hoffman, G. E., & Brennand, K. J. (2018). Mapping regulatory variants in hiPSC models. Nature Genetics, 50(1), 1–2.  https://doi.org/10.1038/s41588-017-0017-4CrossRefPubMedGoogle Scholar
  238. 238.
    Roussos, P., Guennewig, B., Kaczorowski, D. C., Barry, G., & Brennand, K. J. (2016). Activity-dependent changes in gene expression in schizophrenia human-induced pluripotent stem cell neurons. JAMA Psychiatry, 73(11), 1180–1188.  https://doi.org/10.1001/jamapsychiatry.2016.2575CrossRefPubMedPubMedCentralGoogle Scholar
  239. 239.
    Yoshimizu, T., Pan, J. Q., Mungenast, A. E., Madison, J. M., Su, S., Ketterman, J., et al. (2015). Functional implications of a psychiatric risk variant within CACNA1C in induced human neurons. Molecular Psychiatry, 20(2), 162–169.  https://doi.org/10.1038/mp.2014.143CrossRefPubMedGoogle Scholar
  240. 240.
    Forrest, M. P., Zhang, H., Moy, W., McGowan, H., Leites, C., Dionisio, L. E., et al. (2017). Open chromatin profiling in hiPSC-derived neurons prioritizes functional noncoding psychiatric risk variants and highlights neurodevelopmental loci. Cell Stem Cell, 21(3), 305–318. e308.  https://doi.org/10.1016/j.stem.2017.07.008CrossRefPubMedPubMedCentralGoogle Scholar
  241. 241.
    Powell, S. K., Gregory, J., Akbarian, S., & Brennand, K. J. (2017). Application of CRISPR/Cas9 to the study of brain development and neuropsychiatric disease. Molecular and Cellular Neurosciences, 82, 157–166.  https://doi.org/10.1016/j.mcn.2017.05.007CrossRefPubMedPubMedCentralGoogle Scholar
  242. 242.
    Ho, S. M., Hartley, B. J., Flaherty, E., Rajarajan, P., Abdelaal, R., Obiorah, I., et al. (2017). Evaluating synthetic activation and repression of neuropsychiatric-related genes in hiPSC-derived NPCs, neurons, and astrocytes. Stem Cell Reports, 9(2), 615–628.  https://doi.org/10.1016/j.stemcr.2017.06.012CrossRefPubMedPubMedCentralGoogle Scholar
  243. 243.
    Jiang, Y., Loh, Y. E., Rajarajan, P., Hirayama, T., Liao, W., Kassim, B. S., et al. (2017). The methyltransferase SETDB1 regulates a large neuron-specific topological chromatin domain. Nature Genetics, 49(8), 1239–1250.  https://doi.org/10.1038/ng.3906CrossRefPubMedPubMedCentralGoogle Scholar
  244. 244.
    Rajarajan, P., Jiang, Y., Kassim, B. S., & Akbarian, S. (2018b). Chromosomal conformations and epigenomic regulation in schizophrenia. Progress in Molecular Biology and Translational Science, 157, 21–40.  https://doi.org/10.1016/bs.pmbts.2017.11.022CrossRefPubMedPubMedCentralGoogle Scholar
  245. 245.
    Zarrei, M., MacDonald, J. R., Merico, D., & Scherer, S. W. (2015). A copy number variation map of the human genome. Nature Reviews Genetics, 16(3), 172–183.  https://doi.org/10.1038/nrg3871CrossRefPubMedGoogle Scholar
  246. 246.
    Ahn, K., Gotay, N., Andersen, T. M., Anvari, A. A., Gochman, P., Lee, Y., et al. (2014). High rate of disease-related copy number variations in childhood onset schizophrenia. Molecular Psychiatry, 19(5), 568–572.  https://doi.org/10.1038/mp.2013.59CrossRefPubMedGoogle Scholar
  247. 247.
    Flaherty E. K., Brennand K. J., (2017) Using hiPSCs to model neuropsychiatric copy number variations (CNVs) has potential to reveal underlying disease mechanisms. Brain Research 1655:283–293Google Scholar
  248. 248.
    Gothelf, D., Eliez, S., Thompson, T., Hinard, C., Penniman, L., Feinstein, C., et al. (2005). COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome. Nature Neuroscience, 8(11), 1500–1502.  https://doi.org/10.1038/nn1572CrossRefPubMedGoogle Scholar
  249. 249.
