Schizophrenia environmental factors

Schizophrenia environmental factors DEFAULT

The environment and schizophrenia


  1. 1

    McGrath, J. et al. A systematic review of the incidence of schizophrenia: the distribution of rates and the influence of sex, urbanicity, migrant status and methodology. BMC Med.2, 13 (2004)Important report, bringing together a massive amount of data, summarizing the epidemiological evidence on the influences of sex, urbanicity and migrant status on the onset of schizophrenia.

    PubMedPubMed Central Google Scholar

  2. 2

    Perälä, J. et al. Lifetime prevalence of psychotic and bipolar I disorders in a general population. Arch. Gen. Psychiatry64, 19–28 (2007)

    PubMedPubMed Central Google Scholar

  3. 3

    van Os, J., Linscott, R. J., Myin-Germeys, I., Delespaul, P. & Krabbendam, L. A systematic review and meta-analysis of the psychosis continuum: evidence for a psychosis proneness-persistence-impairment model of psychotic disorder. Psychol. Med.39, 179–195 (2009)

    CASPubMed Google Scholar

  4. 4

    van Os, J. & Kapur, S. Schizophrenia. Lancet374, 635–645 (2009)

    CASPubMed Google Scholar

  5. 5

    Cantor-Graae, E. & Selten, J. P. Schizophrenia and migration: a meta-analysis and review. Am. J. Psychiatry162, 12–24 (2005)

    PubMed Google Scholar

  6. 6

    March, D. et al. Psychosis and place. Epidemiol. Rev.30, 84–100 (2008)Systematic review on the spatial variation in the distribution of psychotic disorder, indicating an important role for social exposures.

    PubMed Google Scholar

  7. 7

    Krabbendam, L. & van Os, J. Schizophrenia and urbanicity: a major environmental influence–conditional on genetic risk. Schizophr. Bull.31, 795–799 (2005)

    PubMed Google Scholar

  8. 8

    Kelly, B. D. et al. Schizophrenia and the city: a review of literature and prospective study of psychosis and urbanicity in Ireland. Schizophr. Res.116, 75–89 (2010)

    PubMed Google Scholar

  9. 9

    Keller, M. C., Medland, S. E. & Duncan, L. E. Are extended twin family designs worth the trouble? A comparison of the bias, precision, and accuracy of parameters estimated in four twin family models. Behav. Genet.40, 377–393 (2010)

    PubMed Google Scholar

  10. 10

    Hutchinson, G. et al. Morbid risk of schizophrenia in first-degree relatives of white and African-Caribbean patients with psychosis. Br. J. Psychiatry169, 776–780 (1996)

    CASPubMed Google Scholar

  11. 11

    van Os, J., Hanssen, M., Bak, M., Bijl, R. V. & Vollebergh, W. Do urbanicity and familial liability coparticipate in causing psychosis? Am. J. Psychiatry160, 477–482 (2003)

    PubMed Google Scholar

  12. 12

    van Os, J., Rutten, B. P. & Poulton, R. Gene-environment interactions in schizophrenia: review of epidemiological findings and future directions. Schizophr. Bull.34, 1066–1082 (2008)

    PubMedPubMed Central Google Scholar

  13. 13

    Guo, S. W. Gene-environment interaction and the mapping of complex traits: some statistical models and their implications. Hum. Hered.50, 286–303 (2000)

    CASPubMed Google Scholar

  14. 14

    Polanczyk, G. et al. Etiological and clinical features of childhood psychotic symptoms: results from a birth cohort. Arch. Gen. Psychiatry67, 328–338 (2010)Prospective study on a very well characterized UK birth cohort, showing alterations in developmental pathways in children with expression of liability for psychotic syndrome in the form of subclinical psychotic experiences.

    PubMedPubMed Central Google Scholar

  15. 15

    Kendler, K. S. et al. Sources of individual differences in depressive symptoms: analysis of two samples of twins and their families. Am. J. Psychiatry151, 1605–1614 (1994)

    CASPubMed Google Scholar

  16. 16

    Chen, L. S., Rice, T. K., Thompson, P. A., Barch, D. M. & Csernansky, J. G. Familial aggregation of clinical and neurocognitive features in sibling pairs with and without schizophrenia. Schizophr. Res.111, 159–166 (2009)

    PubMedPubMed Central Google Scholar

  17. 17

    Toulopoulou, T. et al. Substantial genetic overlap between neurocognition and schizophrenia: genetic modeling in twin samples. Arch. Gen. Psychiatry64, 1348–1355 (2007)

    PubMed Google Scholar

  18. 18

    Maric, N. et al. Is our concept of schizophrenia influenced by Berkson’s bias? Soc. Psychiatry Psychiatr. Epidemiol.39, 600–605 (2004)

    CASPubMed Google Scholar

  19. 19

    Dominguez, M. D., Saka, M. C., Lieb, R., Wittchen, H. U. & van Os, J. Early expression of negative/disorganized symptoms predicting psychotic experiences and subsequent clinical psychosis: a 10-year study. Am. J. Psychiatry167, 1075–1082 (2010)

    PubMed Google Scholar

  20. 20

    Dominguez, M. D., Wichers, M., Lieb, R., Wittchen, H. U. & van Os, J. Evidence that onset of clinical psychosis is an outcome of progressively more persistent subclinical psychotic experiences: an 8-year cohort study. Schizophr. Bull. . 10.1093/schbul/sbp022 (21 May 2009)

  21. 21

    Read, J., van Os, J., Morrison, A. P. & Ross, C. A. Childhood trauma, psychosis and schizophrenia: a literature review with theoretical and clinical implications. Acta Psychiatr. Scand.112, 330–350 (2005)

    CASPubMed Google Scholar

  22. 22

    Bendall, S., Jackson, H. J., Hulbert, C. A. & McGorry, P. D. Childhood trauma and psychotic disorders: a systematic, critical review of the evidence. Schizophr. Bull.34, 568–579 (2008)

    PubMed Google Scholar

  23. 23

    Morgan, C. & Fisher, H. Environment and schizophrenia: childhood trauma—a critical review. Schizophr. Bull.33, 3–10 (2007)

    PubMed Google Scholar

  24. 24

    Schreier, A. et al. Prospective study of peer victimization in childhood and psychotic symptoms in a nonclinical population at age 12 years. Arch. Gen. Psychiatry66, 527–536 (2009)

    PubMed Google Scholar

  25. 25

    Arseneault, L. et al. Childhood trauma and children’s emerging psychotic symptoms: a genetically sensitive longitudinal cohort study. Am. J. Psychiatry (in the press)

  26. 26

    Elklit, A. & Shevlin, M. Female sexual victimization predicts psychosis: a case-control study based on the Danish registry system. Schizophr. Bull. . 10.1093/schbul/sbq048 (20 May 2010)

  27. 27

    Fisher, H. L. et al. Reliability and comparability of psychosis patients’ retrospective reports of childhood abuse. Schizophr. Bull. . 10.1093/schbul/sbp103 (23 September 2009)

  28. 28

    Janssen, I. et al. Childhood abuse as a risk factor for psychotic experiences. Acta Psychiatr. Scand.109, 38–45 (2004)

    CASPubMed Google Scholar

  29. 29

    Bourque, F., van der Ven, E. & Malla, A. A meta-analysis of the risk for psychotic disorders among first- and second-generation immigrants. Psychol. Med. . 10.1017/S0033291710001406 (21 July 2010)Recent, detailed meta-analytical analysis showing that increased risk of schizophrenia among immigrants persists into the second generation, and that this may be mediated by social context.

  30. 30

    Bresnahan, M. et al. Race and risk of schizophrenia in a US birth cohort: another example of health disparity? Int. J. Epidemiol.36, 751–758 (2007)

    PubMed Google Scholar

  31. 31

    Veling, W. et al. Ethnic density of neighborhoods and incidence of psychotic disorders among immigrants. Am. J. Psychiatry165, 66–73 (2008)

    PubMed Google Scholar

  32. 32

    Boydell, J. et al. Incidence of schizophrenia in ethnic minorities in London: ecological study into interactions with environment. Br. Med. J.323, 1336 (2001)

    CAS Google Scholar

  33. 33

    Morgan, C., Charalambides, M., Hutchinson, G. & Murray, R. M. Migration, ethnicity, and psychosis: toward a sociodevelopmental model. Schizophr. Bull. . 10.1093/schbul/sbq051 (30 May 2010)Excellent review summarizing current evidence and future perspectives on environmental influences on psychotic disorder, particularly ethnic minority group, integrated in a novel sociodevelopmental hypothesis of psychotic disorder.

  34. 34

    Selten, J. P. & Cantor-Graae, E. Social defeat: risk factor for schizophrenia? Br. J. Psychiatry187, 101–102 (2005)

    PubMed Google Scholar

  35. 35

    Mortensen, P. B., Pedersen, M. G. & Pedersen, C. B. Psychiatric family history and schizophrenia risk in Denmark: which mental disorders are relevant? Psychol. Med.40, 201–210 (2010)

    CASPubMed Google Scholar

  36. 36

    Pedersen, C. B. & Mortensen, P. B. Evidence of a dose-response relationship between urbanicity during upbringing and schizophrenia risk. Arch. Gen. Psychiatry58, 1039–1046 (2001)

    CASPubMed Google Scholar

  37. 37

    van Os, J., Driessen, G., Gunther, N. & Delespaul, P. Neighbourhood variation in incidence of schizophrenia. Evidence for person-environment interaction. Br. J. Psychiatry176, 243–248 (2000)

    CASPubMed Google Scholar

  38. 38

    Zammit, S. et al. Individuals, schools, and neighborhood: a multilevel longitudinal study of variation in incidence of psychotic disorders. Arch. Gen. Psychiatry67, 914–922 (2010)Fascinating longitudinal study showing how individual-level risk factors may vary from protective to risk-increasing depending on the degree to which they are the norm or the exception in relation to the wider social environment.

    PubMed Google Scholar

  39. 39

    Morrison, P. D. et al. The acute effects of synthetic intravenous Δ9-tetrahydrocannabinol on psychosis, mood and cognitive functioning. Psychol. Med.39, 1607–1616 (2009)

    CASPubMed Google Scholar

  40. 40

    D’Souza, D. C. et al. Delta-9-tetrahydrocannabinol effects in schizophrenia: implications for cognition, psychosis, and addiction. Biol. Psychiatry57, 594–608 (2005)A methodologically rigorous human experimental study on the short-term effects of delta-9-tetrahydrocannabinol (the main psychotropic component of cannabis) on cognitive and clinical phenotypes in schizophrenia.

    PubMed Google Scholar

  41. 41

    Minozzi, S. et al. An overview of systematic reviews on cannabis and psychosis: discussing apparently conflicting results. Drug Alcohol Rev.29, 304–317 (2010)

    PubMed Google Scholar

  42. 42

    Ferdinand, R. F. et al. Cannabis use predicts future psychotic symptoms, and vice versa. Addiction100, 612–618 (2005)

    PubMed Google Scholar

  43. 43

    Fergusson, D. M., Horwood, L. J. & Swain-Campbell, N. R. Cannabis dependence and psychotic symptoms in young people. Psychol. Med.33, 15–21 (2003)

    CASPubMed Google Scholar

  44. 44

    Veling, W., Mackenbach, J. P., van Os, J. & Hoek, H. W. Cannabis use and genetic predisposition for schizophrenia: a case-control study. Psychol. Med.38, 1251–1256 (2008)

    CASPubMed Google Scholar

  45. 45

    Genetic Risk and Outcome in Psychosis (GROUP) Investigators. Evidence that familial liability for psychosis is expressed as differential sensitivity to cannabis: an analysis of patient-sibling and sibling-control pairs. Arch. Gen. Psychiatry 10.1001/archgenpsychiatry.2010.132 (4 October 2010)

  46. 46

    van Winkel, R. Genetic Risk and Outcome in Psychosis (GROUP) Investigators. Family-based analysis of genetic variation underlying psychosis-inducing effects of cannabis: sibling analysis and proband follow-up. Arch. Gen. Psychiatry (in the press)Elegant gene–environment interaction study, combining a hypothesis-based with a more systematic approach, suggestive of interaction of cannabis with specific molecular markers of genetic variation.

  47. 47

    Di Forti, M. et al. High-potency cannabis and the risk of psychosis. Br. J. Psychiatry195, 488–491 (2009)

    PubMedPubMed Central Google Scholar

  48. 48

    Cannon, M., Jones, P. B. & Murray, R. M. Obstetric complications and schizophrenia: historical and meta-analytic review. Am. J. Psychiatry159, 1080–1092 (2002)

    PubMed Google Scholar

  49. 49

    van Os, J., Pedersen, C. B. & Mortensen, P. B. Confirmation of synergy between urbanicity and familial liability in the causation of psychosis. Am. J. Psychiatry161, 2312–2314 (2004)

    PubMed Google Scholar

  50. 50

    Frith, C. D. & Corcoran, R. Exploring ‘theory of mind’ in people with schizophrenia. Psychol. Med.26, 521–530 (1996)

    CASPubMed Google Scholar

  51. 51

    Shergill, S. S., Samson, G., Bays, P. M., Frith, C. D. & Wolpert, D. M. Evidence for sensory prediction deficits in schizophrenia. Am. J. Psychiatry162, 2384–2386 (2005)

    PubMed Google Scholar

  52. 52

    Mason, O. J. & Brady, F. The psychotomimetic effects of short-term sensory deprivation. J. Nerv. Ment. Dis.197, 783–785 (2009)

    PubMed Google Scholar

  53. 53

    Galdos, M. et al. Affectively salient meaning in random noise: a task sensitive to psychosis liability. Schizophr. Bull . 10.1093/schbul/sbq029 (1 April 2010)

  54. 54

    Peterson, C. C. & Siegal, M. Deafness, conversation and theory of mind. J. Child Psychol. Psychiatry36, 459–474 (1995)

    CASPubMed Google Scholar

  55. 55

    Colvert, E. et al. Do theory of mind and executive function deficits underlie the adverse outcomes associated with profound early deprivation?: findings from the English and Romanian adoptees study. J. Abnorm. Child Psychol.36, 1057–1068 (2008)

    PubMed Google Scholar

  56. 56

    David, A., Malmberg, A., Lewis, G., Brandt, L. & Allebeck, P. Are there neurological and sensory risk factors for schizophrenia? Schizophr. Res.14, 247–251 (1995)

    CASPubMed Google Scholar

  57. 57

    Stefanis, N., Thewissen, V., Bakoula, C., van Os, J. & Myin-Germeys, I. Hearing impairment and psychosis: a replication in a cohort of young adults. Schizophr. Res.85, 266–272 (2006)

    PubMed Google Scholar

  58. 58

    Malaspina, D. et al. Traumatic brain injury and schizophrenia in members of schizophrenia and bipolar disorder pedigrees. Am. J. Psychiatry158, 440–446 (2001)

    CASPubMed Google Scholar

  59. 59

    Barkus, E. & Murray, R. M. Substance use in adolescence and psychosis: clarifying the relationship. Annu. Rev. Clin. Psychol.6, 365–389 (2010)

    PubMed Google Scholar

  60. 60

    Martín-Rodríguez, J. F. & León-Carríon, J. Theory of mind deficits in patients with acquired brain injury: a quantitative review. Neuropsychologia48, 1181–1191 (2010)

    PubMed Google Scholar

  61. 61

    Homer, B. D. et al. Methamphetamine abuse and impairment of social functioning: a review of the underlying neurophysiological causes and behavioral implications. Psychol. Bull.134, 301–310 (2008)

    PubMed Google Scholar

  62. 62

    Fett, A. K. et al. The relationship between neurocognition and social cognition with functional outcomes in schizophrenia: a meta-analysis. Neurosci. Biobehav. Rev. . 10.1016/j.neubiorev.2010.07.001 (8 July 2010)

  63. 63

    Arnsten, A. F. Stress signalling pathways that impair prefrontal cortex structure and function. Nature Rev. Neurosci.10, 410–422 (2009)

    CAS Google Scholar

  64. 64

    Kaschube, M., Wolf, F., Geisel, T. & Lowel, S. Genetic influence on quantitative features of neocortical architecture. J. Neurosci.22, 7206–7217 (2002)

    CASPubMed Google Scholar

  65. 65

    Glaser, J. P., van Os, J., Portegijs, P. J. & Myin-Germeys, I. Childhood trauma and emotional reactivity to daily life stress in adult frequent attenders of general practitioners. J. Psychosom. Res.61, 229–236 (2006)

    PubMed Google Scholar

  66. 66

    Wichers, M. et al. Mechanisms of gene-environment interactions in depression: evidence that genes potentiate multiple sources of adversity. Psychol. Med.39, 1077–1086 (2009)

    CASPubMed Google Scholar

  67. 67

    Lieberman, J. A., Sheitman, B. B. & Kinon, B. J. Neurochemical sensitization in the pathophysiology of schizophrenia: deficits and dysfunction in neuronal regulation and plasticity. Neuropsychopharmacology17, 205–229 (1997)

    CASPubMed Google Scholar

  68. 68

    Carboni, E. et al. Prenatal restraint stress: an in vivo microdialysis study on catecholamine release in the rat prefrontal cortex. Neuroscience168, 156–166 (2010)

    CASPubMed Google Scholar

  69. 69

    Howes, O. D. & Kapur, S. The dopamine hypothesis of schizophrenia: version III–the final common pathway. Schizophr. Bull.35, 549–562 (2009)

    PubMedPubMed Central Google Scholar

  70. 70

    Thomas, D. Gene-environment-wide association studies: emerging approaches. Nature Rev. Genet.11, 259–272 (2010)

    CASPubMed Google Scholar

  71. 71

    Darroch, J. Biologic synergism and parallelism. Am. J. Epidemiol.145, 661–668 (1997)

    CASPubMed Google Scholar

  72. 72

    Caspi, A. & Moffitt, T. E. Gene-environment interactions in psychiatry: joining forces with neuroscience. Nature Rev. Neurosci.7, 583–590 (2006)

    CAS Google Scholar

  73. 73

    Schmidt-Kastner, R., van Os, J., Steinbusch, H. W. M. & Schmitz, C. Gene regulation by hypoxia and the neurodevelopmental origin of schizophrenia. Schizophr. Res.84, 253–271 (2006)

    PubMed Google Scholar

  74. 74

    Rutten, B. P. & Mill, J. Epigenetic mediation of environmental influences in major psychotic disorders. Schizophr. Bull.35, 1045–1056 (2009)

    PubMedPubMed Central Google Scholar

  75. 75

    Keen, D. V., Reid, F. D. & Arnone, D. Autism, ethnicity and maternal immigration. Br. J. Psychiatry196, 274–281 (2010)

    CASPubMed Google Scholar

  76. 76

    Gardener, H., Spiegelman, D. & Buka, S. L. Prenatal risk factors for autism: comprehensive meta-analysis. Br. J. Psychiatry195, 7–14 (2009)

    PubMedPubMed Central Google Scholar

  77. 77

    Miller, B. et al. Meta-analysis of paternal age and schizophrenia risk in male versus female offspring. Schizophr, Bull . 10.1093/schbul/sbq011 (25 February 2010)

  78. 78

    McMillan, K. A., Enns, M. W., Cox, B. J. & Sareen, J. Comorbidity of axis I and II mental disorders with schizophrenia and psychotic disorders: findings from the National Epidemiologic Survey on Alcohol and Related Conditions. Can. J. Psychiatry54, 477–486 (2009)

    PubMed Google Scholar

  79. 79

    Hanssen, M. et al. How psychotic are individuals with non-psychotic disorders? Soc. Psychiatry Psychiatr. Epidemiol.38, 149–154 (2003)

    CASPubMed Google Scholar

  80. 80

    Weiser, M. et al. Cognitive performance of male adolescents is lower than controls across psychiatric disorders: a population-based study. Acta Psychiatr. Scand.110, 471–475 (2004)

    CASPubMed Google Scholar

  81. 81

    Weiser, M. et al. Subtle cognitive dysfunction in nonaffected siblings of individuals affected by nonpsychotic disorders. Biol. Psychiatry63, 602–608 (2008)Innovative study reporting familial clustering of cognitive dysfunction in psychiatric disorders that cuts across diagnostic psychiatric entities.

    PubMed Google Scholar

  82. 82

    Argyropoulos, S. V. et al. Twins discordant for schizophrenia: psychopathology of the non-schizophrenic co-twins. Acta Psychiatr. Scand.118, 214–219 (2008)

    CASPubMed Google Scholar

  83. 83

    Goodwin, R. D., Fergusson, D. M. & Horwood, L. J. Neuroticism in adolescence and psychotic symptoms in adulthood. Psychol. Med.33, 1089–1097 (2003)

    CASPubMed Google Scholar

  84. 84

    Rodgers, B. Behaviour and personality in childhood as predictors of adult psychiatric disorder. J. Child Psychol. Psychiatry31, 393–414 (1990)

    CASPubMed Google Scholar

  85. 85

    Myin-Germeys, I. et al. Experience sampling research in psychopathology: opening the black box of daily life. Psychol. Med.39, 1533–1547 (2009)

    CASPubMed Google Scholar

  86. 86

    Myin-Germeys, I., Delespaul, P. & van Os, J. Behavioural sensitization to daily life stress in psychosis. Psychol. Med.35, 733–741 (2005)

    CASPubMed Google Scholar

  87. 87

    Wichers, M. et al. The catechol-O-methyl transferase Val158Met polymorphism and experience of reward in the flow of daily life. Neuropsychopharmacology33, 3030–3036 (2008)

    CASPubMed Google Scholar

  88. 88

    Dreher, J. C., Kohn, P., Kolachana, B., Weinberger, D. R. & Berman, K. F. Variation in dopamine genes influences responsivity of the human reward system. Proc. Natl Acad. Sci. USA106, 617–622 (2009)

    ADSCASPubMed Google Scholar

  89. 89

    Weiser, M. et al. Social and cognitive functioning, urbanicity and risk for schizophrenia. Br. J. Psychiatry191, 320–324 (2007)

    PubMed Google Scholar

  90. 90

    Habets, P. et al. Reduced cortical thickness as an outcome of differential sensitivity to environmental risks in schizophrenia. Biol. Psychiatry . 10.1016/j.biopsych.2010.08.010 (16 October 2010)

  91. 91

    Grace, A. A., Floresco, S. B., Goto, Y. & Lodge, D. J. Regulation of firing of dopaminergic neurons and control of goal-directed behaviors. Trends Neurosci.30, 220–227 (2007)Comprehensive review summarizing the regulation of mesolimbic dopamine signalling in the integration of top-down cognitive control and bottom-up input.

    CASPubMed Google Scholar

  92. 92

    Mueller, S. C. et al. Early-life stress is associated with impairment in cognitive control in adolescence: an fMRI study. Neuropsychologia48, 3037–3044 (2010)

    PubMedPubMed Central Google Scholar

  93. 93

    Pruessner, J. C., Champagne, F., Meaney, M. J. & Dagher, A. Dopamine release in response to a psychological stress in humans and its relationship to early life maternal care: a positron emission tomography study using [11C]raclopride. J. Neurosci.24, 2825–2831 (2004)PET imaging study showing long-term influence of parental care during early life on dopamine release in the ventral striatum under psychosocial stress in adulthood.

