Gene–Environment Interactions for Searchers: Collaboration between Epidemiology and Molecular Genetics

  • Jim van Os
  • Bart P.F. Rutten
  • Richie Poulton


Attempts to discover genes that relate directly to psychotic disorder (i.e., the simple “main effects” approach) have been frustrating and often disappointing, resulting in the expression of methodological concerns (Harrison and Weinberger 2005; Norton et al. 2006) (Collier 2008; Sullivan 2008; O’Donovan et al. 2008; Crow 2008). On the other hand, epidemiological research has unveiled high observed rates of schizophrenia in large cities, immigrant populations, traumatised individuals and cannabis users, at least some of which is thought to be the result of underlying environmental exposures. Exciting findings in other areas of psychiatry have motivated researchers to turn their attention to better understanding the complex ways in which nature interacts with nurture to produce psychosis.


Genetic Moderation Genetic Risk Environment Interaction Environmental Exposure Psychotic Disorder 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Parts of this chapter appeared as: van Os, J., Poulton, R. (2008). Environmental vulnerability and genetic-environmental interactions. In: The Recognition and Management of Early Psychosis: A Preventive Approach, 2nd edition (eds. H. Jackson and P. McGorry). Cambridge University Press: Cambridge; van Os J, Rutten BP, Poulton R. Gene-environment interactions in schizophrenia: review of epidemiological findings and future directions. Schizophrenia Bulletin 34:1066–1082, 2009.


  1. Arango C, Moreno C, Martinez S, Parellada M, Desco M, Moreno D, Fraguas D, Gogtay N, James A, Rapoport J. (2008). Longitudinal brain changes in early-onset psychosis. Schizophr Bull 34:341–53.PubMedCrossRefGoogle Scholar
  2. Arnsten AF, Goldman Rakic PS. (1998). Noise stress impairs prefrontal cortical cognitive function in monkeys: evidence for a hyperdopaminergic mechanism. Arch Gen Psychiatry 55: 362–8.PubMedCrossRefGoogle Scholar
  3. Arranz MJ, de Leon J. (2007). Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research. Mol Psychiatry 12:707–47.PubMedCrossRefGoogle Scholar
  4. Barkus E, Stirling J, Hopkins R, McKie S, Lewis S. (2007). Cognitive and neural processes in non-clinical auditory hallucinations. Br J Psychiatry Suppl 51:s76–s81.PubMedCrossRefGoogle Scholar
  5. Barnett JH, Heron J, Ring SM, Golding J, Goldman D, Xu K, Jones PB. (2007b). Gender-specific effects of the catechol-O-methyltransferase Val108/158Met polymorphism on cognitive function in children. Am J Psychiatry 164:142–9.Google Scholar
  6. Barnett JH, Jones PB, Robbins TW, Muller U. (2007a). Effects of the catechol-O-methyltransferase Val158Met polymorphism on executive function: a meta-analysis of the Wisconsin Card Sort Test in schizophrenia and healthy controls. Mol Psychiatry 12:502–9.Google Scholar
  7. Baron M, Gruen R. (1988). Risk factors in schizophrenia. Season of birth and family history [see comments]. Br J Psychiatry 152:460–5.PubMedCrossRefGoogle Scholar
  8. Boileau I, Dagher A, Leyton M, Gunn RN, Baker GB, Diksic M, Benkelfat C. (2006). Modeling sensitization to stimulants in humans: an [11C]raclopride/positron emission tomography study in healthy men. Arch Gen Psychiatry 63:1386–95.PubMedCrossRefGoogle Scholar