    Gothelf, D., Feinstein, C., Thompson, T., Gu, E., Penniman, L., Van Stone, E., et al. (2007). Risk factors for the emergence of psychotic disorders in adolescents with 22q11.2 deletion syndrome. The American Journal of Psychiatry, 164(4), 663–669.  https://doi.org/10.1176/ajp.2007.164.4.663CrossRefPubMedGoogle Scholar
  250. 250.
    Murphy, K. C., Jones, L. A., & Owen, M. J. (1999). High rates of schizophrenia in adults with velo-cardio-facial syndrome. Archives of General Psychiatry, 56(10), 940–945.PubMedGoogle Scholar
  251. 251.
    Pedrosa, E., Sandler, V., Shah, A., Carroll, R., Chang, C., Rockowitz, S., et al. (2011). Development of patient-specific neurons in schizophrenia using induced pluripotent stem cells. Journal of Neurogenetics, 25(3), 88–103.  https://doi.org/10.3109/01677063.2011.597908CrossRefPubMedGoogle Scholar
  252. 252.
    Lin, M., Pedrosa, E., Hrabovsky, A., Chen, J., Puliafito, B. R., Gilbert, S. R., et al. (2016). Integrative transcriptome network analysis of iPSC-derived neurons from schizophrenia and schizoaffective disorder patients with 22q11.2 deletion. BMC Systems Biology, 10(1), 105.  https://doi.org/10.1186/s12918-016-0366-0CrossRefPubMedPubMedCentralGoogle Scholar
  253. 253.
    Zhao, D., Lin, M., Chen, J., Pedrosa, E., Hrabovsky, A., Fourcade, H. M., et al. (2015). MicroRNA profiling of neurons generated using induced pluripotent stem cells derived from patients with schizophrenia and schizoaffective disorder, and 22q11.2 Del. PLoS One, 10(7), e0132387.  https://doi.org/10.1371/journal.pone.0132387CrossRefPubMedPubMedCentralGoogle Scholar
  254. 254.
    Toyoshima, M., Akamatsu, W., Okada, Y., Ohnishi, T., Balan, S., Hisano, Y., et al. (2016). Analysis of induced pluripotent stem cells carrying 22q11.2 deletion. Translational Psychiatry, 6(11), e934.  https://doi.org/10.1038/tp.2016.206CrossRefPubMedPubMedCentralGoogle Scholar
  255. 255.
    Warnica, W., Merico, D., Costain, G., Alfred, S. E., Wei, J., Marshall, C. R., et al. (2015). Copy number variable microRNAs in schizophrenia and their neurodevelopmental gene targets. Biological Psychiatry, 77(2), 158–166.  https://doi.org/10.1016/j.biopsych.2014.05.011CrossRefPubMedGoogle Scholar
  256. 256.
    Yoon, K. J., Nguyen, H. N., Ursini, G., Zhang, F., Kim, N. S., Wen, Z., et al. (2014). Modeling a genetic risk for schizophrenia in iPSCs and mice reveals neural stem cell deficits associated with adherens junctions and polarity. Cell Stem Cell, 15(1), 79–91.  https://doi.org/10.1016/j.stem.2014.05.003CrossRefPubMedPubMedCentralGoogle Scholar
  257. 257.
    McCarthy S. E., Makarov V., Kirov G., Addington A. M., McClellan J., Yoon S., et al. (2009) Microduplications of 16p11.2 are associated with schizophrenia. Nature Genetics 41 (11):1223–1227Google Scholar
  258. 258.
    Deshpande, A., Yadav, S., Dao, D. Q., Wu, Z. Y., Hokanson, K. C., Cahill, M. K., et al. (2017). Cellular phenotypes in human iPSC-derived neurons from a genetic model of autism spectrum disorder. Cell Reports, 21(10), 2678–2687.  https://doi.org/10.1016/j.celrep.2017.11.037CrossRefPubMedPubMedCentralGoogle Scholar
  259. 259.
    Rujescu, D., Ingason, A., Cichon, S., Pietilainen, O. P., Barnes, M. R., Toulopoulou, T., et al. (2009). Disruption of the neurexin 1 gene is associated with schizophrenia. Human Molecular Genetics, 18(5), 988–996.  https://doi.org/10.1093/hmg/ddn351CrossRefPubMedGoogle Scholar
  260. 260.