    CASPubMed Google Scholar

  94. 94

    Sheu, Y. S., Polcari, A., Anderson, C. M. & Teicher, M. H. Harsh corporal punishment is associated with increased T2 relaxation time in dopamine-rich regions. Neuroimage53, 412–419 (2010)

    PubMed Google Scholar

  95. 95

    Taylor, S. E., Eisenberger, N. I., Saxbe, D., Lehman, B. J. & Lieberman, M. D. Neural responses to emotional stimuli are associated with childhood family stress. Biol. Psychiatry60, 296–301 (2006)

    PubMed Google Scholar

  96. 96

    Jager, G., Block, R. I., Luijten, M. & Ramsey, N. F. Cannabis use and memory brain function in adolescent boys: a cross-sectional multicenter functional magnetic resonance imaging study. J. Am. Acad. Child Adolesc. Psychiatry49, 561–572 (2010)

    PubMedPubMed Central Google Scholar

  97. 97

    Nestor, L., Hester, R. & Garavan, H. Increased ventral striatal BOLD activity during non-drug reward anticipation in cannabis users. Neuroimage49, 1133–1143 (2010)

    PubMed Google Scholar

  98. 98

    Nestor, L., Roberts, G., Garavan, H. & Hester, R. Deficits in learning and memory: parahippocampal hyperactivity and frontocortical hypoactivity in cannabis users. Neuroimage40, 1328–1339 (2008)

    PubMed Google Scholar

  99. 99

    Yücel, M. et al. Regional brain abnormalities associated with long-term heavy cannabis use. Arch. Gen. Psychiatry65, 694–701 (2008)

    PubMed Google Scholar

Download references


The authors thank P. R. Hof, C. Morgan and M. Wichers for comments on earlier versions of this paper. Supported by the Geestkracht program of the Dutch Health Research Council (ZON-MW, grant number 10-000-1002), and the European Community's Seventh Framework Program under grant agreement No. HEALTH-F2-2009-241909 (Project EU-GEI).

Author information


  1. European Graduate School for Neuroscience, SEARCH, Maastricht University Medical Centre, 6200 MD Maastricht, The Netherlands

    Jim van Os, Gunter Kenis & Bart P. F. Rutten

  2. Department of Psychosis Studies, King’s College London, King’s Health Partners, Institute of Psychiatry, London SE5 8AF, UK

    Jim van Os

Corresponding author

Correspondence to Jim van Os.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

About this article

Cite this article

van Os, J., Kenis, G. & Rutten, B. The environment and schizophrenia. Nature468, 203–212 (2010).

Download citation

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

Further reading

  • A genetic risk score using human chromosomal-scale length variation can predict schizophrenia

    • Christopher Toh
    •  & James P. Brody

    Scientific Reports (2021)

  • Integrative omics of schizophrenia: from genetic determinants to clinical classification and risk prediction

    • Fanglin Guan
    • , Tong Ni
    • , Weili Zhu
    • , L. Keoki Williams
    • , Long-Biao Cui
    • , Ming Li
    • , Justin Tubbs
    • , Pak-Chung Sham
    •  & Hongsheng Gui

    Molecular Psychiatry (2021)

  • Dysregulation of complement and coagulation pathways: emerging mechanisms in the development of psychosis

    • Meike Heurich
    • , Melanie Föcking
    • , David Mongan
    • , Gerard Cagney
    •  & David R. Cotter

    Molecular Psychiatry (2021)

  • Investigation of glycaemic traits in psychiatric disorders using Mendelian randomisation revealed a causal relationship with anorexia nervosa

    • Danielle M. Adams
    • , William R. Reay
    • , Michael P. Geaghan
    •  & Murray J. Cairns

    Neuropsychopharmacology (2021)

  • Neurodevelopment regulators miR-137 and miR-34 family as biomarkers for early and adult onset schizophrenia

    • Bao-Yu Chen
    • , Jin-Jia Lin
    • , Ming-Kun Lu
    • , Hung-Pin Tan
    • , Fong-Lin Jang
    •  & Sheng-Hsiang Lin

    npj Schizophrenia (2021)


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


The Role of Genetic and Environmental Factors in the Development of Schizophrenia

Craddock N, O'Donovan MC, Owen MJ (2005), The genetics of schizophrenia and bipolar disorder: dissecting psychosis. J Med Genet 42(3):193-204.

Dohrenwend BP, Levav I, Shrout PE et al. (1992), Socioeconomic status and psychiatric disorders: the causation-selection issue. Science 255(5047):946-952.

Doolin MT, Barbaux S, McDonnell M et al. (2002), Maternal genetic effects, exerted by genes involved in homocysteine remethylation, influence the risk of spina bifida. Am J Hum Genet 71(5):1222-1226.

Harrison PJ, Weinberger DR (2005), Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. [Published erratum Mol Psychiatry 10(4):420.] Mol Psychiatry 10(1):40-68.

Howes OD, McDonald C, Cannon M et al. (2004), Pathways to schizophrenia: the impact of environmental factors. Int J Neuropsychopharmacol 7(suppl 1):S7-S13.

Kalkman HO, Loetscher E (2003), GAD(67): the link between the GABA-deficit hypothesis and the dopaminergic- and glutamatergic theories of psychosis. J Neural Transm 110(7):803-812.

Kendler KS, Gruenberg AM, Kinney DK (1994), Independent diagnoses of adoptees and relatives as defined by DSM-III in the provincial and national samples of the Danish Adoption Study of Schizophrenia. Arch Gen Psychiatry 51(6):456-468.

Keshavan MS (1999), Development, disease and degeneration in schizophrenia: a unitary pathophysiological model. J Psychiatr Res 33(6):513-521.

Kornhuber J, Weller M (1997), Psychotogenicity and N-methyl-D-aspartate receptor antagonism: implications for neuroprotective pharmacotherapy. Biol Psychiatry 41(2):135-144.

Lewis CM, Levinson DF, Wise LH et al. (2003), Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: schizophrenia. Am J Hum Genet 73(1):34-48.

Lewis SW, Murray RM (1987), Obstetric complications, neurodevelopmental deviance, and the risk of schizophrenia. J Psychiatr Res 21(4):413-421.

Marcelis M, Takei N, van Os J (1999), Urbanization and risk for schizophrenia: does the effect operate before or around the time of illness onset? Psychol Med 29(5):1197-1203.

Marzullo G, Fraser FC (2005), Similar rhythms of seasonal conceptions in neural tube defects and schizophrenia: a hypothesis of oxidant stress and the photoperiod. Birth Defects Res A Clin Mol Teratol 73(1):1-5.

Murakami S, Matsubara N, Saitoh M et al. (2001), The relation between plasma homocysteine concentration and methylenetetrahydrofolate reductase gene polymorphism in pregnant women. J Obstet Gynaecol Res 27(6):349-352.

Numakawa T, Yagasaki Y, Ishimoto T et al. (2004), Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia. Hum Mol Genet 13(21):2699-2708.

Palomo T, Archer T, Kostrzewa RM, Beninger RJ (2004), Gene-environment interplay in schizopsychotic disorders. Neurotox Res 6(1):1-9.

Petronis A, Gottesman II, Kan P et al. (2003), Monozygotic twins exhibit numerous epigenetic differences: clues to twin discordance? Schizophr Bull 29(1):169-178.

Procopio M (2005), Does god play dice with schizophrenia? A probabilistic model for the understanding of causation in mental illness. Med Hypotheses 64(4):872-877.

Rapoport JL, Addington AM, Frangou S (2005), The neurodevelopmental model of schizophrenia: update 2005. Mol Psychiatry 10(6):614.

Regland B, Germgard T, Gottfries CG et al. (1997), Homozygous thermolabile methylenetetrahydrofolate reductase in schizophrenia-like psychosis. J Neural Transm 104(8-9):931-941.

Risch N (1990), Genetic linkage and complex diseases, with special reference to psychiatric disorders. Genet Epidemiol 7(1):3-16; discussion 17-45.

Schosser A, Aschauer HN (2004), [In search of susceptibility genes for schizophrenia.] Wien Klin Wochenschr 116(24):827-833.

Sullivan PF, Kendler KS, Neale MC (2003), Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry 60(12):1187-1192.

Susser E, Neugebauer R, Hoek HW et al. (1996), Schizophrenia after prenatal famine. Further evidence. Arch Gen Psychiatry 53(1):25-31 [see comment].

Tienari P, Wynne LC, Sorri A et al. (2004), Genotype-environment interaction in schizophrenia-spectrum disorder. Long-term follow-up study of Finnish adoptees. Br J Psychiatry 184:216-222.

Torrey EF, Miller J, Rawlings R, Yolken RH (1997), Seasonality of births in schizophrenia and bipolar disorder: a review of the literature. Schizophr Res 28(1):1-38.

Virgos C, Martorell L, Simo JM et al. (1999), Plasma homocysteine and the methylenetetrahydrofolate reductase C677T gene variant: lack of association with schizophrenia. Neuroreport 10(10):2035-2038.

Wei J, Hemmings GP (2005), Gene, gut and schizophrenia: the meeting point for the gene-environment interaction in developing schizophrenia. Med Hypotheses 64(3):547-552.

Weickert CS, Straub RE, McClintock BW et al. (2004), Human dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain. Arch Gen Psychiatry 61(6):544-555.

  1. Wv bankruptcy filings
  2. Change crossword clue 5 letters
  3. Surf matlab
  4. Asset class sap

Non-Genetic Factors in Schizophrenia


Purpose of Review

We review recent developments on risk factors in schizophrenia.

Recent Findings

The way we think about schizophrenia today is profoundly different from the way this illness was seen in the twentieth century. We now know that the etiology of schizophrenia is multifactorial and reflects an interaction between genetic vulnerability and environmental contributors. Environmental risk factors such as pregnancy and birth complications, childhood trauma, migration, social isolation, urbanicity, and substance abuse, alone and in combination, acting at a number of levels over time, influence the individual’s likelihood to develop the disorder.


Environmental risk factors together with the identification of a polygenic risk score for schizophrenia, research on gene–environment interaction and environment–environment interaction have hugely increased our knowledge of the disorder.


Schizophrenia has a well-established genetic component, which can now be estimated using the polygenic risk score for schizophrenia [1, 2••]. In the ground-breaking meta-analysis of genome-wide association study (GWAS) of schizophrenia, 108 schizophrenia-associated loci were identified [2••]. The loci implicated include genes involved in dopamine synthesis, calcium channel regulation, immunity, and glutamate neuroreceptors. However, this and subsequent GWAS studies explain only a minority of the variance in the liability for schizophrenia in the general population. This reflects the fact that a significant proportion of the liability may be due to gene–environment interactions [3] or to epigenetic mechanisms reflecting the effect of environmental factors. Indeed, growing evidence shows that non-genetic risk factors not only contribute to the illness but also suggest ways in which we may find potential subgroups of subjects at higher risk and therefore influence clinical management.

Pregnancy and Birth Complications

Obstetric complications are well-documented as a risk factor for schizophrenia [4•,5,6,7]; increased susceptibility has been associated with emergency cesarean section, bleeding during pregnancy, preeclampsia [6], and low birth weight [8,9,10]. Use of forceps and low birth weight predict earlier age of onset of psychosis [11].

Some epidemiologic studies have also suggested that exposure to viruses and other infectious agents such as influenza, toxoplasmosis, and herpes simplex virus type 2, contracted during pregnancy [12, 13] and around the time of conception [14], are associated with a later risk of psychotic disorders. However, these results have not always been replicated. For example, a recent meta-analysis by Selten et al. has shown insufficient evidence to prove an association between second-trimester influenza exposure and psychotic outcome in the offspring [15••].

Four main pathogenic mechanisms have been suggested as involved: fetal malnutrition, prematurity, hypoxic-ischemic events, and maternal infections during pregnancy or delivery [4•, 16,17,18,19,20]. Moreover, elevated markers of inflammation, including maternal C-reactive protein [21] and interleukin-8 [22] have been found in mothers of patients with schizophrenia. Late winter or spring birth has often been reported as risk factor for schizophrenia [8, 23,24,25]. However, it has a very small effect [26]; whether it is secondary to maternal infection or nutritional deficiency remains unclear.

Advanced Parental Age

Increased paternal age, from age higher than 34 and upwards [27, 28], has been associated with schizophrenia [29,30,31]. An attractive theory suggests that age-associated increase in sporadic de novo mutations in male germ cells may play a role [32,33,34]. However, this was discounted by a study from Denmark that suggests that late marriage and reproduction may be due to personality attributes of fathers [35].

A less consistent pattern of findings has emerged regarding maternal age at birth and risk of schizophrenia in offspring. In one study, age younger than 19 and age older than 40 years [36] appeared to increase the risk. However, in another cohort study, the risk appeared decreased in offspring of mothers older than 30 years [37]. Lopez-Castroman et al. (2010) found a significant linear association increase only with advancing maternal age [38].

Trauma and Social Adversities

Trauma and social adversities in different forms, either during childhood or adulthood, have been extensively investigated as potential risk factors for schizophrenia. Varese and colleagues, in a meta-analysis of case-control, prospective, and cross-sectional cohort studies, reported strong evidence that childhood adversity (defined as sexual abuse, physical abuse, emotional/psychological abuse, neglect, parental death, and bullying) was associated with increased risk for psychosis in adulthood (overall OR = 2.78) [39•]. There is an association between permanent separation from, or death of, one or both parents and psychosis [40,41,42,43], victimization and bullying and psychosis [44,45,46]. A robust link between childhood trauma and schizophrenic symptoms has been found [47,48,49] with childhood trauma being associated with the most severe forms of positive symptomatology in adulthood, particularly hallucinations [49,50,51], and affective symptoms [52]. Life events more proximal to the onset of illness, defined as situations that bring about positive or negative changes in personal circumstances and/or involve an element of threat, have been investigated [53,54,55]. The most recent review and meta-analysis of the relationship between life events and psychosis has suggested around a threefold increased odds of life events in the period prior to psychosis onset, with the time period under consideration ranging between 3 months and 3.6 years [55].

Social Class and Isolation

Some reports link social inequality at birth with schizophrenia. Socioeconomic status (usually measured by paternal occupation) has been reported to be associated with an increased risk of psychosis [56,57,58,59,60]. However, while some findings are positive, there are a number of conflicting studies showing no association between psychosis and low social class at birth [41] or even a link with high social class [61, 62].

Markers of isolation/disadvantage, alone and cumulative, are also associated with psychosis [42, 43, 63]. First-episode psychosis patients are more likely to live alone; be single or unemployed; live in a rented accommodation, in overcrowded conditions; and receive an income below official poverty, not only at first contact with psychiatric services but up to 5 years prior to the onset of psychosis, with around a twofold increased odds [43]. The World Health Organization (WHO) studies have reported that despite the better access to biomedical treatment, higher rates of chronic disability and dependency in schizophrenia occur in high- than low-income countries and suggest that something essential to recovery is missing in the social fabric [64].


Meta-analytic reviews show that migrant groups are at increased risk of schizophrenia and other psychotic disorders [65, 66•]. These findings have been consistently replicated in a number of high-income countries: the UK [67], the Netherlands [68], Germany [69], Denmark [70], France [71], Italy [72], and to a lesser extent Canada [73] with some evidence that the risk of schizophrenia and other non-affective psychotic disorders is especially high among refugees compared with non-refugee migrants [74]. Interestingly, the risk appears to persist into the second and third generations [66•, 75].

The level of risk appears to vary by country of origin. A recent meta-analysis of schizophrenia incidence in the UK reported almost a five times greater risk of schizophrenia among people of black Caribbean origin compared with reference UK population (usually white) [76]. Numerous hypotheses have been tested. Higher incidence rates in the country of origin, selective migration, or misdiagnosis of mood disorders do not seem to explain the phenomena [77,78,79,80,81]. However, social adversity exposures at all stages of the migration process (before, during, and after) [82], low ethnic density [83], social isolation [84], discrimination [68], and lack of access to private accommodation and economic opportunities [85] have all been suggested as contributing, so has vitamin D deficiency [86, 87] but as yet little direct evidence for the latter has been found.


Growing up and/or living in an urban environment has frequently been associated with an increased risk of schizophrenia or psychosis in general [88,89,90,91]. A meta-analysis, including a total of 47,087 cases with psychosis, shows a pooled OR for psychosis in urban environment compared with the rural environment of 2.39 (95% CI 1.62–3.51) [92•]. Changing residence in childhood from rural to urban environment doubles the risk of developing schizophrenia [93, 94], and the more years a child spends in an urban area, the greater the risk becomes [95]. Many explanations have been proposed such as greater exposure to prenatal influenza [96], maternal obstetrical complications [97, 98], toxoplasma gondii infection [99], cannabis use [100], social deprivation, income inequality, and social fragmentation [101, 102] but none of them has been verified. Furthermore, while the largest multicentric study of first-episode psychosis patients to date (EU-GEI study) confirmed higher incidence in Northern European cities including London, Amsterdam, and Paris, the increased density effect is not so clear in Southern European settings [103•].

Interestingly, a recent study conducted in Denmark, has pointed out for the first time the protective role of living in, or near to, a green area, showing a dose-response association between the magnitude of greenspace during childhood and the risk of later development of schizophrenia [104•].

Cannabis and Other Substance Use

Substance use is highly prevalent in psychotic patients [105,106,107]. There is good evidence that psychostimulants (such as amphetamines and cocaine) can induce psychosis [108]. There also have been a few suggestions that alcohol misuse and psychosis might be associated [109, 110], and recently, a meta-analysis raised the question of whether tobacco use could be a risk factor for psychosis [111]. However, much greater evidence points to an important aetiological role for cannabis use. Prospective epidemiological studies consistently report an association between cannabis use and schizophrenia [112,113,114] with an estimated two- to threefold increased risk [114, 115]. A dose–response relationship between extent of use and risk of psychosis has been shown in a meta-analysis [116]. The association is stronger in those individuals who used cannabis earlier [113], and who used high potency tetrahydrocannabinol (THC) cannabis or/and more frequently [112, 117, 118]. Indeed, the EU-GEI study has found that if high-potency cannabis was no longer available, around 12% of first-episode psychosis cases across 11 Europe-wide sites could be prevented, rising to 30% in London and 50% in Amsterdam [119•]. The age at which cannabis use begins appears to correlate with the age at onset of psychosis [118, 120, 121] while persistent cannabis use after a first episode is associated with poorer prognosis [122, 123], higher relapse rates, longer hospitalizations, and severe positive symptoms [124].

Cognitive Impairments and Brain Structural Abnormalities

Although schizophrenia usually manifests in adolescence and early adult life, numerous reports suggest that many patients with schizophrenia have a history of delayed developmental milestones in the first year of life [125], lower IQ in childhood [126,127,128], hearing impairment [129], emotional problems, and interpersonal difficulties early in life [130, 131]. Those people who develop psychosis following heavy cannabis use show less evidence of such neurodevelopmental deviance. In particular, they have higher premorbid IQ and better social functioning in childhood than psychotic patients who do not use cannabis [132]. Perhaps being smarter and more sociable enables them to find cannabis dealers and obtain the money for the drug!

Gene–Environment Interaction

It is becoming increasingly clear that none of the risk factors discussed above, by itself, is either necessary or sufficient for the development of schizophrenia. Most of show a modest effect (twofold increase in risk) and none seem specific for schizophrenia. Different factors operating at various levels contribute to onset and progression of the disorder. The developmental cascade towards schizophrenia [133] should now include gene–environment interaction (GXE), and environment–environment interaction (EXE) (Fig. 1).

Developmental cascade towards schizophrenia. CNV, copy number variations; SNPs, single nucleotide polymorphisms; ExE, environment–environment interaction; GxE, gene–environment interaction

Full size image

Interest has turned to the possibility of gene × environmental interactions. Preliminary reports suggested interactions between functional polymorphisms in the catechol-O-methyltransferase gene [134], or the DRD2 genotype (OMIM 126450) [135], and the AKT1 genotype (C/C rs2494732) [136, 137] and cannabis use, on risk of psychosis. However, all of these studies are relatively small and in need of replication. A few preliminary studies have examined interactions between the polygenic risk score for schizophrenia (e.g., Trotta et al. [138]; Ursini et al. [139]) but there are not sufficient studies yet to evaluate this adequately. The largest and most recently published study to date, analyzing the associations of polygenic risk score for schizophrenia and environmental exposures in 1699 patients and 1542 unrelated controls, shows an additive interaction between polygenic risk score and lifetime regular cannabis use and exposure to early life adversities (sexual abuse, emotional abuse, emotional neglect, and bullying), but not with the presence of other exposures such as hearing impairment, winter birth, physical abuse, or physical neglect [140••] confirming the need for future confirmatory studies.

Cumulative Effect of Environmental Risk Factors

A few studies have now started examining the additive effect of multiple environmental factors on risk of psychosis as aggregate index of total number of risk factors or weighted sum. Cougnard et al. reported an additive interaction between exposure to three risk factors—cannabis use, childhood trauma, and urbanicity—and baseline psychotic experiences in predicting persistent psychotic symptoms three years later in the general population [141]. Stepniak et al. found that individuals who had been exposed to 4 or more environmental risk factors had a significantly lower age of onset than those exposed to 3 factors [142]. As a predictor tool, Padmanabhan et al., in a pilot study, explored the association of cumulative environmental risk (including nine risk factors) with conversion to psychosis in a family high-risk population [143].

Neurochemical Mechanisms

Different systems: dopaminergic (DA), glutamatergic, neuroinflammation/immune, and more recently endocannabinoid (eCB), have all been investigated to understand the exact mechanism(s) by which some non-genetic risk factors can affect brain function. The predominant biological theory of schizophrenia highlights the role of the excess presynaptic synthesis of DA in the striatum in the onset of positive symptoms [144•, 145]. Consistent with this view, the diathesis–stress model suggests that the hypothalamus–pituitary–adrenal (HPA) axis may trigger a cascade of events resulting in neural circuit dysfunction, including alterations in DA signaling [146]. Epidemiological studies are consistent with a key role of stress/cortisol in the onset of psychosis. Higher levels of diurnal cortisol have been reported in patients compared with controls or patients on antipsychotic treatments for less than 2 weeks [147] and high baseline cortisol levels appear to facilitate transition to psychotic level symptoms in at-risk youths [148]. Mizrahi et al., investigating the DA release in response to a psychosocial stress challenge in psychosis-related disorders, found that the largest stress-induced changes in salivary cortisol was present in the schizophrenia group, followed by the clinical high-risk group, with an association between the percent change in the cortisol response and the stress-induced DA release in the associative striatum [149].

New data provide intriguing evidence of an association between migration [150], hearing impairment [151], childhood abuse [152], low parental care [153], and elevation in striatal dopamine synthesis. Acute administration of THC, the active ingredient of cannabis, has been reported to increase dopamine release [154]. However, paradoxically, chronic cannabis use [155] and also difficult premature birth [156] are associated with decreased striatal dopamine. Perhaps DA receptor sensitivity or dysregulation in response to stress may be one pathway through which the different exposures interact with genetic vulnerability to confer a higher risk of schizophrenia [144].