  9. Boks MP, Schipper M, Schubart CD, Sommer IE, Kahn RS, Ophoff RA. (2007). Investigating gene environment interaction in complex diseases: increasing power by selective sampling for environmental exposure. Int J Epidemiol 36:1363–9.PubMedCrossRefGoogle Scholar
  10. Bombin I, Arango C, Mayoral M, Castro-Fornieles J, Gonzalez-Pinto A, Gonzalez-Gomez C, Moreno D, Parellada M, Baeza I, Graell M, Otero S, Saiz PA, Patino-Garcia A. (2008). DRD3, but not COMT or DRD2, genotype affects executive functions in healthy and first-episode psychosis adolescents. Am J Med Genet B Neuropsychiatr Genet 147:873–9.Google Scholar
  11. Boos HB, Aleman A, Cahn W, Pol HH, Kahn RS. (2007). Brain volumes in relatives of patients with schizophrenia: a meta-analysis. Arch Gen Psychiatry 64:297–304.PubMedCrossRefGoogle Scholar
  12. Boydell J, van Os J, McKenzie K, Allardyce J, Goel R, McCreadie RG, Murray RM. (2001). Incidence of schizophrenia in ethnic minorities in London: ecological study into interactions with environment. BMJ 323:1336–8.PubMedCrossRefGoogle Scholar
  13. Brunelin J, d’Amato T, van Os J, Cochet A, Suaud-Chagny MF, Saoud M. (2008). Effects of acute metabolic stress on the dopaminergic and pituitary–adrenal axis activity in patients with schizophrenia, their unaffected siblings and controls. Schizophr Res 100:206–211.PubMedCrossRefGoogle Scholar
  14. Buckholtz JW, Sust S, Tan HY, Mattay VS, Straub RE, Meyer-Lindenberg A, Weinberger DR, Callicott JH. (2007). fMRI evidence for functional epistasis between COMT and RGS4. Mol Psychiatry 12:893–5, 885.PubMedCrossRefGoogle Scholar
  15. Byrne M, Agerbo E, Ewald H, Eaton WW, Mortensen PB. (2003). Parental age and risk of schizophrenia: a case–control study. Arch Gen Psychiatry 60:673–8.PubMedCrossRefGoogle Scholar
  16. Canli T, Lesch KP. (2007). Long story short: the serotonin transporter in emotion regulation and social cognition. Nat Neurosci 10:1103–9.PubMedCrossRefGoogle Scholar
  17. Cannon M, Clarke MC. (2005). Risk for schizophrenia – broadening the concepts, pushing back the boundaries. Schizophr Res 79:5–13.PubMedCrossRefGoogle Scholar
  18. Cannon TD, Mednick SA, Parnas J, Schulsinger F, Praestholm J, Vestergaard A. (1993). Developmental brain abnormalities in the offspring of schizophrenic mothers. I. Contributions of genetic and perinatal factors [see comments]. Arch Gen Psychiatry 50:551–64.PubMedGoogle Scholar
  19. Cannon TD, van Erp TG, Rosso IM, Huttunen M, Lonnqvist J, Pirkola T, Salonen O, Valanne L, Poutanen VP, Standertskjold-Nordenstam CG. (2002). Fetal hypoxia and structural brain abnormalities in schizophrenic patients, their siblings, and controls. Arch Gen Psychiatry 59:35–41.PubMedCrossRefGoogle Scholar
  20. Cantor-Graae E, Selten JP. (2005). Schizophrenia and migration: a meta-analysis and review. Am J Psychiatry 162:12–24.PubMedCrossRefGoogle Scholar
  21. Carter JW, Parnas J, Cannon TD, Schulsinger F, Mednick SA. (1999). MMPI variables predictive of schizophrenia in the Copenhagen High-Risk Project: a 25-year follow-up. Acta Psychiatr Scand 99:432–40.PubMedCrossRefGoogle Scholar
  22. Carter JW, Schulsinger F, Parnas J, Cannon T, Mednick SA. (2002). A multivariate prediction model of schizophrenia. Schizophr Bull 28:649–82.PubMedGoogle Scholar
  23. Caspi A, Moffitt TE, Cannon M, McClay J, Murray R, Harrington H, Taylor A, Arseneault L, Williams B, Braithwaite A, Poulton R, Craig IW. (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 × environment interaction. Biol Psychiatry 57:1117–27.PubMedCrossRefGoogle Scholar