    Zeng, L., Zhang, P., Shi, L., Yamamoto, V., Lu, W., & Wang, K. (2013). Functional impacts of NRXN1 knockdown on neurodevelopment in stem cell models. PLoS One, 8(3), e59685.  https://doi.org/10.1371/journal.pone.0059685CrossRefPubMedPubMedCentralGoogle Scholar
  261. 261.
    Pak, C., Danko, T., Zhang, Y., Aoto, J., Anderson, G., Maxeiner, S., et al. (2015). Human neuropsychiatric disease modeling using conditional deletion reveals synaptic transmission defects caused by heterozygous mutations in NRXN1. Cell Stem Cell, 17(3), 316–328.  https://doi.org/10.1016/j.stem.2015.07.017CrossRefPubMedPubMedCentralGoogle Scholar
  262. 262.
    Flaherty E., Zhu S., Barretto N., Cheng E., Michael Deans P. J., Fernando M. B., et al. (2019) Neuronal impact of patient-specific aberrant NRXN1α splicing. Nature Genetics 51 (12):1679–1690Google Scholar
  263. 263.
    Jacobs, P., Brunton, M., Frackiewicz, A., Newton, M., Cook, P., & Robson, E. (1970). Studies on a family with three cytogenetic markers. Annals of Human Genetics, 33, 325–336.Google Scholar
  264. 264.
    St Clair, D., Blackwood, D., Muir, W., Carothers, A., Walker, M., Spowart, G., et al. (1990). Association within a family of a balanced autosomal translocation with major mental illness. Lancet, 336(8706), 13–16.PubMedGoogle Scholar
  265. 265.
    Millar, J. K., Wilson-Annan, J. C., Anderson, S., Christie, S., Taylor, M. S., Semple, C. A., et al. (2000). Disruption of two novel genes by a translocation co-segregating with schizophrenia. Human Molecular Genetics, 9(9), 1415–1423.PubMedGoogle Scholar
  266. 266.
    Sachs, N. A., Sawa, A., Holmes, S. E., Ross, C. A., DeLisi, L. E., & Margolis, R. L. (2005). A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder. Molecular Psychiatry, 10(8), 758–764.  https://doi.org/10.1038/sj.mp.4001667CrossRefPubMedPubMedCentralGoogle Scholar
  267. 267.
    Green, E. K., Norton, N., Peirce, T., Grozeva, D., Kirov, G., Owen, M. J., et al. (2006). Evidence that a DISC1 frame-shift deletion associated with psychosis in a single family may not be a pathogenic mutation. Molecular Psychiatry, 11(9), 798–799.  https://doi.org/10.1038/sj.mp.4001853CrossRefPubMedGoogle Scholar
  268. 268.
    Chiang, C. H., Su, Y., Wen, Z., Yoritomo, N., Ross, C. A., Margolis, R. L., et al. (2011). Integration-free induced pluripotent stem cells derived from schizophrenia patients with a DISC1 mutation. Molecular Psychiatry, 16(4), 358–360.  https://doi.org/10.1038/mp.2011.13CrossRefPubMedPubMedCentralGoogle Scholar
  269. 269.
    Wen, Z., Nguyen, H. N., Guo, Z., Lalli, M. A., Wang, X., Su, Y., et al. (2014). Synaptic dysregulation in a human iPS cell model of mental disorders. Nature, 515(7527), 414–418.  https://doi.org/10.1038/nature13716CrossRefPubMedPubMedCentralGoogle Scholar
  270. 270.
    Murai, K., Sun, G., Ye, P., Tian, E., Yang, S., Cui, Q., et al. (2016). The TLX-miR-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia iPSC model. Nature Communications, 7, 10965.  https://doi.org/10.1038/ncomms10965CrossRefPubMedPubMedCentralGoogle Scholar
  271. 271.
    Yalla, K., Elliott, C., Day, J. P., Findlay, J., Barratt, S., Hughes, Z. A., et al. (2018). FBXW7 regulates DISC1 stability via the ubiquitin-proteosome system. Molecular Psychiatry, 23(5), 1278–1286.  https://doi.org/10.1038/mp.2017.138CrossRefPubMedGoogle Scholar
  272. 272.