A compelling case is made for the role of glutamate/NMDA receptors in schizophrenia, originally suggested as a mechanism underlying the psychotogenic effects of PCP and ketamine [157]. There is now strong evidence in support of the hypothesis that hypofunction of NMDA receptors contributes to the symptoms of schizophrenia [158, 159]; some reports suggest that dopamine dysregulation in schizophrenia may be secondary to glutamatergic dysfunction in some cases at least [160, 161]. Furthermore, glutamatergic neurotransmission has been shown to mediate the effects of both acute and chronic stress [162].

Just as amphetamine-induced psychosis gave rise to the dopamine hypothesis and ketamine-induced psychosis to the glutamate hypotheses, so cannabis-induced psychosis has provoked interest in the endocannabinoid system [163]. Certainly, the endogenous cannabinoid system (eCB) is altered in schizophrenia. The CB1 receptor densities and anandamide levels have been reported abnormally in patients with schizophrenia [164, 165]; among other function, the eCB system appears to regulate the HPA axis [166,167,168]. It has been suggested that a dysregulation of this system (that could be induced for example by exogenous cannabis) can interact with neurotransmitter systems in such a way that an “endocannabinoid hypothesis” can be integrated into the neurobiological hypotheses of schizophrenia [164].

Another possible molecular mechanism underlying psychosis risk is neuroinflammation and abnormalities of the immune system [169, 170•]. A recent meta-analysis examining peripheral inflammatory markers shows that some markers such as interleukin 6 (IL-6), tumor necrosis factor α (TNFα), soluble IL-2 receptor (sIL-2R), and IL-1 receptor antagonist (IL-1RA) increase in acute episodes and tend to decrease after successful treatment [171]. The effects of childhood trauma on inflammation have been well-studied. Individuals exposed to childhood trauma have significantly elevated baseline peripheral inflammatory markers in adulthood [172, 173]. Another recently studied hypothesis implicates the immune system. Autoimmune diseases are reported to occur in 3.6% of patients with schizophrenia [174]. Mechanisms through which systemic immune activation affect risk of psychopathology include the effects of inflammation on concurrent brain function, the effects of early immune activation on brain development, the sensitization of immune brain cells to subsequent psychosocial stressors, and the cross-sensitization of the HPA axis response to subsequent psychosocial stressors [172]. It has been speculated that inflammation-mediated pathways may serve as a final common pathway for environmental risk factors such as early childhood adversity, adolescent cannabis use, and social exclusion [170]. However, hard evidence supporting this hypothesis remains elusive.


Epidemiological studies have consistently shown a pattern of association between environmental risk factors and later onset of psychosis, which is suggestive of a causal relationship. However, there are a number of reasons why the association between environmental risk factors and psychotic outcomes may be overestimated or underestimated such as bias (where incorrect estimates are due to measurements or sample selection), chance, confounding (third explanation for the association), and reverse causation (where psychosis increases risk of an environmental exposure), which should be taken in consideration when causality is inferred. Studying gene–environment interaction and gene–environment correlation (rGE) (genetic effects on environment exposure) may clarify the position [175, 176].

Future research should also explore potential protective factors in groups who have a lower risk of psychotic disorders. A new field of research includes big data and predictive models, where traditional paper notes have been replaced with electronic patient records. In line with this direction, there have been initial successful applications of machine learning algorithms to diagnose psychosis [177]. As with diagnostic tools for cardiovascular risk, schizophrenia will in the near future probably require a combination of diagnostic approaches, including measures of genetic risk, environmental risk factors, and imaging.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.

    International Schizophrenia C, Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460(7256):748–52.

    Google Scholar

  2. 2.

    •• Schizophrenia Working Group of the Psychiatric Genomics C. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511(7510):421–7. This article is the largest molecular genetic study of schizophrenia, demonstrating the power of GWAS to identify large numbers of risk loci.

    Google Scholar

  3. 3.

    van Os J, Rutten BP, Poulton R. Gene-environment interactions in schizophrenia: review of epidemiological findings and future directions. Schizophr Bull. 2008;34(6):1066–82.

    PubMedPubMed Central Google Scholar

  4. 4.

    • Cannon M, Jones PB, Murray RM. Obstetric complications and schizophrenia: historical and meta-analytic review. Am J Psychiatry. 2002;159(7):1080–92. Comprehensive meta-analytic review of obstetric complications in schizophrenia.

    PubMed Google Scholar

  5. 5.

    Dalman C, Thomas HV, David AS, Gentz J, Lewis G, Allebeck P. Signs of asphyxia at birth and risk of schizophrenia. Population-based case-control study. Br J Psychiatry. 2001;179:403–8.

    CASPubMed Google Scholar

  6. 6.

    Mittal VA, Ellman LM, Cannon TD. Gene-environment interaction and covariation in schizophrenia: the role of obstetric complications. Schizophr Bull. 2008;34(6):1083–94.

    PubMedPubMed Central Google Scholar

  7. 7.

    Kotlicka-Antczak M, Pawelczyk A, Rabe-Jablonska J, Smigielski J, Pawelczyk T. Obstetrical complications and Apgar score in subjects at risk of psychosis. Journal of psychiatric research. 2014;48(1):79–85.

    PubMed Google Scholar

  8. 8.

    Hultman CM, Sparen P, Takei N, Murray RM, Cnattingius S. Prenatal and perinatal risk factors for schizophrenia, affective psychosis, and reactive psychosis of early onset: case-control study. BMJ. 1999;318(7181):421–6.

    CASPubMedPubMed Central Google Scholar

  9. 9.

    Abel KMWS, Susser ES, Dalman C, Pedersen MG, Mortensen PB, Webb RT. Birth weight, schizophrenia, and adult mental disorder: is risk confined to the smallest babies? Arch Gen Psychiatry. 2010;67(9):923–30.

    PubMed Google Scholar

  10. 10.

    Lahti M, Eriksson JG, Heinonen K, Kajantie E, Lahti J, Wahlbeck K, et al. Maternal grand multiparity and the risk of severe mental disorders in adult offspring. PloS one. 2014;9(12):e114679.

    PubMedPubMed Central Google Scholar

  11. 11.

    Rubio-Abadal E, Ochoa S, Barajas A, Banos I, Dolz M, Sanchez B, et al. Birth weight and obstetric complications determine age at onset in first episode of psychosis. Journal of psychiatric research. 2015;65:108–14.

    CASPubMed Google Scholar

  12. 12.

    Buka SL, Tsuang MT, Torrey EF, Klebanoff MA, Bernstein D, Yolken RH. Maternal infections and subsequent psychosis among offspring. Arch Gen Psychiatry. 2001;58(11):1032–7.

    CASPubMed Google Scholar

  13. 13.

    Brown AS, Derkits EJ. Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry. 2010;167(3):261–80.

    PubMedPubMed Central Google Scholar

  14. 14.

    Babulas V, Factor-Litvak P, Goetz R, Schaefer CA, Brown AS. Prenatal exposure to maternal genital and reproductive infections and adult schizophrenia. Am J Psychiatry. 2006;163(5):927–9.

    PubMed Google Scholar

  15. 15.

    • Selten JP, Termorshuizen F. The serological evidence for maternal influenza as risk factor for psychosis in offspring is insufficient: critical review and meta-analysis. Schizophr Res. 2017;183:2–9. Most recent review and meta-analysis of the association between maternal influenza and schizophrenia.

    PubMed Google Scholar

  16. 16.

    Jones PB, Rantakallio P, Hartikainen AL, Isohanni M, Sipila P. Schizophrenia as a long-term outcome of pregnancy, delivery, and perinatal complications: a 28-year follow-up of the 1966 north Finland general population birth cohort. Am J Psychiatry. 1998;155(3):355–64.

    CASPubMed Google Scholar

  17. 17.

    Geddes JR, Verdoux H, Takei N, Lawrie SM, Bovet P, Eagles JM, et al. Schizophrenia and complications of pregnancy and labor: an individual patient data meta-analysis. Schizophr Bull. 1999;25(3):413–23.

    CASPubMed Google Scholar

  18. 18.

    Cannon TD, Rosso IM, Hollister JM, Bearden CE, Sanchez LE, Hadley T. A prospective cohort study of genetic and perinatal influences in the etiology of schizophrenia. Schizophr Bull. 2000;26(2):351–66.

    CASPubMed Google Scholar

  19. 19.

    Rosso IM, Cannon TD, Huttunen T, Huttunen MO, Lonnqvist J, Gasperoni TL. Obstetric risk factors for early-onset schizophrenia in a Finnish birth cohort. Am J Psychiatry. 2000;157(5):801–7.

    CASPubMed Google Scholar

  20. 20.

    Byrne M, Agerbo E, Bennedsen B, Eaton WW, Mortensen PB. Obstetric conditions and risk of first admission with schizophrenia: a Danish national register based study. Schizophr Res. 2007;97(1-3):51–9.

    PubMed Google Scholar

  21. 21.

    Canetta S, Sourander A, Surcel HM, Hinkka-Yli-Salomaki S, Leiviska J, Kellendonk C, et al. Elevated maternal C-reactive protein and increased risk of schizophrenia in a national birth cohort. Am J Psychiatry. 2014;171(9):960–8.

    PubMedPubMed Central Google Scholar

  22. 22.

    Brown AS, Hooton J, Schaefer CA, Zhang H, Petkova E, Babulas V, et al. Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring. Am J Psychiatry. 2004;161(5):889–95.

    PubMed Google Scholar

  23. 23.

    Torrey EF, Rawlings RR, Ennis JM, Merrill DD, Flores DS. Birth seasonality in bipolar disorder, schizophrenia, schizoaffective disorder and stillbirths. Schizophr Res. 1996;21(3):141–9.

    CASPubMed Google Scholar

  24. 24.

    Torrey EF, Miller J, Rawlings R, Yolken RH. Seasonality of births in schizophrenia and bipolar disorder: a review of the literature. Schizophr Res. 1997;28(1):1–38.

    CASPubMed Google Scholar

  25. 25.

    Mortensen PB, Pedersen CB, Westergaard T, Wohlfahrt J, Ewald H, Mors O, et al. Effects of family history and place and season of birth on the risk of schizophrenia. N Engl J Med. 1999;340(8):603–8.

    CASPubMed Google Scholar

  26. 26.

    Carter JW, Schulsinger F, Parnas J, Cannon T, Mednick SA. A multivariate prediction model of schizophrenia. Schizophr Bull. 2002;28(4):649–82.

    PubMed Google Scholar

  27. 27.

    Hubert A, Szoke A, Leboyer M, Schurhoff F. Influence of paternal age in schizophrenia. Encephale. 2011;37(3):199–206.

    CASPubMed Google Scholar

  28. 28.

    Buizer-Voskamp JE, Laan W, Staal WG, Hennekam EA, Aukes MF, Termorshuizen F, et al. Paternal age and psychiatric disorders: findings from a Dutch population registry. Schizophr Res. 2011;129(2-3):128–32.

    PubMedPubMed Central Google Scholar

  29. 29.

    Brown AS, Schaefer CA, Wyatt RJ, Begg MD, Goetz R, Bresnahan MA, et al. Paternal age and risk of schizophrenia in adult offspring. Am J Psychiatry. 2002;159(9):1528–33.

    PubMedPubMed Central Google Scholar

  30. 30.

    Perrin M, Harlap S, Kleinhaus K, Lichtenberg P, Manor O, Draiman B, et al. Older paternal age strongly increases the morbidity for schizophrenia in sisters of affected females. Am J Med Genet B Neuropsychiatr Genet. 2010;153B(7):1329–35.

    PubMed Google Scholar

  31. 31.

    Sipos A, Rasmussen F, Harrison G, Tynelius P, Lewis G, Leon DA, et al. Paternal age and schizophrenia: a population based cohort study. BMJ. 2004;329(7474):1070.

    PubMedPubMed Central Google Scholar

  32. 32.

    Malaspina D, Corcoran C, Fahim C, Berman A, Harkavy-Friedman J, Yale S, et al. Paternal age and sporadic schizophrenia: evidence for de novo mutations. Am J Med Genet. 2002;114(3):299–303.

    PubMedPubMed Central Google Scholar

  33. 33.

    Crow JF. Development. There’s something curious about paternal-age effects. Science (New York, NY). 2003;301(5633):606–7.

    CAS Google Scholar

  34. 34.

    Torrey EF, Buka S, Cannon TD, Goldstein JM, Seidman LJ, Liu T, et al. Paternal age as a risk factor for schizophrenia: how important is it? Schizophr Res. 2009;114(1-3):1–5.

    PubMed Google Scholar

  35. 35.

    Petersen L, Mortensen PB, Pedersen CB. Paternal age at birth of first child and risk of schizophrenia. Am J Psychiatry. 2011;168(1):82–8.

    PubMed Google Scholar

  36. 36.

    Nosarti C, Reichenberg A, Murray RM, Cnattingius S, Lambe MP, Yin L, et al. Preterm birth and psychiatric disorders in young adult life. Arch Gen Psychiatry. 2012;69(6):E1–8.

    PubMed Google Scholar

  37. 37.

    Haukka JK, Suvisaari J, Lonnqvist J. Family structure and risk factors for schizophrenia: case-sibling study. BMC psychiatry. 2004;4:41.

    PubMedPubMed Central Google Scholar

  38. 38.

    Lopez-Castroman J, Gomez DD, Belloso JJ, Fernandez-Navarro P, Perez-Rodriguez MM, Villamor IB, et al. Differences in maternal and paternal age between schizophrenia and other psychiatric disorders. Schizophr Res. 2010;116(2-3):184–90.

    PubMed Google Scholar

  39. 39.

    • Varese F, Smeets F, Drukker M, Lieverse R, Lataster T, Viechtbauer W, et al. Childhood adversities increase the risk of psychosis: a meta-analysis of patient-control, prospective- and cross-sectional cohort studies. Schizophr Bull. 2012;38(4):661–71. Comphrehensive meta-analysis of childhood adversities in psychosis.

    PubMedPubMed Central Google Scholar

  40. 40.

    Agid O, Shapira B, Zislin J, Ritsner M, Hanin B, Murad H, et al. Environment and vulnerability to major psychiatric illness: a case control study of early parental loss in major depression, bipolar disorder and schizophrenia. Mol Psychiatry. 1999;4(2):163–72.

    CASPubMed Google Scholar

  41. 41.

    Morgan C, Kirkbride J, Leff J, Craig T, Hutchinson G, McKenzie K, et al. Parental separation, loss and psychosis in different ethnic groups: a case-control study. Psychol Med. 2007;37(4):495–503.

    PubMed Google Scholar

  42. 42.

    Stilo SA, Di Forti M, Mondelli V, Falcone AM, Russo M, O’Connor J, et al. Social disadvantage: cause or consequence of impending psychosis? Schizophr Bull. 2013;39(6):1288–95.

    PubMed Google Scholar

  43. 43.

    Stilo SA, Gayer-Anderson C, Beards S, Hubbard K, Onyejiaka A, Keraite A, et al. Further evidence of a cumulative effect of social disadvantage on risk of psychosis. Psychol Med. 2017;47(5):913–24.

    CASPubMed Google Scholar

  44. 44.

    Arseneault L, Cannon M, Fisher HL, Polanczyk G, Moffitt TE, Caspi A. Childhood trauma and children’s emerging psychotic symptoms: a genetically sensitive longitudinal cohort study. Am J Psychiatry. 2011;168(1):65–72.

    PubMed Google Scholar

  45. 45.

    Fisher HL, Schreier A, Zammit S, Maughan B, Munafo MR, Lewis G, et al. Pathways between childhood victimization and psychosis-like symptoms in the ALSPAC birth cohort. Schizophr Bull. 2013;39(5):1045–55.

    PubMed Google Scholar

  46. 46.

    Trotta A, Di Forti M, Mondelli V, Dazzan P, Pariante C, David A, et al. Prevalence of bullying victimisation amongst first-episode psychosis patients and unaffected controls. Schizophr Res. 2013;150(1):169–75.

    PubMed Google Scholar

  47. 47.

    Janssen I, Krabbendam L, Bak M, Hanssen M, Vollebergh W, de Graaf R, et al. Childhood abuse as a risk factor for psychotic experiences. Acta Psychiatr Scand. 2004;109(1):38–45.

    CASPubMed Google Scholar

  48. 48.

    Morgan C, Fisher H. Environment and schizophrenia: environmental factors in schizophrenia: childhood trauma-a critical review. Schizophr Bull. 2007;33(1):3–10.

    PubMed Google Scholar

  49. 49.

    Read J, van Os J, Morrison AP, Ross CA. Childhood trauma, psychosis and schizophrenia: a literature review with theoretical and clinical implications. Acta Psychiatr Scand. 2005;112(5):330–50.

    CASPubMed Google Scholar

  50. 50.

    Bentall RP, de Sousa P, Varese F, Wickham S, Sitko K, Haarmans M, et al. From adversity to psychosis: pathways and mechanisms from specific adversities to specific symptoms. Soc Psychiatry Psychiatr Epidemiol. 2014;49(7):1011–22.

    PubMed Google Scholar

  51. 51.

    Whitfield CL, Dube SR, Felitti VJ, Anda RF. Adverse childhood experiences and hallucinations. Child abuse & neglect. 2005;29(7):797–810.

    Google Scholar

  52. 52.

    Matheson SL, Shepherd AM, Pinchbeck RM, Laurens KR, Carr VJ. Childhood adversity in schizophrenia: a systematic meta-analysis. Psychol Med. 2013;43(2):225–38.

    CASPubMed Google Scholar

  53. 53.

    Bebbington P, Wilkins S, Jones P, Foerster A, Murray R, Toone B, et al. Life events and psychosis. Initial results from the Camberwell Collaborative Psychosis Study. Br J Psychiatry. 1993;162:72–9.

    CASPubMed Google Scholar

  54. 54.

    Raune D, Kuipers E, Bebbington P. Stressful and intrusive life events preceding first episode psychosis. Epidemiol Psichiatr Soc. 2009;18(3):221–8.

    PubMed Google Scholar

  55. 55.

    Beards S, Gayer-Anderson C, Borges S, Dewey ME, Fisher HL, Morgan C. Life events and psychosis: a review and meta-analysis. Schizophr Bull. 2013;39(4):740–7.

    PubMedPubMed Central Google Scholar

  56. 56.

    Castle DJ, Scott K, Wessely S, Murray RM. Does social deprivation during gestation and early life predispose to later schizophrenia? Soc Psychiatry Psychiatr Epidemiol. 1993;28(1):1–4.

    CASPubMed Google Scholar

  57. 57.

    Harrison G, Gunnell D, Glazebrook C, Page K, Kwiecinski R. Association between schizophrenia and social inequality at birth: case-control study. Br J Psychiatry. 2001;179:346–50.

    CASPubMed Google Scholar

  58. 58.

    Wicks S, Hjern A, Gunnell D, Lewis G, Dalman C. Social adversity in childhood and the risk of developing psychosis: a national cohort study. Am J Psychiatry. 2005;162(9):1652–7.

    PubMed Google Scholar

  59. 59.

    O’Donoghue B, Lyne JP, Fanning F, Kinsella A, Lane A, Turner N, et al. Social class mobility in first episode psychosis and the association with depression, hopelessness and suicidality. Schizophr Res. 2014;157(1-3):8–11.

    PubMed Google Scholar

  60. 60.

    Seidman LJ, Cherkerzian S, Goldstein JM, Agnew-Blais J, Tsuang MT, Buka SL. Neuropsychological performance and family history in children at age 7 who develop adult schizophrenia or bipolar psychosis in the New England Family Studies. Psychol Med. 2013;43(1):119–31.

    CASPubMed Google Scholar

  61. 61.

    Makikyro T, Isohanni M, Moring J, Oja H, Hakko H, Jones P, et al. Is a child’s risk of early onset schizophrenia increased in the highest social class? Schizophr Res. 1997;23(3):245–52.

    CASPubMed Google Scholar

  62. 62.

    Mulvany F, O’Callaghan E, Takei N, Byrne M, Fearon P, Larkin C. Effect of social class at birth on risk and presentation of schizophrenia: case-control study. BMJ. 2001;323(7326):1398–401.

    CASPubMedPubMed Central Google Scholar

  63. 63.

    Morgan C, Kirkbride J, Hutchinson G, Craig T, Morgan K, Dazzan P, et al. Cumulative social disadvantage, ethnicity and first-episode psychosis: a case-control study. Psychol Med. 2008;38(12):1701–15.

    CASPubMed Google Scholar

  64. 64.

    Jablensky A, Sartorius N. What did the WHO studies really find? Schizophr Bull. 2008;34(2):253–5.

    PubMedPubMed Central Google Scholar

  65. 65.

    Cantor-Graae E, Selten JP. Schizophrenia and migration: a meta-analysis and review. Am J Psychiatry. 2005;162(1):12–24.

    PubMed Google Scholar

  66. 66.

    • Bourque F, van der Ven E, Malla A. A meta-analysis of the risk for psychotic disorders among first- and second-generation immigrants. Psychol Med. 2011;41(5):897–910. This meta-analysis confirms an increased risk for schizophrenia not only in first-generation immigrants, but also in second-generation immigrants.

    CASPubMed Google Scholar

  67. 67.

    Harrison G, Glazebrook C, Brewin J, Cantwell R, Dalkin T, Fox R, et al. Increased incidence of psychotic disorders in migrants from the Caribbean to the United Kingdom. Psychol Med. 1997;27(4):799–806.

    CASPubMed Google Scholar

  68. 68.

    Veling W, Selten JP, Susser E, Laan W, Mackenbach JP, Hoek HW. Discrimination and the incidence of psychotic disorders among ethnic minorities in The Netherlands. International journal of epidemiology. 2007;36(4):761–8.

    PubMed Google Scholar

  69. 69.

    Haasen C, Yagdiran O, Mass R, Krausz M. Schizophrenic disorders among Turkish migrants in Germany. A controlled clinical study. Psychopathology. 2001;34(4):203–8.

    CASPubMed Google Scholar

  70. 70.

    Cantor-Graae E, Pedersen CB. Risk of schizophrenia in second-generation immigrants: a Danish population-based cohort study. Psychol Med. 2007;37(4):485–94.

    PubMed Google Scholar

  71. 71.

    Tortelli A, Morgan C, Szoke A, Nascimento A, Skurnik N, de Caussade EM, et al. Different rates of first admissions for psychosis in migrant groups in Paris. Soc Psychiatry Psychiatr Epidemiol. 2014;49(7):1103–9.

    PubMed Google Scholar

  72. 72.

    Tarricone I, Boydell J, Kokona A, Triolo F, Gamberini L, Sutti E, et al. Risk of psychosis and internal migration: results from the Bologna First Episode Psychosis study. Schizophr Res. 2016;173(1-2):90–3.

    PubMed Google Scholar

  73. 73.

    Anderson KK, Cheng J, Susser E, McKenzie KJ, Kurdyak P. Incidence of psychotic disorders among first-generation immigrants and refugees in Ontario. CMAJ. 2015;187(9):E279–E86.

    PubMedPubMed Central Google Scholar

  74. 74.

    Hollander AC, Dal H, Lewis G, Magnusson C, Kirkbride JB, Dalman C. Refugee migration and risk of schizophrenia and other non-affective psychoses: cohort study of 1.3 million people in Sweden. BMJ. 2016;352:i1030.

    PubMedPubMed Central Google Scholar

  75. 75.