  24. Caspi A, Moffitt TE. (2006). Gene–environment interactions in psychiatry: joining forces with neuroscience. Nat Rev Neurosci 7:583–90.PubMedCrossRefGoogle Scholar
  25. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R. (2003). Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301:386–9.PubMedCrossRefGoogle Scholar
  26. Champoux M, Bennett A, Shannon C, Higley JD, Lesch KP, Suomi SJ. (2002). Serotonin transporter gene polymorphism, differential early rearing, and behavior in rhesus monkey neonates. Mol Psychiatry 7:1058–63.PubMedCrossRefGoogle Scholar
  27. Colhoun HM, McKeigue PM, Davey Smith G. (2003). Problems of reporting genetic associations with complex outcomes. Lancet 361:865–72.PubMedCrossRefGoogle Scholar
  28. Collier DA. (2008). Schizophrenia: the polygene princess and the pea. Psychol Med 1–5.Google Scholar
  29. Collip D, Myin-Germeys I, Van Os J. (2008). Does the concept of “sensitization” provide a plausible mechanism for the putative link between the environment and schizophrenia? Schizophr Bull 34:220–5.PubMedCrossRefGoogle Scholar
  30. Covington HE, 3rd, Miczek KA. (2001). Repeated social-defeat stress, cocaine or morphine. Effects on behavioral sensitization and intravenous cocaine self-administration “binges”. Psychopharmacology (Berl) 158:388–98.CrossRefGoogle Scholar
  31. Crow TJ. (2008). The emperors of the schizophrenia polygene have no clothes. Psychol Med 1–5.Google Scholar
  32. Darroch J. (1997). Biologic synergism and parallelism [see comments]. Am J Epidemiol 145:661–8.PubMedGoogle Scholar
  33. Dassa D, Sham PC, Van Os J, Abel K, Jones P, Murray RM. (1996). Relationship of birth season to clinical features, family history, and obstetric complication in schizophrenia. Psychiatry Res 64:11–7.PubMedCrossRefGoogle Scholar
  34. Davey Smith G, Ebrahim S. (2005). What can mendelian randomisation tell us about modifiable behavioural and environmental exposures? BMJ 330:1076–9.PubMedCrossRefGoogle Scholar
  35. Davis JO, Phelps JA. (1995). Twins with schizophrenia: genes or germs? Schizophr Bull 21:13–8.PubMedGoogle Scholar
  36. EU-GEI. (2008). European Network of Schizophrenia Networks for the Study of Gene Environment Interactions. Schizophrenia aetiology: do gene–environment interactions hold the key? Schizophr Res 102:21–6.Google Scholar
  37. Fanous A, Gardner C, Walsh D, Kendler KS. (2001). Relationship between positive and negative symptoms of schizophrenia and schizotypal symptoms in nonpsychotic relatives. Arch Gen Psychiatry 58:669–673.PubMedCrossRefGoogle Scholar
  38. Featherstone RE, Kapur S, Fletcher PJ. (2007). The amphetamine-induced sensitized state as a model of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 31:1556–71.PubMedCrossRefGoogle Scholar
  39. Filbey FM, Toulopoulou T, Morris RG, McDonald C, Bramon E, Walshe M, Murray RM. (2008). Selective attention deficits reflect increased genetic vulnerability to schizophrenia. Schizophr Res 101:169–75.Google Scholar
  40. Fischer M. (1971). Psychoses in the offspring of schizophrenic monozygotic twins and their normal co-twins. Br J Psychiatry 118:43–52.PubMedCrossRefGoogle Scholar
  41. Flint J. (1992). Implications of genomic imprinting for psychiatric genetics. Psychol Med 22:5–10.PubMedCrossRefGoogle Scholar
  42. Freeman D, Slater M, Bebbington PE, Garety PA, Kuipers E, Fowler D, Met A, Read CM, Jordan J, Vinayagamoorthy V. (2003). Can virtual reality be used to investigate persecutory ideation? J Nerv Ment Dis 191:509–14.PubMedCrossRefGoogle Scholar