    Chiu, F. L., Lin, J. T., Chuang, C. Y., Chien, T., Chen, C. M., Chen, K. H., et al. (2015). Elucidating the role of the A2A adenosine receptor in neurodegeneration using neurons derived from Huntington’s disease iPSCs. Human Molecular Genetics, 24(21), 6066–6079.  https://doi.org/10.1093/hmg/ddv318CrossRefPubMedGoogle Scholar
  273. 273.
    Chien, T., Weng, Y. T., Chang, S. Y., Lai, H. L., Chiu, F. L., Kuo, H. C., et al. (2018). GSK3beta negatively regulates TRAX, a scaffold protein implicated in mental disorders, for NHEJ-mediated DNA repair in neurons. Molecular Psychiatry.  https://doi.org/10.1038/s41380-017-0007-z
  274. 274.
    Srikanth, P., Han, K., Callahan, D. G., Makovkina, E., Muratore, C. R., Lalli, M. A., et al. (2015). Genomic DISC1 disruption in hiPSCs alters Wnt signaling and neural cell fate. Cell Reports, 12(9), 1414–1429.  https://doi.org/10.1016/j.celrep.2015.07.061CrossRefPubMedPubMedCentralGoogle Scholar
  275. 275.
    Bradshaw, N. J., & Porteous, D. J. (2012). DISC1-binding proteins in neural development, signalling and schizophrenia. Neuropharmacology, 62(3), 1230–1241.  https://doi.org/10.1016/j.neuropharm.2010.12.027CrossRefPubMedPubMedCentralGoogle Scholar
  276. 276.
    Camargo, L. M., Collura, V., Rain, J. C., Mizuguchi, K., Hermjakob, H., Kerrien, S., et al. (2007). Disrupted in schizophrenia 1 interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Molecular Psychiatry, 12(1), 74–86.  https://doi.org/10.1038/sj.mp.4001880CrossRefPubMedGoogle Scholar
  277. 277.
    Camargo, L. M., Wang, Q., & Brandon, N. J. (2008). What can we learn from the disrupted in schizophrenia 1 interactome: lessons for target identification and disease biology? Novartis Foundation Symposium, 289, 208–216; discussion 216-221, 238-240.PubMedGoogle Scholar
  278. 278.
    Teng, S., Thomson, P. A., McCarthy, S., Kramer, M., Muller, S., & Lihm, J. (2018). Rare disruptive variants in the DISC1 Interactome and Regulome: association with cognitive ability and schizophrenia. Molecular Psychiatry, 23(5), 1270–1277.  https://doi.org/10.1038/mp.2017.115CrossRefPubMedGoogle Scholar
  279. 279.
    Nakata, K., Lipska, B. K., Hyde, T. M., Ye, T., Newburn, E. N., Morita, Y., et al. (2009). DISC1 splice variants are upregulated in schizophrenia and associated with risk polymorphisms. Proceedings of the National Academy of Sciences of the United States of America, 106(37), 15873–15878.  https://doi.org/10.1073/pnas.0903413106CrossRefPubMedPubMedCentralGoogle Scholar
  280. 280.
    Wilkinson, B., Evgrafov, O. V., Zheng, D., Hartel, N., Knowles, J. A., Graham, N. A., et al. (2018). Endogenous cell type-specific disrupted in schizophrenia 1 interactomes reveal protein networks associated with neurodevelopmental disorders. Biological Psychiatry, 85, 305.  https://doi.org/10.1016/j.biopsych.2018.05.009CrossRefPubMedPubMedCentralGoogle Scholar
  281. 281.
    Turner, T. N., Yi, Q., Krumm, N., Huddleston, J., Hoekzema, K., Stessman, H. A., et al. (2017). denovo-db: a compendium of human de novo variants. Nucleic Acids Research, 45(D1), D804–D811.  https://doi.org/10.1093/nar/gkw865CrossRefPubMedGoogle Scholar
  282. 282.
    Bakircioglu, M., Carvalho, O. P., Khurshid, M., Cox, J. J., Tuysuz, B., Barak, T., et al. (2011). The essential role of centrosomal NDE1 in human cerebral cortex neurogenesis. American Journal of Human Genetics, 88(5), 523–535.  https://doi.org/10.1016/j.ajhg.2011.03.019CrossRefPubMedPubMedCentralGoogle Scholar
  283. 283.