    Amad A, Guardia D, Salleron J, Thomas P, Roelandt JL, Vaiva G. Increased prevalence of psychotic disorders among third-generation migrants: results from the French Mental Health in General Population survey. Schizophr Res. 2013;147(1):193–5.

    PubMed Google Scholar

  76. 76.

    Tortelli A, Errazuriz A, Croudace T, Morgan C, Murray RM, Jones PB, et al. Schizophrenia and other psychotic disorders in Caribbean-born migrants and their descendants in England: systematic review and meta-analysis of incidence rates, 1950-2013. Soc Psychiatry Psychiatr Epidemiol. 2015;50(7):1039–55.

    CASPubMedPubMed Central Google Scholar

  77. 77.

    Mahy GE, Mallett R, Leff J, Bhugra D. First-contact incidence rate of schizophrenia on Barbados. Br J Psychiatry. 1999;175:28–33.

    CASPubMed Google Scholar

  78. 78.

    Selten JP, Hoek HW. Does misdiagnosis explain the schizophrenia epidemic among immigrants from developing countries to Western Europe? Soc Psychiatry Psychiatr Epidemiol. 2008;43(12):937–9.

    PubMed Google Scholar

  79. 79.

    van der Ven E, Dalman C, Wicks S, Allebeck P, Magnusson C, van Os J, et al. Testing Odegaard’s selective migration hypothesis: a longitudinal cohort study of risk factors for non-affective psychotic disorders among prospective emigrants. Psychol Med. 2015;45(4):727–34.

    PubMed Google Scholar

  80. 80.

    Kirkbride JB, Barker D, Cowden F, Stamps R, Yang M, Jones PB, et al. Psychoses, ethnicity and socio-economic status. Br J Psychiatry. 2008;193(1):18–24.

    CASPubMed Google Scholar

  81. 81.

    Kirkbride JB, Hameed Y, Ioannidis K, Ankireddypalli G, Crane CM, Nasir M, et al. Ethnic minority status, age-at-immigration and psychosis risk in rural environments: evidence from the SEPEA study. Schizophr Bull. 2017;43(6):1251–61.

    PubMedPubMed Central Google Scholar

  82. 82.

    Morgan C, Charalambides M, Hutchinson G, Murray RM. Migration, ethnicity, and psychosis: toward a sociodevelopmental model. Schizophr Bull. 2010;36(4):655–64.

    PubMedPubMed Central Google Scholar

  83. 83.

    Boydell J, van Os J, McKenzie K, Allardyce J, Goel R, McCreadie RG, et al. Incidence of schizophrenia in ethnic minorities in London: ecological study into interactions with environment. BMJ. 2001;323(7325):1336–8.

    CASPubMedPubMed Central Google Scholar

  84. 84.

    Veling W, Susser E, van Os J, Mackenbach JP, Selten JP, Hoek HW. Ethnic density of neighborhoods and incidence of psychotic disorders among immigrants. Am J Psychiatry. 2008;165(1):66–73.

    PubMed Google Scholar

  85. 85.

    Porter M, Haslam N. Predisplacement and postdisplacement factors associated with mental health of refugees and internally displaced persons: a meta-analysis. JAMA. 2005;294(5):602–12.

    CASPubMed Google Scholar

  86. 86.

    McGrath JJ, Welham JL. Season of birth and schizophrenia: a systematic review and meta-analysis of data from the Southern Hemisphere. Schizophr Res. 1999;35(3):237–42.

    CASPubMed Google Scholar

  87. 87.

    Dealberto MJ. Why are immigrants at increased risk for psychosis? Vitamin D insufficiency, epigenetic mechanisms, or both? Medical hypotheses. 2007;68(2):259–67.

    CASPubMed Google Scholar

  88. 88.

    Marcelis M, Navarro-Mateu F, Murray R, Selten JP, Van Os J. Urbanization and psychosis: a study of 1942-1978 birth cohorts in The Netherlands. Psychol Med. 1998;28(4):871–9.


What are the Genetic and Environmental Causes of Schizophrenia? Part One of Six

Environmental risk factors for psychosis

1. Bleuler E. Section IX: The causes of the disease. In: Zinkin J, trans-ed. Dementia Praecox or the Group of Schizophrenias. New York, NY: International Universities Press Inc; 1950[Google Scholar]

2. Kraepelin E. Frequency and causes. In: Barclay RM, trans-ed. Dementia Praecox and Paraphrenia. Edinburgh, UK: E&S Livingstone; 1919[Google Scholar]

3. Cardno AG., Marshall EJ., Coid B., et al. Heritability estimates for psychotic disorders: the Maudsley twin psychosis series. Arch Gen Psychiatry.1999;56:162–168. [PubMed] [Google Scholar]

4. Tsuang MT., Stone WS., Faraone SV. Genes, environment and schizophrenia. Br J Psychiatry Suppl.2001;40:s18–24. [PubMed] [Google Scholar]

5. van Os J., Sham P. Gene-environment correlation and interaction in schizophrenia. In: Murray RM, Jones PB, Susser E, van Os J, Cannon M, eds. The Epidemiology of Schizophrenia. Cambridge, UK: Cambridge University Press; 2003:235–253.[Google Scholar]

6. Murray RM., Lewis SW. Is schizophrenia a neurodevelopmental disorder? BMJ (Clin Res Ed).1987;295:681–682.[PMC free article] [PubMed] [Google Scholar]

7. Cannon M., Tarrant CJ., Huttunen MO., Jones P. Childhood development and later schizophrenia: evidence from genetic high-risk and birth cohort studies. In: Murray RM, Jones P, Susser E, van Os J, Cannon M, eds. The Epidemiology of Schizophrenia. Cambridge, UK: Cambridge University Press; 2003:100–123.[Google Scholar]

8. Wright IC., Rabe-Hesketh S., Woodruff PW., David AS., Murray RM., BuIImore ET. Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry.2000;157:16–25. [PubMed] [Google Scholar]

9. McGrath J., EI-Saadi O., Grim V., et al. Minor physical anomalies and quantitative measures of the head and face in patients with psychosis. Arch Gen Psychiatry.2002;59:458–464. [PubMed] [Google Scholar]

10. Rosanoff A., Handy L., Plesset I., Brush S. The etiology of so-called schizophrenic psychoses: with special reference to their occurrence in twins. Am J Psychiatry.1934;91:247–286.[Google Scholar]

11. Arseneault L., Cannon M., Poulton R., Murray R., Caspi A., Moffitt TE. Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study. BMJ.2002;325:1212–1213.[PMC free article] [PubMed] [Google Scholar]

12. Rosso IM., Cannon TD., Huttunen T., Huttunen MO., Lonnqvist J., Gasperoni TL. Obstetric risk factors for early-onset schizophrenia in a Finnish birth cohort. Am J Psychiatry.2000;157:801–807. [PubMed] [Google Scholar]

13. Verdoux H., Geddes JR., Takei N., et al. Obstetric complications and age at onset in schizophrenia: an international collaborative meta-analysis of individual patient data. Am J Psychiatry.1997;154:1220–1227. [PubMed] [Google Scholar]

14. McNeil TF., Cantor-Graae E., Weinberger DR. Relationship of obstetric complications and differences in size of brain structures in monozygotic twin pairs discordant for schizophrenia. Am J Psychiatry.2000;157:203–212. [PubMed] [Google Scholar]

15. Cannon TD., van Erp TG., Rosso IM., et al. Fetal hypoxia and structural brain abnormalities in schizophrenic patients, their siblings, and controls. Arch Gen Psychiatry.2002;59:35–41. [PubMed] [Google Scholar]

16. Stefanis N., Frangou S., Yakeley J., et al. Hippocampal volume reduction in schizophrenia: effects of genetic risk and pregnancy and birth complications. Biol Psychiatry.1999;46:697–702. [PubMed] [Google Scholar]

17. Cantor-Graae E., Ismail B., McNeil TF. Are neurological abnormalities in schizophrenic patients and their siblings the result of perinatal trauma? Acta Psychiatr Scand.2000;101:142–147. [PubMed] [Google Scholar]

18. O'Callaghan E., Larkin C., Kinsella A., Waddington JL. Obstetric complications, the putative familial-sporadic distinction, and tardive dyskinesia in schizophrenia. Br J Psychiatry.1990;157:578–584. [PubMed] [Google Scholar]

19. Cannon TD., Rosso IM., HoIIïster JM., Bearden CE., Sanchez LE., Hadley T. A prospective cohort study of genetic and perinatal influences in the etiology of schizophrenia. Schizophr Bull.2000;26:351–366. [PubMed] [Google Scholar]

20. Harrison PJ., Owen MJ. Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet.2003;361:417–419. [PubMed] [Google Scholar]

21. Fearon P., Cotter P., Murray RM. Is the association between obstetric complications and schizophrenia mediated by glutaminergic excitotoxic damage in the foetal/neonatal brain? In: Reveley M, Deacon B, ed. Psychopharmacology of Schizophrenia. London, UK: Chapman and Hall; 2000:21–40.[Google Scholar]

22. Fearon P., O'Connell P., Frangou S., et al. Brain volumes in adult survivors of very low birth weight: a sibling-controlled study. Pediatrics.2004;114:367–371. [PubMed] [Google Scholar]

23. Nosarti C., AI-Asady MH., Frangou S., Stewart AL., Rifkin L., Murray RM. Adolescents who were born very preterm have decreased brain volumes. Brain.2002;125(Pt 7):1616–1623. [PubMed] [Google Scholar]

24. Bradbury TN., Miller GA. Season of birth in schizophrenia: a review of evidence, methodology, and etiology. Psychol Bull.1985;98:569–594. [PubMed] [Google Scholar]

25. McGrath JJ., Welham JL. Season of birth and schizophrenia: a systematic review and meta-analysis of data from the Southern Hemisphere. Schizophr Res.1999;35:237–242. [PubMed] [Google Scholar]

26. Davies G., Welham J., Chant D., Torrey EF., McGrath J. A systematic review and meta-analysis of Northern Hemisphere season of birth studies in schizophrenia. Schizophr Bull.2003;29:587–593. [PubMed] [Google Scholar]

27. Torrey EF., Miller J., Rawlings R., Yolken RH. Seasonality of births in schizophrenia and bipolar disorder: a review of the literature. Schizophr Res.1997;28:1–38. [PubMed] [Google Scholar]

28. Bagalkote H., Pang D., Jones PB. Maternal influenza and schizophrenia. Int J Ment Health.2001;29:3–21.[Google Scholar]

29. Brown AS. Prenatal infection and adult schizophrenia: a review and synthesis, int J Ment Health.2001;29:22–37.[Google Scholar]

30. Dean K., Bramon E., Murray RM. The causes of schizophrenia: neurodevelopmental and other risk factors. J Psychiatr Pract.2003;9:442–454. [PubMed] [Google Scholar]

31. Mednick SA., Machon RA., Huttunen MO., Bonett D. Adult schizophrenia following prenatal exposure to an influenza epidemic. Arch Gen Psychiatry.1988;45:189–192. [PubMed] [Google Scholar]

32. Takei N., Mortensen PB., Klaening U., et al. Relationship between in utero exposure to influenza epidemics and risk of schizophrenia in Denmark. Biol Psychiatry.1996;40:817–824. [PubMed] [Google Scholar]

33. Westergaard T., Mortensen PB., Pedersen CB., Wohlfahrt J., Melbye M. Exposure to prenatal and childhood infections and the risk of schizophrenia: suggestions from a study of sibship characteristics and influenza prevalence. Arch Gen Psychiatry.1999;56:993–998. [PubMed] [Google Scholar]

34. Torrey EF., Bowler AE., Rawlings R. Schizophrenia and the 1957 influenza epidemic. Schizophr Res.1992;6:100.[Google Scholar]

35. Limosin F., Rouillon F., Payan C., Cohen JM., Strub N. Prenatal exposure to influenza as a risk factor for adult schizophrenia. Acta Psychiatr Scand.2003;107:331–335. [PubMed] [Google Scholar]

36. Cannon M KR., Susser E., Jones P. Prenatal and perinatal risk factors for schizophrenia. In: Murray R, Jones PB, Susser E, Van Os J, Cannon M, eds. The Epidemiology of Schizophrenia. Cambridge, UK: Cambridge University Press; 2003:74–99.[Google Scholar]

37. Crow TJ., Done DJ. Prenatal exposure to influenza does not cause schizophrenia. Br J Psychiatry.1992;161:390–393. [PubMed] [Google Scholar]

38. Cannon M., Cotter D., Coffey VP., et al. Prenatal exposure to the 1957 influenza epidemic and adult schizophrenia: a follow-up study. Br J Psychiatry.1996;168:368–371. [PubMed] [Google Scholar]

39. Shi L., Fatemi SH., Sidwell RW., Patterson PH. Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J Neurosci.2003;23:297–302.[PMC free article] [PubMed] [Google Scholar]

40. Brown AS., Cohen P., Harkavy-Friedman J., et al. A. E. Bennett Research Award. Prenatal rubella, premorbid abnormalities, and adult schizophrenia. Biol Psychiatry.2001;49:473–486. [PubMed] [Google Scholar]

41. Suvisaari J., Haukka J., Tanskanen A., Hovi T., Lonnqvist J. Association between prenatal exposure to poliovirus infection and adult schizophrenia. Am J Psychiatry.1999;156:1100–1102. [PubMed] [Google Scholar]

42. Buka SL., Tsuang MT., Torrey EF., Klebanoff MA., Bernstein D., Yolken RH. Maternal infections and subsequent psychosis among offspring. Arch Gen Psychiatry.2001;58:1032–1037. [PubMed] [Google Scholar]

43. Brown AS., Begg MD., Gravensteïn S., et al. Serologic evidence of prenatal influenza in the etiology of schizophrenia. Arch Gen Psychiatry.2004;61:774–780. [PubMed] [Google Scholar]

44. Koponen H., Rantakallio P., Veijola J., Jones P., Jokelainen J., Isohanni M. Childhood central nervous system infections and risk for schizophrenia. Eur Arch Psychiatry Clin Neurosci.2004;254:9–13. [PubMed] [Google Scholar]

45. Gattaz WF., Abrahao AL., Foccacia R. Childhood meningitis, brain maturation and the risk of psychosis. Eur Arch Psychiatry Clin Neurosci.2004;254:23–26. [PubMed] [Google Scholar]

46. Torrey EF., Yolken RH. Toxoplasma gondii and schizophrenia. Emerg Infect Dis.2003;9:1375–1380.[PMC free article] [PubMed] [Google Scholar]

47. Kinney D. Prenatal stress and risk for schizophrenia. Int J Ment Health.2001;29:62–72.[Google Scholar]

48. Susser E., Hoek HW., Brown A. Neurodevelopmental disorders after prenatal famine: the story of the Dutch Famine Study. Am J Epidemiol.1998;147:213–216. [PubMed] [Google Scholar]

49. Sacker A., Done DJ., Crow TJ., Golding J. Antecedents of schizophrenia and affective illness. Obstetric complications. Br J Psychiatry.1995;166:734–741. [PubMed] [Google Scholar]

50. HoIIister JM., Laing P., Mednick SA. Rhesus incompatibility as a risk factor for schizophrenia in male adults. Arch Gen Psychiatry.1996;53:19–24. [PubMed] [Google Scholar]

51. van Os J., Selten JP. Prenatal exposure to maternal stress and subsequent schizophrenia. The May 1940 invasion of The Netherlands. Br J Psychiatry.1998;172:324–326. [PubMed] [Google Scholar]

52. Selten JP., van der Graaf Y., van Duursen R., Gispen-de Wied CC., Kahn RS. Psychotic illness after prenatal exposure to the 1953 Dutch Flood Disaster. Schizophr Res.1999;35:243–245. [PubMed] [Google Scholar]

53. Huttunen MO., Niskanen P. Prenatal loss of father and psychiatric disorders. Arch Gen Psychiatry.1978;35:429–431. [PubMed] [Google Scholar]

54. Selten JP., Cantor-Graae E., Nahon D., Levav I., Aleman A., Kahn RS. No relationship between risk of schizophrenia and prenatal exposure to stress during the Six-Day War or Yom Kippur War in Israel. Schizophr Res.2003;63:131–135. [PubMed] [Google Scholar]

55. Maki P., Veijola J., Rantakallio P., Jokelainen J., Jones PB., Isohanni M. Schizophrenia in the offspring of antenatally depressed mothers: a 31 -year follow-up of the Northern Finland 1966 Birth Cohort. Schizophr Res.2004;66:79–81. [PubMed] [Google Scholar]

56. Barker DJ. Mothers, Babies and Health in Later Life. Edinburgh, UK: Churchill Livingstone; 1998[Google Scholar]

57. Brown AS., Susser ES., Butler PD., Richardson Andrews R., Kaufmann CA., Gorman JM. Neurobiological plausibility of prenatal nutritional deprivation as a risk factor for schizophrenia. J Nerv Ment Dis.1996;184:71–85. [PubMed] [Google Scholar]

58. Jones PB., Rantakallio P., Hartikainen AL., Isohanni M., Sipila P. Schizophrenia as a long-term outcome of pregnancy, delivery, and perinatal complications: a 28-year follow-up of the 1966 north Finland general population birth cohort. Am J Psychiatry.1998;155:355–364. [PubMed] [Google Scholar]

59. Schaefer CA., Brown AS., Wyatt RJ., et al. Maternal prepregnant body mass and risk of schizophrenia in adult offspring. Schizophr Bull.2000;26:275–286. [PubMed] [Google Scholar]

60. Hoek HW., Brown AS., Susser E. The Dutch famine and schizophrenia spectrum disorders. Soc Psychiatry Psychiatr Epidemiol.1998;33:373–379. [PubMed] [Google Scholar]

61. Wahlbeck K., Forsen T., Osmond C., Barker DJ., Eriksson JG. Association of schizophrenia with low maternal body mass index, small size at birth, and thinness during childhood. Arch Gen Psychiatry.2001;58:48–52. [PubMed] [Google Scholar]

62. Susser ES., Lin SP. Schizophrenia after prenatal exposure to the Dutch Hunger Winter of 1944-1945. Arch Gen Psychiatry.1992;49:983–988. [PubMed] [Google Scholar]

63. Susser E., Neugebauer R., Hoek HW., et al. Schizophrenia after prenatal famine. Further evidence. Arch Gen Psychiatry.1996;53:25–31. [PubMed] [Google Scholar]

64. Hulshoff Pol HE., Hoek HW., Susser E., et al. Prenatal exposure to famine and brain morphology in schizophrenia. Am J Psychiatry.2000;157:1170–1172. [PubMed] [Google Scholar]

65. McGrath J. Hypothesis: is low prenatal vitamin D a risk-modifying factor for schizophrenia? Schizophr Res.1999;40:173–177. [PubMed] [Google Scholar]

66. McGrath J., Saari K., Hakko H., et al. Vitamin D supplementation during the first year of life and risk of schizophrenia: a Finnish birth cohort study. Schizophr Res.2004;67:237–245. [PubMed] [Google Scholar]

67. McGrath J., Eyles D., Mowry B., Yolken R., Buka S. Low maternal vitamin D as a risk factor for schizophrenia: a pilot study using banked sera. Schizophr Res.2003;63:73–78. [PubMed] [Google Scholar]

68. Ozer S., Ulusahïn A., Ulusoy S., et al. Is vitamin D hypothesis for schizophrenia valid? Independent segregation of psychosis in a family with vitami n-D-dependent rickets type HA. Prog Neuropsychopharmacol Biol Psychiatry.2004;28:255–266. [PubMed] [Google Scholar]

69. Muntjewerff JW., van der Put N., Eskes T., et al. Homocysteine metabolism and B-vitamins in schizophrenic patients: low plasma folate as a possible independent risk factor for schizophrenia. Psychiatry Res.2003;121:1–9. [PubMed] [Google Scholar]

70. Mirsky AF., Silberman EK., Latz A., Nagler S. Adult outcomes of high-risk children: differential effects of town and kibbutz rearing. Schizophr Bull.1985;11:150–154. [PubMed] [Google Scholar]

71. Cannon M., Caspi A., Moffitt TE., et al. Evidence for early-childhood, pandevelopmental impairment specific to schizophreniform disorder: results from a longitudinal birth cohort. Arch Gen Psychiatry.2002;59:449–456. [PubMed] [Google Scholar]

72. Agid O., Shapira B., Zislin J., et al. Environment and vulnerability to major psychiatric illness: a case control study of early parental loss in major depression, bipolar disorder and schizophrenia. Mol Psychiatry.1999;4:163–172. [PubMed] [Google Scholar]

73. Jones P., Rodgers B., Murray R., Marmot M. Child development risk factors for adult schizophrenia in the British 1946 birth cohort. Lancet.1994;344:1398–1402. [PubMed] [Google Scholar]

74. Tïenari P., Wynne LC., Moring J., et al. The Finnish adoptive family study of schizophrenia. Implications for family research. Br J Psychiatry Suppl.1994:20–26. [PubMed] [Google Scholar]

75. Read J., Perry BD., Moskowitz A., Connolly J. The contribution of early traumatic events to schizophrenia in some patients: a traumagenic neurodevelopmental model. Psychiatry.2001;64:319–345. [PubMed] [Google Scholar]

76. Garety PA., Kuipers E., Fowler D., Freeman D., Bebbington PE. A cognitive model of the positive symptoms of psychosis. Psychol Med.2001;31:189–195. [PubMed] [Google Scholar]

77. Mullen PE., Martin JL., Anderson JC., Romans SE., Herbison GP. Childhood sexual abuse and mental health in adult life. Br J Psychiatry.1993;163:721–732. [PubMed] [Google Scholar]

78. Read J., Argyle N. Hallucinations, delusions, and thought disorder among adult psychiatric inpatients with a history of child abuse. Psychiatr Serv.1999;50:1467–1472. [PubMed] [Google Scholar]

79. Janssen I., Krabbendam L., Bak M., et al. Childhood abuse as a risk factor for psychotic experiences. Acta Psychiatr Scand.2004;109:38–45. [PubMed] [Google Scholar]

80. Sachdev P. Schizophrenia-like psychosis following traumatic brain injury. J Neuropsychiatry Clin Neurosci.2001;13:533–534. [PubMed] [Google Scholar]

81. Nielsen AS., Mortensen PB., O'Callaghan E., Mors O., Ewald H. Is head injury a risk factor for schizophrenia? Schizophr Res.2002;55:93–98. [PubMed] [Google Scholar]

82. Wilcox JA., Nasrallah HA. Childhood head trauma and psychosis. Psychiatry Res.1987;21:303–306. [PubMed] [Google Scholar]

83. AbdelMalik P., Husted J., Chow EW., Bassett AS. Childhood head injury and expression of schizophrenia in multiply affected families. Arch Gen Psychiatry.2003;60:231–236.[PMC free article] [PubMed] [Google Scholar]

84. Murray RM., Grech A., Philips P., Johnson S. The relationship between substance abuse and schizophrenia. In: Murray R, Jones PB, Susser E, van Os J, Cannon M, eds. The Epidemiology of Schizophrenia. Cambridge, UK: Cambridge University Press; 2003:317–342.[Google Scholar]

85. Chen CK., Lin SK., Sham PC., et al. Pre-morbid characteristics and co-morbidity of metamphetamine users with and without psychosis. Psychol Med.2003;33:1407–1414. [PubMed] [Google Scholar]