  43. Gottesman, II, Bertelsen A. (1989). Confirming unexpressed genotypes for schizophrenia. Risks in the offspring of Fischer’s Danish identical and fraternal discordant twins [see comments]. Arch Gen Psychiatry 46:867–72.PubMedGoogle Scholar
  44. Gottesman, II, Shields J. (1976). A critical review of recent adoption, twin, and family studies of schizophrenia: behavioral genetics perspectives. Schizophr Bull 2:360–401.PubMedGoogle Scholar
  45. Greenwood TA, Braff DL, Light GA, Cadenhead KS, Calkins ME, Dobie DJ, Freedman R, Green MF, Gur RE, Gur RC, Mintz J, Nuechterlein KH, Olincy A, Radant AD, Seidman LJ, Siever LJ, Silverman JM, Stone WS, Swerdlow NR, Tsuang DW, Tsuang MT, Turetsky BI, Schork NJ. (2007). Initial heritability analyses of endophenotypic measures for schizophrenia: the consortium on the genetics of schizophrenia. Arch Gen Psychiatry 64:1242–50.PubMedCrossRefGoogle Scholar
  46. Hall FS, Wilkinson LS, Humby T, Robbins TW. (1999). Maternal deprivation of neonatal rats produces enduring changes in dopamine function. Synapse 32:37–43.PubMedCrossRefGoogle Scholar
  47. Hamamura T, Fibiger HC. (1993). Enhanced stress-induced dopamine release in the prefrontal cortex of amphetamine-sensitized rats. Eur J Pharmacol 237:65–71.PubMedCrossRefGoogle Scholar
  48. Hamer D. (2002). Genetics. Rethinking behavior genetics. Science 298:71–2.PubMedCrossRefGoogle Scholar
  49. Hanssen M, Krabbendam L, Vollema M, Delespaul P, Van Os J. (2006). Evidence for instrument and family-specific variation of subclinical psychosis dimensions in the general population. J Abnorm Psychol 115:5–14.PubMedCrossRefGoogle Scholar
  50. Harrison PJ, Weinberger DR. (2005). Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 10:40–68; image 5.PubMedCrossRefGoogle Scholar
  51. Henquet C, Krabbendam L, Spauwen J, Kaplan C, Lieb R, Wittchen HU, van Os J. (2005). Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people. BMJ 330:11.PubMedCrossRefGoogle Scholar
  52. Henquet C, Rosa A, Krabbendam L, Papiol S, Fananas L, Drukker M, Ramaekers JG, van Os J. (2006). An experimental study of catechol-o-methyltransferase Val158Met moderation of delta-9-tetrahydrocannabinol-induced effects on psychosis and cognition. Neuropsychopharmacology 31:2748–57.PubMedCrossRefGoogle Scholar
  53. Hirvonen J, van Erp TG, Huttunen J, Aalto S, Nagren K, Huttunen M, Lonnqvist J, Kaprio J, Hietala J, Cannon TD. (2005). Increased caudate dopamine D2 receptor availability as a genetic marker for schizophrenia. Arch Gen Psychiatry 62:371–8.PubMedCrossRefGoogle Scholar
  54. Howes OD, McDonald C, Cannon M, Arseneault L, Boydell J, Murray RM. (2004). Pathways to schizophrenia: the impact of environmental factors. Int J Neuropsychopharmacol 7(Suppl 1):S7–S13.PubMedCrossRefGoogle Scholar
  55. Hutchinson G, Takei N, Fahy TA, Bhugra D, Gilvarry C, Moran P, Mallett R, Sham P, Leff J, Murray RM. (1996). Morbid risk of schizophrenia in first-degree relatives of white and African-Caribbean patients with psychosis. Br J Psychiatry 169:776–80.PubMedCrossRefGoogle Scholar
  56. Huttunen J, Heinimaa M, Svirskis T, Nyman M, Kajander J, Forsback S, Solin O, Ilonen T, Korkeila J, Ristkari T, McGlashan T, Salokangas RK, Hietala J. (2008). Striatal dopamine synthesis in first-degree relatives of patients with schizophrenia. Biol Psychiatry 63:114–7.PubMedCrossRefGoogle Scholar