    Ye, F., Kang, E., Yu, C., Qian, X., Jacob, F., Yu, C., et al. (2017). DISC1 regulates neurogenesis via modulating kinetochore attachment of Ndel1/Nde1 during mitosis. Neuron, 96(5), 1041–1054. e1045.  https://doi.org/10.1016/j.neuron.2017.10.010CrossRefPubMedPubMedCentralGoogle Scholar
  284. 284.
    Mathieson, I., Munafo, M. R., & Flint, J. (2012). Meta-analysis indicates that common variants at the DISC1 locus are not associated with schizophrenia. Molecular Psychiatry, 17(6), 634–641.  https://doi.org/10.1038/mp.2011.41CrossRefPubMedGoogle Scholar
  285. 285.
    Richards, A. L., Leonenko, G., Walters, J. T., Kavanagh, D. H., Rees, E. G., Evans, A., et al. (2016). Exome arrays capture polygenic rare variant contributions to schizophrenia. Human Molecular Genetics, 25(5), 1001–1007.  https://doi.org/10.1093/hmg/ddv620CrossRefPubMedPubMedCentralGoogle Scholar
  286. 286.
    Farrell, M. S., Werge, T., Sklar, P., Owen, M. J., Ophoff, R. A., O'Donovan, M. C., et al. (2015). Evaluating historical candidate genes for schizophrenia. Molecular Psychiatry, 20(5), 555–562.  https://doi.org/10.1038/mp.2015.16CrossRefPubMedPubMedCentralGoogle Scholar
  287. 287.
    Sullivan, P. F. (2013). Questions about DISC1 as a genetic risk factor for schizophrenia. Molecular Psychiatry, 18(10), 1050–1052.  https://doi.org/10.1038/mp.2012.182CrossRefPubMedPubMedCentralGoogle Scholar
  288. 288.
    Lee I. S., Carvalho C. M. B., Douvaras P., Ho S-M, Hartley B. J., Zuccherato L. W., et al. (2015) Characterization of molecular and cellular phenotypes associated with a heterozygous CNTNAP2 deletion using patient-derived hiPSC neural cells. npj Schizophrenia 1 (1)Google Scholar
  289. 289.
    Flaherty, E., Deranieh, R. M., Artimovich, E., Lee, I. S., Siegel, A. J., Levy, D. L., et al. (2017). Patient-derived hiPSC neurons with heterozygous CNTNAP2 deletions display altered neuronal gene expression and network activity. NPJ Schizophrenia, 3, 35.  https://doi.org/10.1038/s41537-017-0033-5CrossRefPubMedPubMedCentralGoogle Scholar
  290. 290.
    de Vrij, F. M., Bouwkamp, C. G., Gunhanlar, N., Shpak, G., Lendemeijer, B., Baghdadi, M., et al. (2018). Candidate CSPG4 mutations and induced pluripotent stem cell modeling implicate oligodendrocyte progenitor cell dysfunction in familial schizophrenia. Molecular Psychiatry, 24, 757.  https://doi.org/10.1038/s41380-017-0004-2CrossRefPubMedPubMedCentralGoogle Scholar
  291. 291.
    Guennewig, B., Bitar, M., Obiorah, I., Hanks, J., O'Brien, E. A., Kaczorowski, D. C., et al. (2018). THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Translational Psychiatry, 8(1), 89.  https://doi.org/10.1038/s41398-018-0137-3CrossRefPubMedPubMedCentralGoogle Scholar
  292. 292.
    Obiorah, I. V., Muhammad, H., Stafford, K., Flaherty, E. K., & Brennand, K. J. (2017). THC treatment alters glutamate receptor gene expression in human stem cell-derived neurons. Molecular Neuropsychiatry, 3(2), 73–84.  https://doi.org/10.1159/000477762CrossRefPubMedPubMedCentralGoogle Scholar
  293. 293.
    Khandaker, G. M., Zimbron, J., Lewis, G., & Jones, P. B. (2013). Prenatal maternal infection, neurodevelopment and adult schizophrenia: a systematic review of population-based studies. Psychological Medicine, 43(2), 239–257.  https://doi.org/10.1017/S0033291712000736CrossRefPubMedGoogle Scholar
  294. 294.