86. Mathers DC., Ghodse AH. Cannabis and psychotic illness. Br J Psychiatry.1992;161:648–653. [PubMed] [Google Scholar]

87. D'Souza DC., Abi-Saad W., Madonick S., Wray Y., et al. Cannabinoids and psychosis: evidence from studies with iv THC in schizophrenia patients and controls. Schizophr Res.2000;41 (special issue):33.[Google Scholar]

88. Hall W., Degenhardt L. Is there a specific “cannabis psychosis”? In: Castle DJ, Murray RM, eds. Marijuana and Madness. Cambridge, UK: Cambridge University Press; 2004[Google Scholar]

89. Andreasson S., AHebeck P., Engstrom A., Rydberg U. Cannabis and schizophrenia. A longitudinal study of Swedish conscripts. Lancet.1987;2:1483–1486. [PubMed] [Google Scholar]

90. Zammit S., AHebeck P., Andreasson S., Lundberg I., Lewis G. Self-reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort study. BMJ.2002;325:1199.[PMC free article] [PubMed] [Google Scholar]

91. Weiser M., Knobler HY., Noy S., Kaplan Z. Clinical characteristics of adolescents later hospitalized for schizophrenia. Am J Med Genet.2002;114:949–955. [PubMed] [Google Scholar]

92. Fergusson DM., Horwood LJ., Swain-Campbell NR. Cannabis dependence and psychotic symptoms in young people. Psychol Med.2003;33:15–21. [PubMed] [Google Scholar]

93. van Os J., Bak M., Hanssen M., Bjjl RV., de Graaf R., Verdoux H. Cannabis use and psychosis: a longitudinal population-based study. Am J Epidemiol.2002;156:319–327. [PubMed] [Google Scholar]

94. Arseneault L., Cannon M., Witton J., Murray RM. Causal association between cannabis and psychosis: examination of the evidence. Br J Psychiatry.2004;184:110–117. [PubMed] [Google Scholar]

95. Smit F., Bolier L., Cuypers P. Cannabis use and the risk of later schizophrenia: a review. Addiction.2004;99:425–430. [PubMed] [Google Scholar]

96. Veen ND., Selten JP., van der Tweel I., Feller WG., Hoek HW., Kahn RS. Cannabis use and age at onset of schizophrenia. Am J Psychiatry.2004;161:501–506. [PubMed] [Google Scholar]

97. Kapur S. Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry.2003;160:13–23. [PubMed] [Google Scholar]

98. Lamelle M., Abi-Dargham A., van Dyck CH., et al. Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci USA.1996;93:9235–9240.[PMC free article] [PubMed] [Google Scholar]

99. Wolf ME., White FJ., Nassar R., et al. Differential development of autoreceptor subsensitivity and enhanced dopamine release during amphetamine sensitisation. J Pharmacol Exp Ther.1993;264:249–255. [PubMed] [Google Scholar]

100. Bartlett E., Hallin A., Chapman B., Angrist B. Selective sensitization to the psychosis-inducing effects of cocaine: a possible marker for addiction relapse vulnerability? Neuropsychopharmacology.1997;16:77–82. [PubMed] [Google Scholar]

101. Berridge KC., Robinson TE. What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res Brain Res Rev.1998;28:309–369. [PubMed] [Google Scholar]

102. Selten JP., Cantor-Graae E. Schizophrenia and migration. In: Gattaz WF, Hafner H, eds. Search for the Causes of Schizophrenia. Berlin, Germany: Steinkopff Verlag; 2004:3–25.[Google Scholar]

103. Kiev A. Psychiatric morbidity of West Indian immigrants in an urban group practice. Br J Psychiatry.1965;111:51–56. [PubMed] [Google Scholar]

104. Harrison G., Owens D., Holton A., Neilson D., Boot D. A prospective study of severe mental disorder in Afro-Caribbean patients. Psychol Med.1988;18:643–657. [PubMed] [Google Scholar]

105. Cochrane R., Bal SS. Mental hospital admission rates of immigrants to England: a comparison of 1971 and 1981. Soc Psychiatry Psychiatr Epidemiol.1989;24:2–11. [PubMed] [Google Scholar]

106. Castle D., Wessely S., Der G., Murray RM. The incidence of operationally defined schizophrenia in Camberwell, 1965-84. Br J Psychiatry.1991;159:790–794. [PubMed] [Google Scholar]

107. Harrison G., Glazebrook C., Brewin J., et al. Increased incidence of psychotic disorders in migrants from the Caribbean to the United Kingdom. Psychol Med.1997;27:799–806. [PubMed] [Google Scholar]

108. Mortensen PB., Pedersen CB., Westergaard T., et al. Effects of family history and place and season of birth on the risk of schizophrenia. N Engl J Med.1999;340:603–608. [PubMed] [Google Scholar]

109. Zolkowska K., Cantor-Graae E., McNeil TF. Increased rates of psychosis among immigrants to Sweden: is migration a risk factor for psychosis? Psychol Med.2001;31:669–678. [PubMed] [Google Scholar]

110. Sharpley M., Hutchinson G., McKenzie K., Murray RM. Understanding the excess of psychosis among the African-Caribbean population in England. Review of current hypotheses. Br J Psychiatry Suppl.2001;40:s60–s68. [PubMed] [Google Scholar]

111. Hutchinson G., Takei N., Bhugra D., et al. Increased rate of psychosis among African-Caribbeans in Britain is not due to an excess of pregnancy and birth complications. Br J Psychiatry.1997;171:145–147. [PubMed] [Google Scholar]

112. Boydell J., van Os J., McKenzie K., et al. Incidence of schizophrenia in ethnic minorities in London: ecological study into interactions with environment. BMJ.2001;323:1336–1338.[PMC free article] [PubMed] [Google Scholar]

113. Mallett R., Leff J., Bhugra D., Pang D., Zhao JH. Social environment, ethnicity and schizophrenia. A case-control study. Soc Psychiatry Psychiatr Epidemiol.2002;37:329–335. [PubMed] [Google Scholar]

114. Eaton W., Harrison G. Ethnic disadvantage and schizophrenia. Acta Psychiatr Scand Suppl.2000:38–43. [PubMed] [Google Scholar]

115. Freeman H. Schizophrenia and city residence. Br J Psychiatry Suppl.1994:39–50. [PubMed] [Google Scholar]

116. Lewis G., David A., Andreasson S., AHebeck P. Schizophrenia and city life. Lancet.1992;340:137–140. [PubMed] [Google Scholar]

117. Sundquist K., Frank G., Sundquist J. Urbanisation and incidence of psychosis and depression: follow-up study of 4.4 million women and men in Sweden. Br J Psychiatry.2004;184:293–298. [PubMed] [Google Scholar]

118. Pedersen CB., Mortensen PB. Evidence of a dose-response relationship between urbanicity during upbringing and schizophrenia risk. Arch Gen Psychiatry.2001;58:1039–1046. [PubMed] [Google Scholar]

119. Mortensen PB. Urban-rural differences in the risk for schizophrenia, int J Ment Health.2000;29:101–110.[Google Scholar]

120. Van Os J. Does the urban environment cause psychosis? Br J Psychiatry.2004;184:287–288. [PubMed] [Google Scholar]

121. Harrison G., Gunnell D., Glazebrook C., Page K., Kwiecinski R. Association between schizophrenia and social inequality at birth: case-control study. Br J Psychiatry.2001;179:346–350. [PubMed] [Google Scholar]

122. Mulvany F., O'Callaghan E., Takei N., Byrne M., Fearon P., Larkin C. Effect of social class at birth on risk and presentation of schizophrenia: case-control study. BMJ.2001;323:1398–1401.[PMC free article] [PubMed] [Google Scholar]

123. Byrne M., Agerbo E., Eaton WW., Mortensen PB. Parental socio-economic status and risk of first admission with schizophrenia- a Danish national register-based study. Soc Psychiatry Psychiatr Epidemiol.2004;39:87–96. [PubMed]


Environmental factors schizophrenia

[Environmental risk factors for schizophrenia: a review]

Background: Evidence of variations in schizophrenia incidence rates has been found in genetically homogenous populations, depending on changes within time or space of certain environmental characteristics. The consideration of the impact of environmental risk factors in etiopathogenic studies has put the environment in the forefront of research regarding psychotic illnesses. Various environmental factors such as urbanicity, migration, cannabis, childhood traumas, infectious agents, obstetrical complications and psychosocial factors have been associated with the risk of developing schizophrenia. These risk factors can be biological, physical, psychological as well as social and may operate at different times in an individual's life (fetal period, childhood, adolescence and early adulthood). Whilst some of these factors act on an individual level, others act on a populational level, modulating the individual risk. These factors can have a direct action on the development of schizophrenia, or on the other hand act as markers for directly implicated factors that have not yet been identified.

Literature findings: This article summarizes the current knowledge on this subject. An extensive literature search was conducted via the search engine Pubmed. Eight risk factors were selected and developed in the following paper: urbanicity (or living in an urban area), cannabis, migration (and ethnic density), obstetrical complications, seasonality of birth, infectious agents (and inflammatory responses), socio-demographic factors and childhood traumas. For each of these factors, we provide information on the importance of the risk, the vulnerability period, hypotheses made on the possible mechanisms behind the factors and the level of proof the current research offers (good, medium, or insufficient) according to the amount, type, quality and concordance of the studies at hand. Some factors, such as cannabis, are "unique" in their influence on the development of schizophrenia since it labels only one risk factor. Others, such as obstetrical complications, are grouped (or "composed") in that they include various sub-factors that can influence the development of schizophrenia.

Discussion: The data reviewed clearly demonstrates that environmental factors have an influence on the risk of developing schizophrenia. For certain factors - cannabis, migration, urbanicity, obstetrical complications, seasonality - there is enough evidence to establish an association with the risk of schizophrenia. This association, however, remains weak (especially for seasonality). With the exception of cannabis, no direct link can yet be established. Concerning the three remaining factors - childhood traumas, infectious agents, socio-demographic factors - the available proof is insufficient. One main limitation concerning all environmental factors is the generalization of results due to the fact that the studies were conducted on geographically limited populations. The current state of knowledge does not allow us to determine the mechanisms by which these factors may act.

Conclusion: Further research is needed to fill the gaps in our understanding of the subject. In response to this need, a collaborative European project (European Study of Gene-Environment Interactions [EU GEI]) was set-up. This study proposes the analysis of those environmental factors that influence the incidence of schizophrenia in various European countries, in both rural and urban settings, migrant and native populations, as well as their interaction with genetic factors.

What are the Causes of Schizophrenia?

Environmental Risk Factors for Schizophrenia and Bipolar Disorder and Their Relationship to Genetic Risk: Current Knowledge and Future Directions


Schizophrenia (SZ) and bipolar disorder (BD) are severe psychiatric disorders affecting ∼0.7 and ∼1.0% of the population, respectively (McGrath et al., 2008; Merikangas et al., 2011). Both have a typical onset during late teenage years or in the early 20s and are associated with substantial morbidity and premature mortality (Lambert et al., 2003; Carney and Jones, 2006; Kilbourne et al., 2009). Furthermore, the clinical presentations of these disorders can overlap. Delusions and hallucinations occur in nearly all cases of SZ but also in about half of cases of BD (Coryell et al., 2001; American Psychiatric Association, 2013). Depressed mood, an essential feature of BD, can be hard to distinguish from the negative symptoms of SZ. Both BD and SZ often present with symptoms of grandiosity or paranoia.

Considering their similarities, it is not surprising that the etiological sources for these disorders have been compared, and the genetic foundations are substantially shared (Lichtenstein et al., 2009; Bulik-Sullivan et al., 2015). Risk for both disorders stems primarily from genetic sources, with heritability estimates from twin and family studies ranging from 64–81% for SZ (Sullivan et al., 2003; Lichtenstein et al., 2009) and 60–85% for BD (Smoller and Finn, 2003). Although there is significant shared genetic risk between several psychiatric disorders, the strongest correlation is between SZ and BD (rg = 0.60–0.68) (Lichtenstein et al., 2009; Lee et al., 2013; Pettersson et al., 2016; Brainstorm Consortium, 2018). Great strides have been made in revealing the specific genetic loci associated with these disorders. Genome-wide association studies (GWAS) have now discovered 270 single nucleotide polymorphisms (SNPs) conferring risk for SZ (Ripke et al., 2020) and 64 for BD (Mullins et al., 2020), with some overlapping associations. However, many of these common genetic variants are not shared between these disorders, and other forms of genetic variation, such as copy number variants (CNVs) (Malhotra and Sebat, 2012; Marshall et al., 2017) and rare variants identified through sequencing (Purcell et al., 2014; Goes et al., 2016), appear to play a much larger role in the genetic architecture of SZ than BD.

Discovery of the environmental sources of risk has not kept pace with the dramatic advances in understanding the genetic underpinnings for SZ and BD, and the extent to which genetic sharing of risk may be mirrored for environmental factors is not well known. Speculation and investigation regarding the risk for SZ and BD which is derived from environmental factors stretches back for decades, with particular focus on exposures early in life, such as: winter/spring birth, obstetric complications (OCs), infections, and adverse childhood experiences (ACEs). However, urban living, migration, and cannabis use are usually later exposures which have also been the focus of intense interest in relation to SZ and, to a lesser extent, BD (Table 1). Of the numerous studies of environmental risk factors for SZ, some have yielded reproducible findings. While for BD, there have been fewer studies, usually with smaller sample sizes and inconsistent findings.

Table 1. Summary of existing evidence for environmental exposures and genetic risk for BD and SZ.

Furthermore, risk from genetic and environmental sources may not contribute in an additive manner, since the impact of an environmental exposure may depend on the genetic makeup of the person experiencing it. These gene-by-environment (G×E) interactions partly explain why only some people who experience environmental exposures associated with SZ or BD actually develop these disorders, and identifying the genetic risk factors conferring vulnerability to specific environmental insults may open opportunities for prevention for these devastating disorders. Additionally, providing a comprehensive etiological picture of these disorders necessitates an understanding of the relationship between the genetic and environmental factors which contribute to the shared and disorder-specific symptoms.

Examining interaction effects requires even larger sample sizes than for genes or environmental factors alone, which poses an additional challenge when investigating psychiatric disorders which affect a small proportion of the population. Indeed, the early G×E studies involving candidate genes were often underpowered, prone to publication bias, and usually lacked replication (Duncan and Keller, 2011). Greater certainty in the genetic markers conferring risk for SZ and BD and larger samples have improved these studies over time. Additionally, methodological advancements have provided an alternative approach to examining individual SNPs or genes. Polygenic risk scores (PRS) index genomic risk for a disease or trait by aggregating the effects of SNPs across the genome weighted by their effect size from a discovery GWAS in a separate sample (International Schizophrenia, Consortium, Purcell et al., 2009). PRS are individual measures of genomic risk which are continuous and normally distributed in the population, and they can be used to test for interactions with environmental measures. Several studies using either individual or aggregated genetic markers have investigated the relationship between environmental exposures and genetic risk for BD and SZ (Figure 1).

Figure 1. Summary of the types of G×E interactions. (A) Genetic effect with no exposure effects, meaning the variation in disease probability is stable across a range of environments; (B) Environmental effect with no genetic effects, meaning the variation in disease probability is stable across different genotypes; (C) Additive effects occur when disease probability results from the addition of the genetic and environmental factors. The exposure results in the same degree of increase in disease probability; (D) Interaction effects when genetic risk determines sensitivity to environmental factors. When there is no exposure, disease probability is low regardless of genetic risk, but in the presence of an exposure, those with high genetic risk have markedly increased probability of disease.

This review presents a thorough examination of the current evidence for environmental exposures which have been studied in relation to SZ and BD, and when available, their reported interactions with different forms of genetic risk. We also evaluate emerging environmental risk factors and conclude by addressing the current knowledge gaps and future directions for this field of research.

Environmental Risk Factors

Although SZ and BD arise predominantly through genetic risk, ∼15–40% of risk for both is derived from environmental factors (Smoller and Finn, 2003; Sullivan et al., 2003). There have been numerous studies of environmental risk factors for SZ which have yielded some reproducible findings. The same cannot be said for BD, for which there have been fewer studies, usually with smaller sample sizes, inconsistent findings, and no firm conclusions. Although the environmental risk factors for SZ and BD have been extensively reviewed separately (Brown, 2011; Marangoni et al., 2016; Belbasis et al., 2018), there has been little research concomitantly examining both disorders.

Previous research on environmental risk factors has predominantly focused on OCs, infections, season of birth, migration, urbanicity, cannabis use or ACEs (Table 1). Each of these key exposures and their relation to genetic factors will be discussed further.

Obstetric Complications

In systematic reviews, complications during pregnancy or delivery, or abnormal fetal growth and development have been associated with later development of SZ in offspring (Cannon M. et al., 2002). However, associations between distinct OCs and SZ are inconsistent across studies (Cannon M. et al., 2002) and evidence for associations with BD is weak (Scott et al., 2006). Oxygen insufficiency is a common feature across several consistently associated OCs and there is support for fetal hypoxia as an underlying mechanism from both observational studies (Dalman et al., 2001; Cannon T. D. et al., 2002; Byrne et al., 2007) and animal model studies (Boksa, 2004). For example, perinatal asphyxia has been associated with over 4× increased odds of SZ after controlling for other OCs, maternal psychosis, and socioeconomic status in a Swedish study (Dalman et al., 2001). Similarly, indicators of hypoxia, along with prematurity, were also associated with SZ in data from the Danish registries (Byrne et al., 2007). In the United States Collaborative Perinatal Project, individuals with 3+ hypoxia-related OCs were over 5× more likely to develop SZ compared to those with no hypoxia-related OCs (Cannon et al., 2000). Furthermore, the effects of fetal hypoxia are exacerbated in those born small for gestational age (Cannon T. D. et al., 2002), which indicates interactions between individual OCs, complicating interpretation of their effects.

Although there is limited evidence for a role of OCs in BD (Scott et al., 2006), length of gestation may play a role. A recent meta-analysis found that early (<37 weeks) or late gestational age (>39–42 weeks) increased risk of BD (Rodriguez et al., 2021), with one of the included studies finding a stronger risk for extreme prematurity (<32 weeks’ gestation) (Nosarti et al., 2012). As neither low nor high birth weight are associated with BD in meta-analyses (Scott et al., 2006), these findings point to an independent or confounding factor influencing pregnancy duration, rather than fetal growth (Rodriguez et al., 2021).

Concurrent examination of OCs and later development of psychiatric disorders was carried out in a small study (n = 333) which found that inadequate weight gain in mothers was positively associated with offspring development of schizophrenia spectrum disorders, but negatively associated with BD and major depression (Pugliese et al., 2019). Other distinctions between the two were that schizophrenia spectrum disorder was also positively associated with maternal stress, infections, and peripartum asphyxia, while BD was associated with a small head circumference (<32 cm) at birth.

The association between hypoxia-related OCs and SZ is greater in those with higher genetic risk (Mittal et al., 2008), and sibling studies have found a higher incidence of hypoxia-related OCs in SZ patients compared to their siblings without SZ (Cannon et al., 2000). Familial risk may also play a role in BD and OCs, as Singh et al. (2007) found that children of parents with BD may be at greater risk of OCs, compared to children of people without BD. Low birth weight was independently associated with increased risk of developing BD in offspring of parents with this disorder (Wals et al., 2003).

Methodological differences hinder inferences from the OC studies. Some examine the wide range of complications individually using definitions which often vary between studies, while others aggregate several OCs into a composite score. For individual OCs, the lack of standardization contributes to the inconsistent findings, and combining measures amplifies the problem in addition to introducing the possibility that inclusion of less harmful OCs in scores could dilute the overall effects.

One study reported a stronger association between a PRS derived from SZ-associated SNPs and SZ in those with OCs compared to those who did not experience OCs, with the most significantly associated SNPs mapping to genes highly expressed in placental tissue (Ursini et al., 2018). However, another study which applied this approach in five independent samples found no evidence that OCs interact with PRS or modulate the effect of the PRS on risk of SZ (Vassos et al., 2021). Therefore, there is currently insufficient evidence that OCs impact the association between SZ and genomic risk.

Several candidate genes have been investigated for interaction with OCs to modify risk of SZ, although reported interactions have rarely replicated (Schmidt-Kastner et al., 2012). However, a significant interaction was reported for three SNPs within AKT Serine/Threonine Kinase 1 (AKT1) (Nicodemus et al., 2008), one of which was subsequently replicated in a small study, but only in females (n = 67) (Joo et al., 2009). Future studies utilizing significant SNPs derived from SZ and BD GWAS may provide more comprehensive insights into G × E interactions for OCs.


Increasing evidence points to the involvement of the immune system in the etiopathogenesis of psychiatric disorders. Several infectious agents have been associated with SZ, including viral, bacterial and parasitic infections (Arias et al., 2012), while for BD evidence is mixed (Benros et al., 2013; Barichello et al., 2016). When investigating broad groups of infections, factors such as exposure timing, virulence, strain of infection, and methods of assessing infections may lead to heterogeneity in findings. In terms of specific infections implicated in both SZ and BD, the strongest evidence is for Toxoplasma gondii, which has been associated with 25–50% increased odds of BD (Sutterland et al., 2015; de Barros et al., 2017), and 80% increased odds of SZ (Sutterland et al., 2015). T. gondii infection has also been associated with relevant biological processes, including increased dopamine production (Prandovszky et al., 2011), and pro-inflammatory factors related to mania and neuropathologic disorders (Hamdani et al., 2015). Behavioral alterations such as increased aggression and impulsivity (Cook et al., 2015) and increased risk of road traffic accidents (Gohardehi et al., 2018) have also been documented.

The timing of an infection may also be important, and pre- or perinatal elicitation of the immune response may be particularly deleterious during this early stage of development. In a seminal study of the 1957 Finnish influenza epidemic, pregnant women exposed to the virus during their second trimester had offspring with elevated risk of SZ (Mednick et al., 1988). Although findings regarding maternal infections during pregnancy have been mixed in meta-analyses, large register-based studies using clinical infection diagnoses support associations with SZ (Khandaker et al., 2012). Maternal bacterial infection during pregnancy was strongly associated with psychosis in offspring in a large United States study, with more severe effects for multisystemic (compared to localized) infections, and higher risk in males than females (Lee et al., 2020). Similarly, exposure to any bacterial infection in the first trimester increased risk of SZ in a Danish registry study (Sørensen et al., 2008).

A large meta-analysis found that viral central nervous system (CNS) infections in childhood were associated with 2.1× increased risk of adult SZ, but no significant increase was observed for bacterial CNS infections (Khandaker et al., 2012). These findings were substantiated by a large Swedish register study of over one million individuals which investigated the role of specific childhood CNS infections. No evidence supporting a role for any bacterial CNS infections was observed, but two serious viral infections, mumps and cytomegalovirus, were associated with subsequent psychoses (Dalman et al., 2008). Although the number of infections was greater in urban areas, adjustment for this did not influence the results.

For BD, a systematic review found mixed evidence for the role of 10 perinatal infections (Barichello et al., 2016). The strongest evidence was for T. gondii and cytomegalovirus (CMV) with positive reports in 5 of 9, and 5 of 11 studies, respectively. In a small sample from the Child Health and Development Study birth cohort, a strong association between maternal influenza infection and BD was reported using maternal medical records (Parboosing et al., 2013) and for BD with psychotic features using antibodies in maternal serum (Canetta et al., 2014). At present, evidence for a role of perinatal infections in BD is equivocal and investigations postnatally are also needed before firm conclusions can be drawn.