  57. Jacobs N, Kenis G, Peeters F, Derom C, Vlietinck R, van Os J. (2006). Stress-related negative affectivity and genetically altered serotonin transporter function: evidence of synergism in shaping risk of depression. Arch Gen Psychiatry 63:989–96.PubMedCrossRefGoogle Scholar
  58. Jensen J, Willeit M, Zipursky RB, Savina I, Smith AJ, Menon M, Crawley AP, Kapur S. (2008). The formation of abnormal associations in schizophrenia: neural and behavioral evidence. Neuropsychopharmacology 33:473–9.PubMedCrossRefGoogle Scholar
  59. Juarez I, De La Cruz F, Zamudio S, Flores G. (2005). Cesarean plus anoxia at birth induces hyperresponsiveness to locomotor activity by dopamine D2 agonist. Synapse 58:236–42.PubMedCrossRefGoogle Scholar
  60. Juarez I, Silva-Gomez AB, Peralta F, Flores G. (2003). Anoxia at birth induced hyperresponsiveness to amphetamine and stress in postpubertal rats. Brain Res 992:281–7.PubMedCrossRefGoogle Scholar
  61. Kapur S. (2003). Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry 160:13–23.PubMedCrossRefGoogle Scholar
  62. Katan MB. (1986). Apolipoprotein E isoforms, serum cholesterol, and cancer. Lancet 1:507–8.PubMedCrossRefGoogle Scholar
  63. Kendler KS, Eaves LJ. (1986). Models for the joint effect of genotype and environment on liability to psychiatric illness. Am J Psychiatry 143:279–89.PubMedGoogle Scholar
  64. Kendler KS, Hewitt J. (1992). The structure of self-report schizotypy in twins. J Personal Disord 6:1–17.Google Scholar
  65. Kendler KS. (2005). “A gene for…”: the nature of gene action in psychiatric disorders. Am J Psychiatry 162:1243–52.PubMedCrossRefGoogle Scholar
  66. Kendler KS. (2006). Reflections on the relationship between psychiatric genetics and psychiatric nosology. Am J Psychiatry 163:1138–46.PubMedCrossRefGoogle Scholar
  67. Khoury MJ, Beaty TH, Cohen BH. (1993). Genetic Epidemiology. Oxford: Oxford University Press.Google Scholar
  68. Khoury MJ, Millikan R, Little J, Gwinn M. (2004). The emergence of epidemiology in the genomics age. Int J Epidemiol 33:936–44.PubMedCrossRefGoogle Scholar
  69. Kirkbride JB, Fearon P, Morgan C, Dazzan P, Morgan K, Tarrant J, Lloyd T, Holloway J, Hutchinson G, Leff JP, Mallett RM, Harrison GL, Murray RM, Jones PB. (2006). Heterogeneity in incidence rates of schizophrenia and other psychotic syndromes: findings from the 3-center AeSOP study. Arch Gen Psychiatry 63:250–8.PubMedCrossRefGoogle Scholar
  70. Kirkbride JB, Morgan C, Fearon P, Dazzan P, Murray RM, Jones PB. (2007). Neighbourhood-level effects on psychoses: re-examining the role of context. Psychol Med 37:1413–25.PubMedCrossRefGoogle Scholar
  71. Krabbendam L, van Os J. (2005). Schizophrenia and urbanicity: a major environmental influence – conditional on genetic risk. Schizophr Bull 31:795–9.PubMedCrossRefGoogle Scholar
  72. Kringlen E, Cramer G. (1989). Offspring of monozygotic twins discordant for schizophrenia. Arch Gen Psychiatry 46:873–7.PubMedGoogle Scholar
  73. Kunugi H, Nanko S, Takei N, Saito K, Murray RM, Hirose T. (1996). Perinatal complications and schizophrenia. Data from the Maternal and Child Health Handbook in Japan. J Nerv Ment Dis 184:542–6.PubMedCrossRefGoogle Scholar
  74. Lake SL, Lyon H, Tantisira K, Silverman EK, Weiss ST, Laird NM, Schaid DJ. (2003). Estimation and tests of haplotype–environment interaction when linkage phase is ambiguous. Hum Hered 55:56–65.PubMedCrossRefGoogle Scholar