    Kahn, R. S., Sommer, I. E., Murray, R. M., Meyer-Lindenberg, A., Weinberger, D. R., Cannon, T. D., et al. (2015). Schizophrenia. Nature Reviews Disease Primers, 1, 15067.  https://doi.org/10.1038/nrdp.2015.67CrossRefPubMedGoogle Scholar
  295. 295.
    Walsh, N. C., Kenney, L. L., Jangalwe, S., Aryee, K. E., Greiner, D. L., Brehm, M. A., et al. (2017). Humanized mouse models of clinical disease. Annual Review of Pathology, 12, 187–215.  https://doi.org/10.1146/annurev-pathol-052016-100332CrossRefPubMedGoogle Scholar
  296. 296.
    Allswede, D. M., Buka, S. L., Yolken, R. H., Torrey, E. F., & Cannon, T. D. (2016). Elevated maternal cytokine levels at birth and risk for psychosis in adult offspring. Schizophrenia Research, 172(1–3), 41–45.  https://doi.org/10.1016/j.schres.2016.02.022CrossRefPubMedGoogle Scholar
  297. 297.
    Lin, M., Zhao, D., Hrabovsky, A., Pedrosa, E., Zheng, D., & Lachman, H. M. (2014). Heat shock alters the expression of schizophrenia and autism candidate genes in an induced pluripotent stem cell model of the human telencephalon. PLoS One, 9(4), e94968.  https://doi.org/10.1371/journal.pone.0094968CrossRefPubMedPubMedCentralGoogle Scholar
  298. 298.
    Hashimoto-Torii, K., Torii, M., Fujimoto, M., Nakai, A., El Fatimy, R., Mezger, V., et al. (2014). Roles of heat shock factor 1 in neuronal response to fetal environmental risks and its relevance to brain disorders. Neuron, 82(3), 560–572.  https://doi.org/10.1016/j.neuron.2014.03.002CrossRefPubMedPubMedCentralGoogle Scholar
  299. 299.
    Ishii, S., Torii, M., Son, A. I., Rajendraprasad, M., Morozov, Y. M., Kawasawa, Y. I., et al. (2017). Variations in brain defects result from cellular mosaicism in the activation of heat shock signalling. Nature Communications, 8, 15157.  https://doi.org/10.1038/ncomms15157CrossRefPubMedPubMedCentralGoogle Scholar
  300. 300.
    Vallersnes, O. M., Dines, A. M., Wood, D. M., Yates, C., Heyerdahl, F., Hovda, K. E., et al. (2016). Psychosis associated with acute recreational drug toxicity: a European case series. BMC Psychiatry, 16, 293.  https://doi.org/10.1186/s12888-016-1002-7CrossRefPubMedPubMedCentralGoogle Scholar
  301. 301.
    Callaghan, R. C., Cunningham, J. K., Allebeck, P., Arenovich, T., Sajeev, G., Remington, G., et al. (2012). Methamphetamine use and schizophrenia: a population-based cohort study in California. The American Journal of Psychiatry, 169(4), 389–396.  https://doi.org/10.1176/appi.ajp.2011.10070937CrossRefPubMedGoogle Scholar
  302. 302.
    Nielsen, S. M., Toftdahl, N. G., Nordentoft, M., & Hjorthoj, C. (2017). Association between alcohol, cannabis, and other illicit substance abuse and risk of developing schizophrenia: a nationwide population based register study. Psychological Medicine, 47(9), 1668–1677.  https://doi.org/10.1017/S0033291717000162CrossRefPubMedGoogle Scholar
  303. 303.
    de Leon, J., & Diaz, F. J. (2005). A meta-analysis of worldwide studies demonstrates an association between schizophrenia and tobacco smoking behaviors. Schizophrenia Research, 76(2–3), 135–157.  https://doi.org/10.1016/j.schres.2005.02.010CrossRefPubMedGoogle Scholar
  304. 304.
    Pasman, J. A., Verweij, K. J. H., Gerring, Z., Stringer, S., Sanchez-Roige, S., Treur, J. L., et al. (2018). GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia. Nature Neuroscience, 21(9), 1161–1170.  https://doi.org/10.1038/s41593-018-0206-1CrossRefPubMedPubMedCentralGoogle Scholar
  305. 305.
    Chatterton, Z., Hartley, B. J., Seok, M. H., Mendelev, N., Chen, S., Milekic, M., et al. (2017). In utero exposure to maternal smoking is associated with DNA methylation alterations and reduced neuronal content in the developing fetal brain. Epigenetics & Chromatin, 10, 4.  https://doi.org/10.1186/s13072-017-0111-yCrossRefGoogle Scholar
  306. 306.