When examining infections later in life, infection timing needs to be considered to ascertain the direction of the effect, as individuals with SZ and BD generally have higher morbidity and lifestyle factors which increase susceptibility to infection (Regier et al., 1990; Brown et al., 1999). Other factors associated with increased likelihood of infections (e.g., stress, social inequality, and urban living) may also contribute (Marketon and Glaser, 2008; Semenza and Giesecke, 2008; Neiderud, 2015; Pini et al., 2019).

Due to the diverse range of infections associated with these disorders, a proposed mechanism underlying this effect is inflammation. Inflammatory processes can impact neuronal circuits, synaptic plasticity, reuptake of neurotransmitters (e.g., serotonin, noradrenalin, and dopamine), and stimulation of the hypothalamic–pituitary–adrenal (HPA) axis (Dantzer et al., 2008). A pro-inflammatory cytokine profile has been noted in SZ (Momtazmanesh et al., 2019) and BD patients (Barbosa et al., 2014). Defects in innate immunity may stem from genetic predisposition, or arise post-conception, or a combination of both. For instance, the “two-hit” hypothesis (Bayer et al., 1999), proposes that genetic or environmental factors in early life (first hit) disrupt the CNS and increase neurodevelopmental vulnerability to a ‘second hit’ later in life (Maynard et al., 2001). An environmental ‘hit’ could result from the direct mechanisms of a CNS infection or the indirect effects of systemic inflammation in response to any infection (Gardner et al., 2013; Benros and Mortensen, 2020). In large-scale epidemiologic studies, positive associations between autoimmune diseases and psychosis have been identified, suggesting that there may be common inflammatory components (Jeppesen and Benros, 2019).

A potential explanation for mixed results may be due to the influence of familial risk and shared genetic-environmental factors. Studies in Nordic countries which incorporated familial medical information have found no overall increased risk of psychosis in offspring following maternal infection during pregnancy (Clarke et al., 2009; Nielsen et al., 2013; Blomström et al., 2016). However, in mothers with a psychiatric disorder (indicating genetic predisposition) and infection during pregnancy there was increased psychosis risk for the offspring (Clarke et al., 2009; Blomström et al., 2016). Clarke et al. (2009) did not identify the same association for paternal psychiatric disorder, suggesting that it is not overall genetic liability, but rather the acute effects of infections during pregnancy in vulnerable mothers. These studies support possible G×E interactions between familial risk for psychiatric disorders and infections (Clarke et al., 2009; Nielsen et al., 2013; Blomström et al., 2016), but additional research is needed to explicitly test for this.

Genetic variation plays an essential role in the development and functioning of the immune system (Knight, 2013). Multiple lines of evidence support the role of immune genes in SZ (Ripke et al., 2013; Pouget, 2018), suggesting that genetic variation in immune response may underlie susceptibility to infections or aberrant response to them which, in turn, increase risk for SZ. Across several adult psychiatric disorders – including SZ and BD – risk variants have been identified within multiple immune-related pathways and processes (The Network and Pathway Analysis Subgroup of the Psychiatric Genomics Consortium, O’Dushlaine et al., 2015). A strong genetic correlation (rg = 0.5) between susceptibility to infection and psychiatric disorders generally was also found in a GWAS performed in a large Danish cohort (n = 65,534), indicating shared genetic factors (Nudel et al., 2019). In support of this, variation in the MHC region, associated with susceptibility to infectious diseases (Matzaraki et al., 2017), has been repeatedly associated with SZ (Bergen et al., 2012; Mokhtari and Lachman, 2016; Ripke et al., 2020) and recently also with BD (Mullins et al., 2020). In another Danish study, SZ-PRS and a history of infections had independent effects on the risk for SZ (Benros et al., 2016), suggesting that an aggregated measure of genomic risk may inadequately capture the portion of genetic variants mediating risk through interaction with infectious agents.

There is also the possibility that individual SNPs may interact with specific infections to increase risk. A GWAS which aimed to identify gene variants that influence T. gondii seropositivity and their relationship with SZ risk did not find any genome-wide significant loci in two small samples, but there were suggestive associations for two schizophrenia-associated genes, CNTNAP2 and GABAR2 (Wang et al., 2019). They did not find a higher prevalence of T. gondii seropositivity in individuals with SZ compared to controls, which suggests that risk genes for SZ may also be involved in T. gondii susceptibility (rather than a causal relationship). A genome-wide interaction survey found an interaction between a SNP in the CTNNA3 gene and maternal CMV infection increased risk of SZ (Børglum et al., 2014), and was subsequently replicated (Avramopoulos et al., 2015). Candidate gene studies have reported that maternal herpes simplex virus 2 (HSV-2) interactions with GRIN2B increase risk of SZ (Demontis et al., 2011), and for BD, toll-like receptor 2 (TLR2) polymorphisms reportedly interact with T. gondii infection to increase risk (Oliveira et al., 2016). However, independent replication would enhance the certainty of these candidate gene results.

Overall, these findings suggest that infections could have a direct or indirect role in triggering SZ and BD. Intriguingly, there may be some overlap in genetic liability between infections and psychiatric disorders, raising the possibility that immune-related genes mediating susceptibility or response to infections are indirectly risk genes for psychiatric disorders in a similar way as genes associated with nicotine dependence increase risk for lung cancer (Bierut, 2010).

Season of Birth

Numerous studies have found a higher incidence of SZ in people born in the winter/spring months (Torrey et al., 1997; Karlsson et al., 2019), with increased risk at higher latitudes which are subject to greater seasonal variation (Davies et al., 2003). Although a general trend for excess winter/spring births has also been observed for BD, findings are fewer and less consistent than those for SZ (Torrey et al., 1997; Tsuchiya et al., 2003). In a systematic review, six out of nine studies supported an association between a winter/spring birth and risk of BD, but three other studies including one large study of 2.1 million individuals did not find evidence of an association (Tsuchiya et al., 2003).

Within the United Kingdom biobank samples, neither SZ-PRS nor SZ-associated CNVs were associated with season or month of birth, suggesting this is not directly genetically mediated (Escott-Price et al., 2019). However, it has long been hypothesized that seasonal variation in viral exposure, particularly influenza, may underlie the associations between SZ and births early in the year. Interactions between inflammation-related genetic variation in HLA genes (in the human MHC complex) and season of birth have been investigated in an attempt to support this hypothesis, with conflicting findings for HLA-DR1 and winter birth in SZ (Narita et al., 2000; Tochigi et al., 2002). However, there was evidence of a significant interaction between IL-4 (but not other cytokines) and season of birth on a milder diagnosis within the schizophrenia spectrum disorders, schizotypy (Alfimova et al., 2017).

For both SZ and BD, an interaction between the dopamine D4 receptor gene (DRD4) and season of birth has been reported (Chotai et al., 2003). Polymorphisms in MTHFR, TPH1, SLC6A4 have also been investigated in terms of season of birth and SZ, but no significant interactions were identified (Chotai et al., 2003; Muntjewerff et al., 2011). Other potential candidate genes reportedly interacting with season of birth in terms of BD risk include tryptophan hydroxylase (TPH1) (Chotai et al., 2003), and the immune-related gene HLA-G (Debnath et al., 2013), but as with most of the candidate gene studies, these have yet to be replicated.

These genetic findings related to inflammatory genes are consistent with the possibility that the relationship between season of birth and SZ may be mediated by another environmental risk factor with seasonal fluctuations and immune-related processes. While infections have been most often implicated in this, pregnancy and birth complications, sunlight exposure, nutrition, temperature/weather or a combination of these are all viable possibilities.


An increased risk of psychotic disorders, and SZ in particular, in migrants has been identified in several studies (Henssler et al., 2020). Some studies have found elevated risk even in 2nd generation migrants, suggesting that the increased rate is not solely due to experiencing the stress of relocating itself, but of the accompanying social and environmental differences (Cantor-Graae and Selten, 2005). In contrast, elevated rates of BD have not been consistently shown among migrants (Swinnen and Selten, 2007) or their children (Cantor-Graae and Pedersen, 2013). It is possible the effects of migration may be related to specific clinical symptoms. For example, a large study using data from Swedish national registers found migrants had higher risk of psychotic disorders but lower risk of BD without psychosis, compared to Swedish-born individuals (Dykxhoorn et al., 2019).

There are many plausible, and potentially simultaneously occurring, factors which could contribute to increased risk in migrants, such as social factors (socioeconomic disadvantage, discrimination, and social isolation) (Davies et al., 2009), inadequate vitamin D levels (McGrath et al., 2010a), or vulnerability to infection (Rechel et al., 2013). One prominent theory is the social-defeat hypothesis, whereby social stressors, which can be more common among marginalized, vulnerable, socially-excluded or minority groups, may amplify an individual’s underlying risk for developing a psychiatric disorder (Selten et al., 2013). Risk may be related to having a visible minority status, as migrants from Africa moving to places such as Sweden, France, or Canada have highest risk of psychotic disorders (Tortelli et al., 2014; Anderson et al., 2015; Dykxhoorn et al., 2019). However, Finnish immigrants in Sweden have 2× greater incidence of SZ (Leão et al., 2006), indicating that increased risk is also evident for migrants without visible minority status. It has been proposed that patterns of risk may represent an underlying gradient of discrimination in a given country (McGrath, 2011), suggesting a substantial role for social environment on risk for psychosis. A range of other issues should also be considered, including factors related to differential pathways to care, diagnostic inaccuracies due to language and cultural differences, diagnostic bias, differences in genetic risk, and potential confounding due to socioeconomic factors.

No studies have investigated gene–environment interactions between migration and SZ or BD. Trans-ancestry genetic association studies for these disorders are still in nascent stages, but as these mature to more fully capture genetic risk for SZ and BD across populations, we will be better positioned to explore how genetic risk interacts with migration in the development of these disorders.


Urbanicity refers to the impact of residing in an urban area and is generally quantified based on population size or density. A meta-analysis of observational studies supported that there is increased risk of SZ for people living in urban areas compared to more rural areas (Vassos et al., 2012). There have been few studies investigating urbanicity in BD and results are mixed. For example in two large Danish studies, one supported an association for urbanicity at birth (Vassos et al., 2016), while the other did not (Mortensen et al., 2003). Urbanicity may be more strongly correlated with psychotic symptoms, and has been associated with higher rates of BD with psychosis, but not BD without psychosis (Kaymaz et al., 2006). Myriad possibilities have been suggested to mediate the association with urbanicity, such as the social (e.g., social capital, economic stress, or social fragmentation) or physical environment (e.g., air, noise, or light pollution) which require further investigation (Krabbendam and Van Os, 2005; Allardyce and Boydell, 2006).

Colodro-Conde et al. (2018) found that higher genetic risk for SZ was associated with urban living in four distinct samples from three countries. Using Mendelian randomization (MR), they concluded that those with increased genetic liability to SZ tend to reside in more densely populated urban areas and attributed this to selective migration. Similarly, data from the Danish registries also found that those with a higher PRS for SZ were more likely to live in the capital compared to more rural areas at age 15 (but not at birth), with attenuated, but still persisting, risks after adjustment for parental history of mental disorders (Paksarian et al., 2018).

In a large longitudinal cohort of children from the United Kingdom-based Avon Longitudinal Study of Parents and Children (ALSPAC) there was an association between SZ-PRS and neighborhood deprivation – but not necessarily more densely populated areas (Solmi et al., 2018). Similarly, an association between SZ-PRS and neighborhood deprivation was reported using data from Swedish registers, supporting the genetic selection theory that genetic risk for SZ predicts residence in deprived neighborhoods (Sariaslan et al., 2016). This indicates further work is necessary to examine the nuances of ‘urbanicity’ in greater depth, and the extent to which these associations are driven by genetic risk factors (Sariaslan et al., 2016).

Overall, these results suggest that underlying genetic risk may act in combination with urbanicity to increase risk of SZ, but perhaps not through a G×E interaction. More likely scenarios involve either active gene–environment correlation, in which people with increased genetic risk for SZ select an urban environment to live in, or a passive gene–environment correlation, whereby the association is driven by the genotype a child inherits from their parents who also determine their environment. Additional studies investigating these mechanisms are needed, as well as more comprehensive investigation of urbanicity and BD and the facets of urbanicity which may confer risk.

Adverse Childhood Experiences

Childhood adversity has been extensively examined in the context of both BD and SZ with the majority of studies reporting positive associations (Matheson et al., 2013; Bailey et al., 2018; Rowland and Marwaha, 2018). The definition of ACEs across studies spans socioeconomic disadvantage, stressful life events, and childhood trauma. While definitions of stressful life events are highly heterogenous, common themes are: financial difficulties, parental separation, police involvement, neglect, physical/emotional abuse, or death of a family member. Although many studies use retrospective questionnaires, less subjective measures from registry data have also found increased risk (Wicks et al., 2005; Liang et al., 2016).

Childhood trauma is correlated with the severity of distinct symptoms in psychotic disorders, as well as an earlier age of onset in BD (Bailey et al., 2018; Rowland and Marwaha, 2018). Risks tend to be highest for more severe stressful events, such as the death of a first-degree relative, which are associated with developing both SZ (Liang et al., 2016) and BD with psychosis (Abel et al., 2014). Similarly, associations for BD may vary by type of trauma and BD type: BD1 was more prevalent in those who experienced sexual abuse, while experiencing emotional neglect has been associated with developing BD2 (Watson et al., 2014; Janiri et al., 2015).

Parental loss is associated with offspring psychosis irrespective of a family history of psychiatric disorders (Liang et al., 2016). However, a familial component may be evident for specific ACEs: offspring of suicide decedents are at greater risk for suicide (as well as psychotic disorders, drug disorders and violent criminal convictions) than offspring of living parents (Wilcox et al., 2010). Given that severe psychiatric disorders can influence parenting capacity (Ranning et al., 2015) and even children of parents with less severe mental illnesses are more likely to experience adversity (Pierce et al., 2020), it is often difficult to disentangle the factors contributing to psychiatric disorders.

The genetic and environmental effects of childhood trauma may act independently, as a small United Kingdom-based study did not find evidence of an interaction between SZ-PRS and retrospectively reported ACEs (Trotta et al., 2016). However, in individuals with high SZ-PRS, exposure to childhood adversity was associated with subtle psychosis expression, and positive and negative affect (Pries et al., 2020) which supports a possible G×E mechanism. To date, only one study of 402 BD cases has examined the effect of BD-PRS and childhood maltreatment on the clinical expression of BD (Aas et al., 2020). A lower BD-PRS was observed in individuals with BD diagnoses and more severe childhood maltreatment, particularly for emotional abuse, suggesting a possible additive relationship (Aas et al., 2020). There was a significant interaction between BD-PRS and childhood maltreatment with the risk of rapid cycling, but not with other clinical features.

There have also been a handful of G×E interaction studies for childhood trauma and psychiatric disorders involving candidate genes. Lower levels of brain derived neurotropic factor (BDNF), a neurotrophin which promotes growth and differentiation of neurons during brain development as well as synaptic plasticity and maintenance of neurons in adulthood, have been observed in SZ (Buckley et al., 2011). Interactions between childhood trauma and BDNF gene variants have been repeatedly shown in relation to BD and schizophrenia spectrum disorders (Mondelli et al., 2011; Aas et al., 2014; de Castro-Catala et al., 2016). Catechol-O-methyltransferase (COMT), which encodes an enzyme which catalyzes the breakdown of dopamine, has frequently been investigated in relation to ACEs and also cannabis use (Modinos et al., 2013). An interaction between childhood maltreatment and COMT was reported in the later development of psychosis (Vinkers et al., 2013), but this finding has not been consistently replicated (Trotta et al., 2019). There is also some evidence of interactions between early trauma and FKBP Prolyl Isomerase 5 (FKBP5) in mental disorders generally (Collip et al., 2013; Daskalakis and Binder, 2015). Larger studies of genetic risk with sufficient power to study distinct ACEs may provide further insight into potential G×E mechanisms.

Cannabis Use

Cannabis use has been associated with increased risk of psychosis, a symptom of SZ and often BD, across several studies and populations (Marconi et al., 2016), and several longitudinal studies report that cannabis use is associated with subsequent development of SZ specifically (Arseneault et al., 2004). Few studies have examined the relationship between cannabis and BD, but one large longitudinal study found that weekly cannabis use was associated with 2.5× increased incidence of BD (Feingold et al., 2015).

Although cannabis use often co-occurs with the use of other substances, prolonged cannabis use remains associated with higher risk of psychotic symptoms after controlling for use of other drugs at baseline (Kuepper et al., 2011). Other substances, including cocaine/stimulant use have also been independently associated with SZ (Giordano et al., 2015). Associations across illicit drugs may be due to genetic predisposition, shared risk factors, or common neurological pathways (Agrawal et al., 2004; Khokhar et al., 2018). There are comparatively few studies examining the relationship between use of other illicit substances and psychosis; likely due to the reliance on self-reported data, lower prevalences, and the challenges in quantifying the exposure (i.e., potency, purity, and frequency of use). As cannabis is the most widely used recreational drug (WHO, 2018), understanding the mechanisms underlying its associations with psychosis has the greatest potential for harm reduction.

It has been suggested that cannabis use could be a cause or consequence of psychosis, or even that bidirectional relationships may exist. Giordano et al. (2015) found that cannabis abuse (defined using medical diagnoses and criminal convictions) 7 years prior to diagnosis of SZ was associated with 2× increased risk, with higher odds for cannabis use closer to diagnosis. Others have also found that in individuals with no history of psychotic experiences, cannabis use in adolescence precedes the onset of psychotic symptoms (Kuepper et al., 2011). However, some people developing psychosis may attempt to self-medicate with cannabis, even though evidence suggests this may exacerbate symptoms in patients with pre-existing psychiatric disorders. For example, continued cannabis use is associated with higher relapse rates in patients with psychosis (Schoeler et al., 2016), and with exacerbation of manic symptoms in those with pre-existing BD (Gibbs et al., 2015).

There is a significant genetic correlation between lifetime cannabis use and both SZ (rg = 0.25) and BD (rg = 0.29) implying some shared genetic etiology across common variants (Verweij et al., 2017; Pasman et al., 2018). Furthermore, in a sample of 2,082 healthy individuals, SZ-PRS was positively associated with self-reported cannabis use (Power et al., 2014), suggesting that individuals with greater genetic predisposition to SZ use cannabis more frequently. They corroborated this finding in a sample of twins: SZ-PRS burden was highest when both twins were users; intermediate with one twin user; and was lowest if neither twin reported cannabis use. MR has been used to formally discern the causal direction between cannabis use and SZ onset: one study found stronger evidence for a causal link from genetic liability to SZ to cannabis use (Gage et al., 2017), while the other reported the opposite (Vaucher et al., 2018). Additional studies with larger samples will be required before a consistent picture emerges. Overall, Convergent lines of evidence suggest some causal effects of cannabis use on developing SZ, along with a degree of genetic/familial confounding (Gillespie and Kendler, 2020).

French et al. (2015) investigated polygenic risk, cannabis use, and brain imaging measures in 1,577 individuals from three population-based adolescent and youth samples, and found that a higher SZ-PRS was associated with decreased cortical thickness, but only in males who used cannabis. As the age-related trajectories of gray and white matter differ between males and females during adolescence (Lenroot et al., 2007; Paus et al., 2010), sex differences in vulnerability to environmental factors over the course of brain development may also need to be considered in combination with genetic risk.

Cannabis use alone is not a sufficient trigger for psychosis in the general population; however, it could precipitate psychosis in susceptible individuals. Interactions between cannabis use and specific genes may help to explain the associations of cannabis with psychotic disorders. An interaction between cannabis and a SNP in the AKT1 gene, which encodes a protein kinase in the dopamine signaling cascade, has been associated with a 2× greater risk of being diagnosed with a psychiatric disorder in both a sibling study (van Winkel, 2011) and a case-control study (Di Forti et al., 2012). A few studies have identified G×E interactions between cannabis use and variation in the COMT gene on psychosis (Caspi et al., 2005; Vinkers et al., 2013; Alemany et al., 2014), even though results have not always replicated (Zammit et al., 2011). Although these candidate genes are intuitively appealing due to their biological functions, examining the shared genetic etiology between cannabis use and both BD and SZ may be a more fruitful approach for uncovering specific genes conferring vulnerability.

Emerging Risk Factors

The most robust environmental risk factors are the main focus of this review, but other exposures may emerge as key environmental factors in the future as evidence for them mounts. For example, air pollution is a well-established environmental health hazard and carcinogen, with adverse effects that extend beyond respiratory diseases and cancers (IARC Scientific, 2013), including neurological disorders such as Parkinson’s and Alzheimer’s disease (Shi et al., 2020). Furthermore, as proposed mechanisms for mediating the harmful effects of air pollution include oxidative stress, systemic inflammation, and neuroinflammation (Pope et al., 2004; Calderón-Garcidueñas et al., 2008), it is reasonable to speculate that there may be a link between air pollution and other disorders in which these processes are implicated such as SZ and BD. In Denmark, exposure to higher concentrations of ambient nitrogen oxide pollutants in childhood was associated with subsequent development of SZ and may account for some of the association with urbanicity (Antonsen et al., 2020). Similarly, in Sweden, neighborhood air pollution was positively associated with medications dispensed for psychiatric disorders in children and adolescents, although this was not evaluated specifically in relation to SZ or BD (Oudin et al., 2016). In China, even short-term exposure to ambient air pollution has been associated with increased daily outpatient visits for SZ in adults with and without prior SZ diagnoses (Liang et al., 2019). A recent study evaluating risk from different types of environmental pollutants was conducted for 151 million individuals in the United States, and 1.4 million individuals in Denmark (Khan et al., 2019). Taking into account urbanicity and socioeconomic status, they found correlations between air pollution and BD in both countries and also with SZ in Denmark. Although it is the largest and most thorough study on air pollution to date, additional evidence is needed before it can be conclusively established as a risk factor for either disorder.

Additional research is also warranted examining the complex and variable components of ambient air pollutants, as well as indoor air pollutants such as fuels burned for cooking. Cigarette smoke is an air pollutant with abundant evidence of negative health effects, and these include some reports of strong associations with SZ and BD (De Leon and Diaz, 2005; Jackson et al., 2015). The effects are not limited to inhalation of chemicals in tobacco smoke, as there is also evidence for a modest association between non-affective psychosis and ‘snus’ (a smokeless tobacco product) (Munafò et al., 2016). The association has generally been attributed to self-medication and reverse causation (Quigley and MacCabe, 2019). Although this may be true for some individuals, it cannot fully explain the association, and there are a number of alternative biological and genetic explanations (Quigley and MacCabe, 2019). Evidence supports a shared genetic liability between both smoking and psychosis (Kendler et al., 2015), as well as correlation between genetic variants for SZ and nicotine dependence (Quach et al., 2020). MR analyses also suggest a causal relationship between smoking and both SZ and BD (Vermeulen et al., 2019; Wootton et al., 2020). The growing literature in this area suggests that nicotine/smoking will soon gain greater recognition as a contributing risk factor for these disorders.