    Oedegaard, K. J., Alda, M., Anand, A., Andreassen, O. A., Balaraman, Y., Berrettini, W. H., et al. (2016). The pharmacogenomics of bipolar disorder study (PGBD): identification of genes for lithium response in a prospective sample. BMC Psychiatry, 16, 129.  https://doi.org/10.1186/s12888-016-0732-xCrossRefPubMedPubMedCentralGoogle Scholar
  307. 307.
    Ruderfer, D. M., Charney, A. W., Readhead, B., Kidd, B. A., Kahler, A. K., Kenny, P. J., et al. (2016). Polygenic overlap between schizophrenia risk and antipsychotic response: a genomic medicine approach. Lancet Psychiatry, 3(4), 350–357.  https://doi.org/10.1016/S2215-0366(15)00553-2CrossRefPubMedPubMedCentralGoogle Scholar
  308. 308.
    Li, J., Yoshikawa, A., Brennan, M. D., Ramsey, T. L., & Meltzer, H. Y. (2018). Genetic predictors of antipsychotic response to lurasidone identified in a genome wide association study and by schizophrenia risk genes. Schizophrenia Research, 192, 194–204.  https://doi.org/10.1016/j.schres.2017.04.009CrossRefPubMedGoogle Scholar
  309. 309.
    Kim, Y., Giusti-Rodriguez, P., Crowley, J. J., Bryois, J., Nonneman, R. J., Ryan, A. K., et al. (2018). Comparative genomic evidence for the involvement of schizophrenia risk genes in antipsychotic effects. Molecular Psychiatry, 23(3), 708–712.  https://doi.org/10.1038/mp.2017.111CrossRefPubMedGoogle Scholar
  310. 310.
    Readhead, B., Hartley, B. J., Eastwood, B. J., Collier, D. A., Evans, D., & Farias, R. (2018). Expression-based drug screening of neural progenitor cells from individuals with schizophrenia. Nature Communications, 9(1), 4412.  https://doi.org/10.1038/s41467-018-06515-4CrossRefPubMedPubMedCentralGoogle Scholar
  311. 311.
    Xu, M., Lee, E. M., Wen, Z., Cheng, Y., Huang, W. K., Qian, X., et al. (2016). Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nature Medicine, 22(10), 1101–1107.  https://doi.org/10.1038/nm.4184CrossRefPubMedPubMedCentralGoogle Scholar
  312. 312.
    Zhou, T., Tan, L., Cederquist, G. Y., Fan, Y., Hartley, B. J., Mukherjee, S., et al. (2017). High-content screening in hPSC-neural progenitors identifies drug candidates that inhibit Zika virus infection in fetal-like organoids and adult brain. Cell Stem Cell, 21(2), 274–283. e275.  https://doi.org/10.1016/j.stem.2017.06.017CrossRefPubMedPubMedCentralGoogle Scholar
  313. 313.
    Watanabe, M., Buth, J. E., Vishlaghi, N., de la Torre-Ubieta, L., Taxidis, J., Khakh, B. S., et al. (2017). Self-organized cerebral organoids with human-specific features predict effective drugs to combat Zika virus infection. Cell Reports, 21(2), 517–532.  https://doi.org/10.1016/j.celrep.2017.09.047CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Samuel K. Powell
    • 1
    • 2
    • 3
    • 4
    • 5
  • Callan P. O’Shea
    • 2
    • 3
  • Sara Rose Shannon
    • 2
    • 3
  • Schahram Akbarian
    • 2
    • 4
    • 5
  • Kristen J. Brennand
    • 2
    • 3
    • 4
    • 5
    Email author
  1. 1.Medical Scientist Training ProgramIcahn School of Medicine at Mount SinaiNew YorkUSA
  2. 2.Friedman Brain Institute, Icahn School of Medicine at Mount SinaiNew YorkUSA
  3. 3.Department of Genetics and GenomicsIcahn School of Medicine at Mount SinaiNew YorkUSA
  4. 4.Department of NeuroscienceIcahn School of Medicine at Mount SinaiNew YorkUSA
  5. 5.Department of PsychiatryIcahn School of Medicine at Mount SinaiNew YorkUSA

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