Traumatic brain injury (TBI) is reported to precede the onset of a range of psychiatric conditions (Bryant et al., 2010), including SZ and BD (Molloy et al., 2011; Orlovska et al., 2014), although it is difficult to discern whether TBI causes psychiatric symptoms or vice versa. Risk for TBI is greater in individuals with a genetic predisposition to psychosis suggesting possible genetic correlation (Molloy et al., 2011). In siblings discordant for TBI before age 25, siblings who experienced TBI had twice the risk of subsequent psychiatric inpatient hospitalization (Molloy et al., 2011). However, it is not known whether they had higher genetic risk for psychiatric disorders than their siblings without these disorders or TBI. Since children and adolescents who experience TBI have elevated risks of a wide range of medical and social problems in later life (Molloy et al., 2011), further research is required to determine the mechanisms by which these injuries contribute to subsequent problems, including the development of SZ and BD.

Hearing impairment in childhood has been reported as a risk factor for developing psychosis in adolescence (van der Werf et al., 2010), and later life (Linszen et al., 2016), although there was no evidence for an interaction with SZ-PRS (Guloksuz et al., 2019). A connection between hearing impairment and BD has not yet been examined, and the overall paucity of studies on this topic makes it difficult to evaluate the validity of this potential relationship at this time.

There is growing interest in nutritional medicine in psychiatry and the relationship between nutrient deficiencies and psychiatric disorders (Sarris et al., 2015). For example, folate is an essential nutrient obtained from the diet, and there is evidence of lower serum folate levels in individuals with BD and SZ (Wang et al., 2016; Hsieh et al., 2019). Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, a key enzyme in the folate cycle, may be partly driving this association in SZ (Lewis et al., 2005; Yadav et al., 2016) and BD (Peerbooms et al., 2011). Another example is Vitamin D, a neurosteroid essential for brain development and function, which is produced when skin is exposed to sunlight and acquired through dietary sources (Cui et al., 2021). Low levels of vitamin D are well-documented in SZ (Valipour et al., 2014), but only occasionally reported in BD (Cereda et al., 2020). Two studies report an association between neonatal vitamin D deficiency and increased risk of SZ (McGrath et al., 2010b; Eyles et al., 2018). This observation has been theorized to underlie the associations between winter/spring births and SZ, since maternal sun exposure would likely be low in the months preceding birth. Vitamin D may also be relevant as a mediator of the migration association with SZ, particularly for dark-skinned individuals moving from regions with high sun exposure to less sunny areas (Eyles et al., 2013). However, definitive associations with developing SZ have not yet been shown, and little research has been conducted for BD. Furthermore, most studies on nutrient deficiencies have been cross-sectional and additional prospective studies are required to assess potential causal relationships with SZ or BD.

Summary and Future Directions

Several environmental exposures have been investigated in terms of SZ and BD risk, and there is moderate evidence that ACEs and certain types of infections are risk factors for both. For winter/spring birth, OCs, migration, urbanicity, and cannabis use, however, more robust associations have only been identified for SZ. Undoubtedly, the research for BD lags behind the larger body of work for SZ, and it remains unclear whether the reported differences in environmental risk between BD and SZ are due to sample size and methodological differences, or true etiological distinctions. For both disorders, evidence implicating other exposures such as air pollution and nicotine/smoking is still growing, while still other exposures may yet be discovered. Only a small fraction of environmental variables that individuals are exposed to have been investigated, and, in time, more environmental risk factors for SZ and BD will likely come to light.

One possibility for inconsistent associations, particularly for BD, is that some risk factors may be related to specific disease types or symptoms. For instance, while the evidence for urban environmental risk is stronger for SZ (Krabbendam and Van Os, 2005) than for BD in general, there was an association between urban residence and BD1 but not BD2 (Kaymaz et al., 2006) which suggests that urbanicity could be conferring risk for symptoms that are common across SZ and BD1. Similarly, childhood trauma has been associated with increased risk for both SZ and BD, with evidence suggesting a higher prevalence of BD1 in those who experienced sexual abuse, while BD2 is more prevalent following emotional neglect (Watson et al., 2014; Janiri et al., 2015). Similarly, several studies across multiple environmental domains, but most notably for cannabis use, examined psychosis as an outcome. Since psychosis is much more common in BD1 than BD2 (and a defining characteristic of SZ), this also has stratifying effects. Therefore, studies which pool together psychosis, BD types, and types of ACEs may dilute or miss associations.

Sex differences in the prevalence and manifestation of SZ and BD have been widely investigated, but rarely with regard to environmental risk. For some exposures, the rates may differ between the sexes. For example, there is higher reported cannabis use (Hasin et al., 2015) and increased susceptibility to infections in early life in males (WHO, 2007). The effect of an exposure can also differ between the sexes. Despite a lower prevalence of cannabis use disorder, females who do have this disorder have increased risk of BD compared to males (Khan et al., 2013). Furthermore, the immune response to infections differs between the sexes (van Lunzen and Altfeld, 2014), which has ramifications for how these processes may mediate risk for SZ and BD. It is also well documented that male sex is associated with worse pre- and perinatal outcomes (Di Renzo et al., 2007). However, there is mixed evidence as to whether OCs confer higher risk of SZ in males compared to females (Verdoux et al., 1997; Dalman et al., 1999), or just result in earlier age of onset in males (Kirov et al., 1996). As larger studies of environmental measures impacting SZ and BD are conducted, separate estimations of their effects on men and women should be assessed.

Complex disorders arise due to intertwined genetic and environmental influences, and myriad constellations of risk are possible (Figure 2). For instance, people who experience childhood trauma are more likely to compound their risk by using cannabis (Harley et al., 2010). For winter/spring birth, infections, and urbanicity there are several overlapping aspects: there are seasonal fluctuations in most communicable diseases, and there is greater spread of infections in more densely populated urban areas. Then there is the consideration that the risk-increasing effects of urbanicity for psychosis are greater for those with familial risk of psychotic disorder (Van Os et al., 2003). Therefore, familial risk and several environmental factors could have additive or synergistic effects on increasing the risk for psychiatric disorders. To dissect these more complex, multifactorial relationships requires specialized statistical methods, such as structural equation modeling, as well as large, well-characterized cohorts.

Figure 2. Hypothesized relationships between risk factors and genetics in the development of schizophrenia and bipolar disorder. Genetic factors present from birth may interact with environmental factors across the life course to increase the risk of SZ and BD. There may also be complex interrelationships between the environmental risk factors. Dashed lines indicate potential relationships between the identified environmental risk factors. OCs, obstetric complications; ACEs, adverse childhood experiences; SNPs, single nucleotide polymorphisms; CNVs, copy number variants.

Environmental risk factors are not acting in isolation, and investigations of genetic context as a modifying factor have evolved over time. Studies incorporating both genetic data and environmental risk have historically been hindered by insufficient knowledge of the genetic markers conferring risk for SZ and BD. Several candidate genes thought to confer risk for BD or SZ, but demonstrating inconsistent associations, have been investigated for some exposures in G×E interaction studies (Table 1). For example, COMT is reported to interact with both cannabis and ACEs in SZ (Vinkers et al., 2013), while BDNF interactions with ACEs have been associated with both BD and SZ (Mondelli et al., 2011; Aas et al., 2014; de Castro-Catala et al., 2016). As with nearly all candidate gene association studies prior to the GWAS era, these have rarely been replicated.

In comparison to environmental data, harmonization is more attainable for genetic data which are fixed over time within individuals and are more objectively quantifiable. Now that GWAS using samples amalgamated across several studies have revealed numerous loci with high confidence associations, these loci can be tested for interactions with environmental exposures individually or in aggregate (as PRS). Although much progress has been made in identifying the genetic risk factors for both SZ and BD, it is certain that additional genetic associations remain to be discovered. The mechanisms of action linking genetic markers to the behavioral changes characterizing these disorders also require further investigation.

Power has been another key limitation of most prior G×E research. Power calculations using sample sizes from previous G × E studies suggest that some of the reported results may represent false positives (Duncan and Keller, 2011). As larger samples become available, well-powered interaction studies will become feasible.

Some systematic changes to improve this field of research are also warranted. Sampling bias is a common issue in epidemiological research, and this area is no exception. For example, individuals with higher SZ-PRS are more prone to drop out of studies, leading these individuals to be underrepresented and risk underestimated (Martin et al., 2016). Study designs that are robust to this, such as nationally representative register-based studies, could be used more often. There is growing recognition that large electronic health record databases, and in particular, national registers from Nordic countries which hold rich, high-quality data, familial relationships, and cover the entire population of a country, are excellent resources for use in psychiatric research (Allebeck, 2009). Another crucial bias to address is the strong overrepresentation of people of European ancestry in genetic research. Not only does this hinder application of PRS beyond the study population from which the GWAS was conducted, but the lack of diversity may also exacerbate existing health disparities (Martin et al., 2019). Psychiatric GWAS are increasingly incorporating a broader range of populations (Fiorica and Wheeler, 2019; Lam et al., 2019; Bigdeli et al., 2020), but more samples representing global diversity are needed.

In addition to elucidating the developmental origins of SZ and BD, G×E interactions may partially explain the heritability gap between twin studies and molecular heritability estimates. Genetic variants discovered by GWAS so far account for a smaller proportion of variance than was estimated in twin studies, with heritability estimates of around 75 and 80% from twin studies (Smoller and Finn, 2003; Sullivan et al., 2003), and 25 and 22% SNP heritability for BD and SZ, respectively (Lee et al., 2013). One plausible explanation is that GWAS are incompletely capturing the large portion of risk from common variants with small effect sizes, and entirely missing copy number variants and other rare genetic variants (Manolio et al., 2009). Overestimation of heritability in twin studies due to epistatic or epigenetic factors is also possible (Trerotola et al., 2015). However, a key distinction in family studies vs. individuals from the general population is not only the shared genetic components, but also the considerable sharing of environmental exposures.

The high degree of shared genetic risk between psychiatric disorders (Bulik-Sullivan et al., 2015) raises the possibility that environmental exposures could be determining factors for the specific diagnoses that emerge. Few studies have attempted to test this for SZ and BD by concurrently studying environmental risk factors for these disorders, and large-scale, parallel investigations of environmental risk are needed. Studies included in this review used designs ranging from longitudinal register-based population cohorts to cross-sectional studies with retrospective assessments of exposures. The resulting heterogeneity in the sample characteristics, psychiatric outcomes, exposure timings and measurements has hindered interpretation of environmental contributions to risk for BD and SZ. Concurrent examination of BD and SZ will facilitate comparisons of how environmental exposures act independently and in conjunction with genetic risk to shape these diagnoses.

In summary, although some environmental risk factors have been identified for SZ, few have been with certainty for BD, and the extent to which these are shared remains largely unknown. For both disorders, interactions between environmental and genetic risk factors are also not well understood and merit further investigation. Elucidating the mechanisms which give rise to these related conditions may reveal opportunities for prevention efforts and identify therapeutic targets. Further research is needed to understand how environmental and genetic risk factors exert their influences biologically to shape an individual’s propensity for these disorders.

Author Contributions

NR was responsible for the literature search, producing the figures, and drafting and refining the manuscript. SB provided supervision, critical feedback, and revision of the manuscript. Both authors contributed to manuscript preparation and have read and approved the submitted version.


This study was supported by a grant to SB from the United States National Institute of Mental Health (# R01 MH122544).

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The handling editor declared a past co-authorship with one of the authors SB.


Aas, M., Bellivier, F., Bettella, F., Henry, C., Gard, S., Kahn, J. P., et al. (2020). Childhood maltreatment and polygenic risk in bipolar disorders. Bipolar Disord. 22, 174–181. doi: 10.1111/bdi.12851

PubMed Abstract | CrossRef Full Text | Google Scholar

Aas, M., Haukvik, U. K., Djurovic, S., Tesli, M., Athanasiu, L., Bjella, T., et al. (2014). Interplay between childhood trauma and BDNF val66met variants on blood BDNF mRNA levels and on hippocampus subfields volumes in schizophrenia spectrum and bipolar disorders. J. Psychiatric Res. 59, 14–21. doi: 10.1016/j.jpsychires.2014.08.011

PubMed Abstract | CrossRef Full Text | Google Scholar

Abel, K. M., Heuvelman, H. P., Jörgensen, L., Magnusson, C., Wicks, S., Susser, E., et al. (2014). Severe bereavement stress during the prenatal and childhood periods and risk of psychosis in later life: population based cohort study. BMJ 348, f7679–f7679. doi: 10.1136/bmj.f7679

PubMed Abstract | CrossRef Full Text | Google Scholar

Agrawal, A., Neale, M. C., Prescott, C. A., and Kendler, K. S. (2004). Cannabis and other illicit drugs: comorbid use and abuse/dependence in males and females. Behav. Genet. 34, 217–228. doi: 10.1023/b:bege.0000017868.07829.45

CrossRef Full Text | Google Scholar

Alemany, S., Arias, B., Fatjó-Vilas, M., Villa, H., Moya, J., Ibáñez, M. I., et al. (2014). Psychosis-inducing effects of cannabis are related to both childhood abuse and COMT genotypes. Acta Psychiatr. Scand. 129, 54–62. doi: 10.1111/acps.12108

PubMed Abstract | CrossRef Full Text | Google Scholar

Alfimova, M. V., Korovaitseva, G. I., Lezheiko, T. V., and Golimbet, V. E. (2017). Interaction effects of season of birth and cytokine genes on schizotypal traits in the general population. Schizophr. Res. Treatm. 2017:5763094. doi: 10.1155/2017/5763094

PubMed Abstract | CrossRef Full Text | Google Scholar

Allardyce, J., and Boydell, J. (2006). Environment and schizophrenia: review: the wider social environment and schizophrenia. Schizophr. Bull. 32, 592–598. doi: 10.1093/schbul/sbl008

PubMed Abstract | CrossRef Full Text | Google Scholar

American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders, 5th Edn. Arlington, VA: American Psychiatric Association.

Google Scholar

Anderson, K. K., Cheng, J., Susser, E., McKenzie, K. J., and Kurdyak, P. (2015). Incidence of psychotic disorders among first-generation immigrants and refugees in Ontario. Cmaj 187, E279–E286.

Google Scholar

Antonsen, S., Mok, P. L., Webb, R. T., Mortensen, P. B., McGrath, J. J., Agerbo, E., et al. (2020). Exposure to air pollution during childhood and risk of developing schizophrenia: a national cohort study. Lancet Planet. Health 4, e64–e73.

Google Scholar

Arias, I., Sorlozano, A., Villegas, E., Luna, J. D. D., McKenney, K., Cervilla, J., et al. (2012). Infectious agents associated with schizophrenia: a meta-analysis. Schizophr. Res. 136, 128–136. doi: 10.1016/j.schres.2011.10.026

PubMed Abstract | CrossRef Full Text | Google Scholar

Arseneault, L., Cannon, M., Witton, J., and Murray, R. M. (2004). Causal association between cannabis and psychosis: examination of the evidence. Br. J. Psychiatry 184, 110–117. doi: 10.1192/bjp.184.2.110

PubMed Abstract | CrossRef Full Text | Google Scholar

Avramopoulos, D., Pearce, B. D., McGrath, J., Wolyniec, P., Wang, R., Eckart, N., et al. (2015). Infection and inflammation in schizophrenia and bipolar disorder: a genome wide study for interactions with genetic variation. PLoS One 10:e0116696. doi: 10.1371/journal.pone.0116696

PubMed Abstract | CrossRef Full Text | Google Scholar

Bailey, T., Alvarez-Jimenez, M., Garcia-Sanchez, A. M., Hulbert, C., Barlow, E., and Bendall, S. (2018). Childhood trauma is associated with severity of hallucinations and delusions in psychotic disorders: a systematic review and meta-analysis. Schizophr. Bull. 44, 1111–1122. doi: 10.1093/schbul/sbx161

PubMed Abstract | CrossRef Full Text | Google Scholar

Barbosa, I. G., Machado-Vieira, R., Soares, J. C., and Teixeira, A. L. (2014). The immunology of bipolar disorder. Neuroimmunomodulation 21, 117–122.

Google Scholar

Barichello, T., Badawy, M., Pitcher, M., Saigal, P., Generoso, J., Goularte, J., et al. (2016). Exposure to perinatal infections and bipolar disorder: a systematic review. Curr. Mol. Med. 16, 106–118. doi: 10.2174/1566524016666160126143741

PubMed Abstract | CrossRef Full Text | Google Scholar

Bayer, T. A., Falkai, P., and Maier, W. (1999). Genetic and non-genetic vulnerability factors in schizophrenia: the basis of the” two hit hypothesis. J. Psychiatric Res. 33, 543–548. doi: 10.1016/s0022-3956(99)00039-4

CrossRef Full Text | Google Scholar

Belbasis, L., Köhler, C. A., Stefanis, N., Stubbs, B., van Os, J., Vieta, E., et al. (2018). Risk factors and peripheral biomarkers for schizophrenia spectrum disorders: an umbrella review of meta-analyses. Acta Psychiatr. Scand. 137, 88–97. doi: 10.1111/acps.12847

PubMed Abstract | CrossRef Full Text | Google Scholar

Benros, M. E., Trabjerg, B. B., Meier, S., Mattheisen, M., Mortensen, P. B., Mors, O., et al. (2016). Influence of polygenic risk scores on the association between infections and schizophrenia. Biol. Psychiatry 80, 609–616. doi: 10.1016/j.biopsych.2016.04.008

PubMed Abstract | CrossRef Full Text | Google Scholar

Benros, M. E., Waltoft, B. L., Nordentoft, M., Østergaard, S. D., Eaton, W. W., Krogh, J., et al. (2013). Autoimmune diseases and severe infections as risk factors for mood disorders: a nationwide study. JAMA Psychiatry 70, 812–820. doi: 10.1001/jamapsychiatry.2013.1111

PubMed Abstract | CrossRef Full Text | Google Scholar

Benros, M. E., and Mortensen, P. B. (2020). Role of infection, autoimmunity, atopic disorders, and the immune system in schizophrenia: evidence from epidemiological and genetic studies. Curr. Top Behav. Neurosci. 44, 141–159. doi: 10.1007/7854_2019_93

CrossRef Full Text | Google Scholar

Bergen, S. E., O’Dushlaine, C. T., Ripke, S., Lee, P. H., Ruderfer, D. M., Akterin, S., et al. (2012). Genome-wide association study in a Swedish population yields support for greater CNV and MHC involvement in schizophrenia compared with bipolar disorder. Mol. Psychiatry 17, 880–886. doi: 10.1038/mp.2012.73

PubMed Abstract | CrossRef Full Text | Google Scholar

Bierut, L. J. (2010). Convergence of genetic findings for nicotine dependence and smoking related diseases with chromosome 15q24-25. Trends Pharmacol. Sci. 31, 46–51. doi: 10.1016/

PubMed Abstract | CrossRef Full Text | Google Scholar

Bigdeli, T. B., Genovese, G., Georgakopoulos, P., Meyers, J. L., Peterson, R. E., Iyegbe, C. O., et al. (2020). Contributions of common genetic variants to risk of schizophrenia among individuals of African and Latino ancestry. Mol. Psychiatry 25, 2455–2467. doi: 10.1038/s41380-019-0517-y

PubMed Abstract | CrossRef Full Text | Google Scholar

Blomström, Å, Karlsson, H., Gardner, R., Jörgensen, L., Magnusson, C., and Dalman, C. (2016). Associations between maternal infection during pregnancy, childhood infections, and the risk of subsequent psychotic disorder—a Swedish Cohort study of nearly 2 million individuals. Schizophr. Bull. 42, 125–133.

Google Scholar

Børglum, A., Demontis, D., Grove, J., Pallesen, J., Hollegaard, M. V., Pedersen, C., et al. (2014). Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci. Mol. Psychiatry 19, 325–333. doi: 10.1038/mp.2013.2

PubMed Abstract | CrossRef Full Text | Google Scholar

Brainstorm Consortium (2018). Analysis of shared heritability in common disorders of the brain. Science 360:eaa8757.

Google Scholar

Bryant, R. A., O’donnell, M. L., Creamer, M., McFarlane, A. C., Clark, C. R., and Silove, D. (2010). The psychiatric sequelae of traumatic injury. Am. J. Psychiatry 167, 312–320.

Google Scholar

Buckley, P. F., Pillai, A., and Howell, K. R. (2011). Brain-derived neurotrophic factor: findings in schizophrenia. Curr. Opin. Psychiatry 24, 122–127. doi: 10.1097/yco.0b013e3283436eb7

PubMed Abstract | CrossRef Full Text | Google Scholar

Bulik-Sullivan, B., Finucane, H. K., Anttila, V., Gusev, A., Day, F. R., Loh, P.-R., et al. (2015). An atlas of genetic correlations across human diseases and traits. Nat. Genet. 47, 1236–1241. doi: 10.1038/ng.3406

PubMed Abstract | CrossRef Full Text | Google Scholar

Byrne, M., Agerbo, E., Bennedsen, B., Eaton, W. W., and Mortensen, P. B. (2007). Obstetric conditions and risk of first admission with schizophrenia: a Danish national register based study. Schizophr. Res. 97, 51–59. doi: 10.1016/j.schres.2007.07.018

PubMed Abstract | CrossRef Full Text | Google Scholar

Calderón-Garcidueñas, L., Solt, A. C., Henríquez-Roldán, C., Torres-Jardón, R., Nuse, B., Herritt, L., et al. (2008). Long-term air pollution exposure is associated with neuroinflammation, an altered innate immune response, disruption of the blood-brain barrier, ultrafine particulate deposition, and accumulation of amyloid β-42 and α-synuclein in children and young adults. Toxicol. Pathol. 36, 289–310. doi: 10.1177/0192623307313011

PubMed Abstract | CrossRef Full Text | Google Scholar

Canetta, S. E., Bao, Y., Co, M. D. T., Ennis, F. A., Cruz, J., Terajima, M., et al. (2014). Serological documentation of maternal influenza exposure and bipolar disorder in adult offspring. Am. J. Psychiatry 171, 557–563. doi: 10.1176/appi.ajp.2013.13070943

PubMed Abstract | CrossRef Full Text | Google Scholar

Cannon, M., Jones, P. B., and Murray, R. M. (2002). Obstetric complications and schizophrenia: historical and meta-analytic review. Am. J. Psychiatry 159, 1080–1092. doi: 10.1176/appi.ajp.159.7.1080

PubMed Abstract | CrossRef Full Text | Google Scholar

Cannon, T. D., Rosso, I. M., Hollister, J. M., Bearden, C. E., Sanchez, L. E., and Hadley, T. (2000). A prospective cohort study of genetic and perinatal influences in the etiology of schizophrenia. Schizophr. Bull. 26, 351–366. doi: 10.1093/oxfordjournals.schbul.a033458

PubMed Abstract | CrossRef Full Text | Google Scholar

Cannon, T. D., van Erp, T. G., Rosso, I. M., Huttunen, M., Lönnqvist, J., Pirkola, T., et al. (2002). Fetal hypoxia and structural brain abnormalities in schizophrenic patients, their siblings, and controls. Arch. Gen. Psychiatry 59, 35–41. doi: 10.1001/archpsyc.59.1.35

PubMed Abstract | CrossRef Full Text | Google Scholar

Cantor-Graae, E., and Pedersen, C. B. (2013). Full spectrum of psychiatric disorders related to foreign migration: a Danish population-based cohort study. JAMA Psychiatry 70, 427–435. doi: 10.1001/jamapsychiatry.2013.441

PubMed Abstract | CrossRef Full Text | Google Scholar

Carney, C. P., and Jones, L. E. (2006). Medical comorbidity in women and men with bipolar disorders: a population-based controlled study. Psychosom. Med. 68, 684–691. doi: 10.1097/01.psy.0000237316.09601.88

CrossRef Full Text | Google Scholar

Caspi, A., Moffitt, T. E., Cannon, M., McClay, J., Murray, R., Harrington, H., et al. (2005). Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. Biol. Psychiatry 57, 1117–1127. doi: 10.1016/j.biopsych.2005.01.026

PubMed Abstract | CrossRef Full Text | Google Scholar

Cereda, G., Enrico, P., Ciappolino, V., Delvecchio, G., and Brambilla, P. (2020). The role of vitamin D in bipolar disorder: epidemiology and influence on disease activity. J. Affect. Disord. 278, 209–217. doi: 10.1016/j.jad.2020.09.039

PubMed Abstract | CrossRef Full Text | Google Scholar

Chotai, J., Serretti, A., Lattuada, E., Lorenzi, C., and Lilli, R. (2003). Gene–environment interaction in psychiatric disorders as indicated by season of birth variations in tryptophan hydroxylase (TPH), serotonin transporter (5-HTTLPR) and dopamine receptor (DRD4) gene polymorphisms. Psychiatry Res. 119, 99–111. doi: 10.1016/s0165-1781(03)00112-4

CrossRef Full Text | Google Scholar

Clarke, M. C., Tanskanen, A., Huttunen, M., Whittaker, J. C., and Cannon, M. (2009). Evidence for an interaction between familial liability and prenatal exposure to infection in the causation of schizophrenia. Am. J. Psychiatry 166, 1025–1030. doi: 10.1176/appi.ajp.2009.08010031

PubMed Abstract | CrossRef Full Text | Google Scholar

Collip, D., Myin-Germeys, I., Wichers, M., Jacobs, N., Derom, C., Thiery, E., et al. (2013). FKBP5 as a possible moderator of the psychosis-inducing effects of childhood trauma. Br. J. Psychiatry 202, 261–268. doi: 10.1192/bjp.bp.112.115972

PubMed Abstract | CrossRef Full Text | Google Scholar

Colodro-Conde, L., Couvy-Duchesne, B., Whitfield, J. B., Streit, F., Gordon, S., Kemper, K. E., et al. (2018). Association between population density and genetic risk for schizophrenia. JAMA Psychiatry 75, 901–910.

Google Scholar

Cook, T. B., Brenner, L. A., Cloninger, C. R., Langenberg, P., Igbide, A., Giegling, I., et al. (2015). “Latent” infection with Toxoplasma gondii: association with trait aggression and impulsivity in healthy adults. J. Psychiatric Res. 60, 87–94. doi: 10.1016/j.jpsychires.2014.09.019

PubMed Abstract | CrossRef Full Text | Google Scholar

Coryell, W., Leon, A. C., Turvey, C., Akiskal, H. S., Mueller, T., and Endicott, J. (2001). The significance of psychotic features in manic episodes: a report from the NIMH collaborative study. J. Affect. Disord. 67, 79–88. doi: 10.1016/s0165-0327(99)00024-5

CrossRef Full Text | Google Scholar

Dalman, C., Allebeck, P., Cullberg, J., Grunewald, C., and Köster, M. (1999). Obstetric complications and the risk of schizophrenia: a longitudinal study of a national birth cohort. Arch. Gen. Psychiatry 56, 234–240. doi: 10.1001/archpsyc.56.3.234

PubMed Abstract | CrossRef Full Text | Google Scholar

Dalman, C., Allebeck, P., Gunnell, D., Harrison, G., Kristensson, K., Lewis, G., et al. (2008). Infections in the CNS during childhood and the risk of subsequent psychotic illness: a cohort study of more than one million swedish subjects. Am. J. Psychiatry 165, 59–65. doi: 10.1176/appi.ajp.2007.07050740

PubMed Abstract | CrossRef Full Text | Google Scholar

Dalman, C., Thomas, H. V., David, A. S., Gentz, J., Lewis, G., and Allebeck, P. (2001). Signs of asphyxia at birth and risk of schizophrenia. Population-based case-control study. Br. J. Psychiatry 179, 403–408. doi: 10.1192/bjp.179.5.403

PubMed Abstract | CrossRef Full Text | Google Scholar

Dantzer, R., O’Connor, J. C., Freund, G. G., Johnson, R. W., and Kelley, K. W. (2008). From inflammation to sickness and depression: when the immune system subjugates the brain. Nat. Rev, Neurosci. 9, 46–56. doi: 10.1038/nrn2297

PubMed Abstract | CrossRef Full Text | Google Scholar

Daskalakis, N. P., and Binder, E. B. (2015). Schizophrenia in the spectrum of gene–stress interactions: the FKBP5 example. Schizophr. Bull. 41, 323–329. doi: 10.1093/schbul/sbu189

PubMed Abstract | CrossRef Full Text | Google Scholar

Davies, A. A., Basten, A., and Frattini, C. (2009). Migration: a social determinant of the health of migrants. Eurohealth 16, 10–12.

Google Scholar

Davies, G., Welham, J., Chant, D., Torrey, E. F., and McGrath, J. (2003). A systematic review and meta-analysis of northern hemisphere season of birth studies in schizophrenia. Schizophr. Bull. 29, 587–593. doi: 10.1093/oxfordjournals.schbul.a007030

PubMed Abstract | CrossRef Full Text | Google Scholar

de Barros, J. L. V. M., Barbosa, I. G., Salem, H., Rocha, N. P., Kummer, A., Okusaga, O. O., et al. (2017). Is there any association between Toxoplasma gondii infection and bipolar disorder? A systematic review and meta-analysis. J. Affect. Disord. 209, 59–65. doi: 10.1016/j.jad.2016.11.016

PubMed Abstract | CrossRef Full Text | Google Scholar

de Castro-Catala, M., van Nierop, M., Barrantes-Vidal, N., Cristóbal-Narváez, P., Sheinbaum, T., Kwapil, T. R., et al. (2016). Childhood trauma, BDNF Val66Met and subclinical psychotic experiences. Attempt at replication in two independent samples. J. Psychiatric Res. 83, 121–129. doi: 10.1016/j.jpsychires.2016.08.014

PubMed Abstract | CrossRef Full Text | Google Scholar

De Leon, J., and Diaz, F. J. (2005). A meta-analysis of worldwide studies demonstrates an association between schizophrenia and tobacco smoking behaviors. Schizophr. Res. 76, 135–157. doi: 10.1016/j.schres.2005.02.010

PubMed Abstract | CrossRef Full Text | Google Scholar

Debnath, M., Busson, M., Jamain, S., Etain, B., Hamdani, N., Oliveira, J., et al. (2013). The HLA-G low expressor genotype is associated with protection against bipolar disorder. Hum. Immunol. 74, 593–597. doi: 10.1016/j.humimm.2012.11.032

PubMed Abstract | CrossRef Full Text | Google Scholar

Demontis, D., Nyegaard, M., Buttenschøn, H. N., Hedemand, A., Pedersen, C. B., Grove, J., et al. (2011). Association of GRIN1 and GRIN2A-D with schizophrenia and genetic interaction with maternal herpes simplex virus-2 infection affecting disease risk. Am. J. Med. Genet. B Neuropsychiatr. Genet. 156b, 913–922. doi: 10.1002/ajmg.b.31234

PubMed Abstract | CrossRef Full Text | Google Scholar

Di Forti, M., Iyegbe, C., Sallis, H., Kolliakou, A., Falcone, M. A., Paparelli, A., et al. (2012). Confirmation that the AKT1 (rs2494732) genotype influences the risk of psychosis in cannabis users. Biol. Psychiatry 72, 811–816. doi: 10.1016/j.biopsych.2012.06.020

PubMed Abstract | CrossRef Full Text | Google Scholar

Di Renzo, G. C., Rosati, A., Sarti, R. D., Cruciani, L., and Cutuli, A. M. (2007). Does fetal sex affect pregnancy outcome? Gend. Med. 4, 19–30. doi: 10.1016/s1550-8579(07)80004-0

CrossRef Full Text | Google Scholar

Duncan, L. E., and Keller, M. C. (2011). A critical review of the first 10 years of candidate gene-by-environment interaction research in psychiatry. Am. J. Psychiatry 168, 1041–1049. doi: 10.1176/appi.ajp.2011.11020191

PubMed Abstract | CrossRef Full Text | Google Scholar

Dykxhoorn, J., Hollander, A. C., Lewis, G., Magnusson, C., Dalman, C., and Kirkbride, J. B. (2019). Risk of schizophrenia, schizoaffective, and bipolar disorders by migrant status, region of origin, and age-at-migration: a national cohort study of 1.8 million people. Psychol. Med. 49, 2354–2363. doi: 10.1017/s0033291718003227

PubMed Abstract | CrossRef Full Text | Google Scholar

Escott-Price, V., Smith, D. J., Kendall, K., Ward, J., Kirov, G., Owen, M. J., et al. (2019). Polygenic risk for schizophrenia and season of birth within the UK Biobank cohort. Psychol. Med. 49, 2499–2504. doi: 10.1017/S0033291718000454

PubMed Abstract | CrossRef Full Text | Google Scholar

Eyles, D. W., Burne, T. H., and McGrath, J. J. (2013). Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front. Neuroendocrinol. 34:47–64. doi: 10.1016/j.yfrne.2012.07.001

PubMed Abstract | CrossRef Full Text | Google Scholar

Eyles, D. W., Trzaskowski, M., Vinkhuyzen, A. A., Mattheisen, M., Meier, S., Gooch, H., et al. (2018). The association between neonatal vitamin D status and risk of schizophrenia. Sci. Rep. 8, 1–8.

Google Scholar

Feingold, D., Weiser, M., Rehm, J., and Lev-Ran, S. (2015). The association between cannabis use and mood disorders: a longitudinal study. J. Affect. Disord. 172, 211–218. doi: 10.1016/j.jad.2014.10.006

PubMed Abstract | CrossRef Full Text | Google Scholar

Fiorica, P. N., and Wheeler, H. E. (2019). Transcriptome association studies of neuropsychiatric traits in African Americans implicate PRMT7 in schizophrenia. PeerJ 7:e7778. doi: 10.7717/peerj.7778

PubMed Abstract | CrossRef Full Text | Google Scholar

French, L., Gray, C., Leonard, G., Perron, M., Pike, G. B., Richer, L., et al. (2015). Early cannabis use, polygenic risk score for schizophrenia and brain maturation in adolescence. JAMA Psychiatry 72, 1002–1011. doi: 10.1001/jamapsychiatry.2015.1131

PubMed Abstract | CrossRef Full Text | Google Scholar

Gage, S. H., Jones, H. J., Burgess, S., Bowden, J., Davey Smith, G., Zammit, S., et al. (2017). Assessing causality in associations between cannabis use and schizophrenia risk: a two-sample Mendelian randomization study. Psychol. Med. 47, 971–980. doi: 10.1017/S0033291716003172

PubMed Abstract | CrossRef Full Text | Google Scholar

Gardner, R., Dalman, C., Wicks, S., Lee, B., and Karlsson, H. (2013). Neonatal levels of acute phase proteins and later risk of non-affective psychosis. Transl. Psychiatry 3:e228. doi: 10.1038/tp.2013.5

PubMed Abstract | CrossRef Full Text | Google Scholar

Gibbs, M., Winsper, C., Marwaha, S., Gilbert, E., Broome, M., and Singh, S. P. (2015). Cannabis use and mania symptoms: a systematic review and meta-analysis. J. Affect. Disord. 171, 39–47. doi: 10.1016/j.jad.2014.09.016

PubMed Abstract | CrossRef Full Text | Google Scholar

Gillespie, N. A., and Kendler, K. S. (2020). Use of genetically informed methods to clarify the nature of the association between cannabis use and risk for schizophrenia. JAMA Psychiatry 78, 467–468. doi: 10.1001/jamapsychiatry.2020.3564

PubMed Abstract | CrossRef Full Text | Google Scholar

Giordano, G. N., Ohlsson, H., Sundquist, K., Sundquist, J., and Kendler, K. S. (2015). The association between cannabis abuse and subsequent schizophrenia: a Swedish national co-relative control study. Psychol. Med. 45, 407–414. doi: 10.1017/s0033291714001524

PubMed Abstract | CrossRef Full Text | Google Scholar

Goes, F. S., Pirooznia, M., Parla, J. S., Kramer, M., Ghiban, E., Mavruk, S., et al. (2016). Exome sequencing of familial bipolar disorder. JAMA Psychiatry 73, 590–597.

Google Scholar

Gohardehi, S., Sharif, M., Sarvi, S., Moosazadeh, M., Alizadeh-Navaei, R., Hosseini, S. A., et al. (2018). The potential risk of toxoplasmosis for traffic accidents: a systematic review and meta-analysis. Exp. Parasitol. 191, 19–24. doi: 10.1016/j.exppara.2018.06.003

PubMed Abstract | CrossRef Full Text | Google Scholar

Guloksuz, S., Pries, L.-K., Delespaul, P., Kenis, G., Luykx, J. J., Lin, B. D., et al. (2019). Examining the independent and joint effects of molecular genetic liability and environmental exposures in schizophrenia: results from the EUGEI study. World Psychiatry 18, 173–182. doi: 10.1002/wps.20629

PubMed Abstract | CrossRef Full Text | Google Scholar

Hamdani, N., Daban-Huard, C., Lajnef, M., Gadel, R., Le Corvoisier, P., Delavest, M., et al. (2015). Cognitive deterioration among bipolar disorder patients infected by Toxoplasma gondii is correlated to interleukin 6 levels. J. Affect. Disord. 179, 161–166. doi: 10.1016/j.jad.2015.03.038

PubMed Abstract | CrossRef Full Text | Google Scholar

Harley, M., Kelleher, I., Clarke, M., Lynch, F., Arseneault, L., Connor, D., et al. (2010). Cannabis use and childhood trauma interact additively to increase the risk of psychotic symptoms in adolescence. Psychol. Med. 40, 1627–1634. doi: 10.1017/s0033291709991966

PubMed Abstract | CrossRef Full Text | Google Scholar

Hasin, D. S., Saha, T. D., Kerridge, B. T., Goldstein, R. B., Chou, S. P., Zhang, H., et al. (2015). Prevalence of marijuana use disorders in the United States between 2001-2002 and 2012-2013. JAMA Psychiatry 72, 1235–1242. doi: 10.1001/jamapsychiatry.2015.1858

PubMed Abstract | CrossRef Full Text | Google Scholar

Henssler, J., Brandt, L., Müller, M., Liu, S., Montag, C., Sterzer, P., et al. (2020). Migration and schizophrenia: meta-analysis and explanatory framework. Eur. Arch. Psychiatry Clin. Neurosci. 270, 325–335. doi: 10.1007/s00406-019-01028-7

PubMed Abstract | CrossRef Full Text | Google Scholar

Hsieh, Y.-C., Chou, L.-S., Lin, C.-H., Wu, H.-C., Li, D.-J., and Tseng, P.-T. (2019). Serum folate levels in bipolar disorder: a systematic review and meta-analysis. BMC Psychiatry 19:305. doi: 10.1186/s12888-019-2269-2

PubMed Abstract | CrossRef Full Text | Google Scholar

IARC Scientific (2013). Air Pollution and Cancer. Lyon: IARC Scientific.

Google Scholar

International Schizophrenia, Consortium, Purcell, S. M., Wray, N. R., Stone, J. L., Visscher, P. M., et al. (2009). Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752. doi: 10.1038/nature08185

PubMed Abstract | CrossRef Full Text | Google Scholar

Jackson, J. G., Diaz, F. J., Lopez, L., and de Leon, J. (2015). A combined analysis of worldwide studies demonstrates an association between bipolar disorder and tobacco smoking behaviors in adults. Bipolar. Disord. 17, 575–597. doi: 10.1111/bdi.12319

PubMed Abstract | CrossRef Full Text | Google Scholar

Janiri, D., Sani, G., Danese, E., Simonetti, A., Ambrosi, E., Angeletti, G., et al. (2015). Childhood traumatic experiences of patients with bipolar disorder type I and type II. J. Affect. Disord. 175, 92–97. doi: 10.1016/j.jad.2014.12.055

PubMed Abstract | CrossRef Full Text | Google Scholar

Joo, E.-J., Lee, K.-Y., Jeong, S.-H., Roh, M.-S., Kim, S. H., Ahn, Y.-M., et al. (2009). AKT1 gene polymorphisms and obstetric complications in the patients with schizophrenia. Psychiatry Invest. 6, 102–107. doi: 10.4306/pi.2009.6.2.102

PubMed Abstract | CrossRef Full Text | Google Scholar

Karlsson, H., Dal, H., Gardner, R. M., Torrey, E. F., and Dalman, C. (2019). Birth month and later diagnosis of schizophrenia. A population-based cohort study in Sweden. J. Psychiatric Res. 116, 1–6. doi: 10.1016/j.jpsychires.2019.05.025

PubMed Abstract | CrossRef Full Text | Google Scholar

Kaymaz, N., Krabbendam, L., de Graaf, R., Nolen, W., Ten Have, M., and van Os, J. (2006). Evidence that the urban environment specifically impacts on the psychotic but not the affective dimension of bipolar disorder. Soc. Psychiatry Psychiatr. Epidemiol. 41, 679–685. doi: 10.1007/s00127-006-0086-7

PubMed Abstract | CrossRef Full Text | Google Scholar

Kendler, K. S., Lönn, S. L., Sundquist, J., and Sundquist, K. (2015). Smoking and schizophrenia in population cohorts of Swedish women and men: a prospective co-relative control study. Am. J. Psychiatry 172, 1092–1100. doi: 10.1176/appi.ajp.2015.15010126

PubMed Abstract | CrossRef Full Text | Google Scholar

Khan, A., Plana-Ripoll, O., Antonsen, S., Brandt, J., Geels, C., Landecker, H., et al. (2019). Environmental pollution is associated with increased risk of psychiatric disorders in the US and Denmark. PLoS Biol. 17:e3000353. doi: 10.1371/journal.pbio.3000353

PubMed Abstract | CrossRef Full Text | Google Scholar

Khan, S. S., Secades-Villa, R., Okuda, M., Wang, S., Pérez-Fuentes, G., Kerridge, B. T., et al. (2013). Gender differences in cannabis use disorders: results from the national epidemiologic survey of alcohol and related conditions. Drug Alcohol. Dependence 130, 101–108. doi: 10.1016/j.drugalcdep.2012.10.015

PubMed Abstract | CrossRef Full Text | Google Scholar

Khandaker, G. M., Zimbron, J., Dalman, C., Lewis, G., and Jones, P. B. (2012). Childhood infection and adult schizophrenia: a meta-analysis of population-based studies. Schizophr. Res. 139, 161–168. doi: 10.1016/j.schres.2012.05.023

PubMed Abstract | CrossRef Full Text | Google Scholar

Khokhar, J. Y., Dwiel, L. L., Henricks, A. M., Doucette, W. T., and Green, A. I. (2018). The link between schizophrenia and substance use disorder: a unifying hypothesis. Schizophr. Res. 194, 78–85. doi: 10.1016/j.schres.2017.04.016

PubMed Abstract | CrossRef Full Text | Google Scholar

Kilbourne, A. M., Morden, N. E., Austin, K., Ilgen, M., McCarthy, J. F., Dalack, G., et al. (2009). Excess heart-disease-related mortality in a national study of patients with mental disorders: identifying modifiable risk factors. Gen. Hosp. Psychiatry 31, 555–563. doi: 10.1016/j.genhosppsych.2009.07.008

PubMed Abstract | CrossRef Full Text | Google Scholar

Kirov, G., Jones, P. B., Harvey, I., Lewis, S. W., Toone, B. K., Rifkin, L., et al. (1996). Do obstetric complications cause the earlier age at onset in male than female schizophrenics? Schizophr. Res. 20, 117–124. doi: 10.1016/0920-9964(95)00063-1

CrossRef Full Text


You will also be interested:

Causes - Schizophrenia

The exact causes of schizophrenia are unknown. Research suggests a combination of physical, genetic, psychological and environmental factors can make a person more likely to develop the condition.

Some people may be prone to schizophrenia, and a stressful or emotional life event might trigger a psychotic episode. However, it's not known why some people develop symptoms while others do not.

Increased risk


Schizophrenia tends to run in families, but no single gene is thought to be responsible.

It's more likely that different combinations of genes make people more vulnerable to the condition. However, having these genes does not necessarily mean you'll develop schizophrenia.

Evidence that the disorder is partly inherited comes from studies of twins. Identical twins share the same genes.

In identical twins, if a twin develops schizophrenia, the other twin has a 1 in 2 chance of developing it, too. This is true even if they're raised separately. 

In non-identical twins, who have different genetic make-ups, when a twin develops schizophrenia, the other only has a 1 in 8 chance of developing the condition.

While this is higher than in the general population, where the chance is about 1 in 100, it suggests genes are not the only factor influencing the development of schizophrenia.

Brain development

Studies of people with schizophrenia have shown there are subtle differences in the structure of their brains.

These changes are not seen in everyone with schizophrenia and can occur in people who do not have a mental illness. But they suggest schizophrenia may partly be a disorder of the brain.


Neurotransmitters are chemicals that carry messages between brain cells.

There's a connection between neurotransmitters and schizophrenia because drugs that alter the levels of neurotransmitters in the brain are known to relieve some of the symptoms of schizophrenia. 

Research suggests schizophrenia may be caused by a change in the level of 2 neurotransmitters: dopamine and serotonin.

Some studies indicate an imbalance between the 2 may be the basis of the problem. Others have found a change in the body's sensitivity to the neurotransmitters is part of the cause of schizophrenia.

Pregnancy and birth complications

Research has shown people who develop schizophrenia are more likely to have experienced complications before and during their birth, such as:

  • a low birthweight
  • premature labour
  • a lack of oxygen (asphyxia) during birth

It may be that these things have a subtle effect on brain development.


Triggers are things that can cause schizophrenia to develop in people who are at risk.

These include:


The main psychological triggers of schizophrenia are stressful life events, such as:

  • bereavement
  • losing your job or home
  • divorce
  • the end of a relationship
  • physical, sexual or emotional abuse

These kinds of experiences, although stressful, do not cause schizophrenia. However, they can trigger its development in someone already vulnerable to it.

Drug abuse

Drugs do not directly cause schizophrenia, but studies have shown drug misuse increases the risk of developing schizophrenia or a similar illness.

Certain drugs, particularly cannabis, cocaine, LSD or amphetamines, may trigger symptoms of schizophrenia in people who are susceptible.

Using amphetamines or cocaine can lead to psychosis, and can cause a relapse in people recovering from an earlier episode.

Research has shown that teenagers and young adults who use cannabis regularly are more likely to develop schizophrenia in later adulthood.

Want to know more?


250 251 252 253 254