  75. Lange C, DeMeo D, Silverman EK, Weiss ST, Laird NM. (2004). PBAT: tools for family-based association studies. Am J Hum Genet 74:367–9.PubMedCrossRefGoogle Scholar
  76. Li N, Stephens M. (2003). Modeling linkage disequilibrium and identifying recombination hotspots using single-nucleotide polymorphism data. Genetics 165:2213–33.PubMedGoogle Scholar
  77. Linney YM, Murray RM, Peters ER, MacDonald AM, Rijsdijk F, Sham PC. (2003). A quantitative genetic analysis of schizotypal personality traits. Psychol Med 33:803–16.PubMedCrossRefGoogle Scholar
  78. MacDonald AW, Pogue-Geile MF, Debski TT, Manuck S. (2001). Genetic and environmental influences on schizotypy: a community-based twin study. Schizophr Bull 27:47–58.PubMedGoogle Scholar
  79. Malaspina D, Harlap S, Fennig S, Heiman D, Nahon D, Feldman D, Susser ES. (2001). Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry 58:361–7.PubMedCrossRefGoogle Scholar
  80. Marcelis M, Suckling J, Woodruff P, Hofman P, Bullmore E, van Os J. (2003). Searching for a structural endophenotype in psychosis using computational morphometry. Psychiatry Res 122:153–67.PubMedCrossRefGoogle Scholar
  81. Marcelis M, Van Os J, Sham P, Jones P, Gilvarry C, Cannon M, McKenzie K, Murray R. (1998). Obstetric complications and familial morbid risk of psychiatric disorders. Am J Med Genet 81:29–36.PubMedCrossRefGoogle Scholar
  82. McGrath J, Saha S, Welham J, El Saadi O, MacCauley C, Chant D. (2004). 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.PubMedCrossRefGoogle Scholar
  83. Meaney MJ, Szyf M. (2005). Environmental programming of stress responses through DNA methylation: life at the interface between a dynamic environment and a fixed genome. Dialogues Clin Neurosci 7:103–23.PubMedGoogle Scholar
  84. Meyer U, Nyffeler M, Schwendener S, Knuesel I, Yee BK, Feldon J. (2008). Relative prenatal and postnatal maternal contributions to schizophrenia-related neurochemical dysfunction after in utero immune challenge. Neuropsychopharmacology 33:441–56.PubMedCrossRefGoogle Scholar
  85. Meyer-Lindenberg A, Kohn PD, Kolachana B, Kippenhan S, McInerney-Leo A, Nussbaum R, Weinberger DR, Berman KF. (2005). Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype. Nat Neurosci 8:594–6.PubMedCrossRefGoogle Scholar
  86. Meyer-Lindenberg A, Miletich RS, Kohn PD, Esposito G, Carson RE, Quarantelli M, Weinberger DR, Berman KF. (2002). Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci 5:267–71.PubMedCrossRefGoogle Scholar
  87. Meyer-Lindenberg A, Nichols T, Callicott JH, Ding J, Kolachana B, Buckholtz J, Mattay VS, Egan M, Weinberger DR. (2006). Impact of complex genetic variation in COMT on human brain function. Mol Psychiatry 11:867–77, 797.PubMedCrossRefGoogle Scholar
  88. Moffitt TE, Caspi A, Rutter M. (2005). Strategy for investigating interactions between measured genes and measured environments. Arch Gen Psychiatry 62:473–81.PubMedCrossRefGoogle Scholar
  89. Mortensen PB, Pedersen CB, Westergaard T, Wohlfahrt J, Ewald H, Mors O, Andersen PK, Melbye M. (1999). Effects of family history and place and season of birth on the risk of schizophrenia [see comments]. N Engl J Med 340:603–8.PubMedCrossRefGoogle Scholar
  90. Motulsky AG. (1977). Ecogenetics: genetic variation in susceptibility to environmental agents. In: Armendares S, Lisker R. (eds.), Human Genetics. Amsterdam, Excerpta Medica, pp. 375–85.Google Scholar
  91. Murray GK, Corlett PR, Clark L, Pessiglione M, Blackwell AD, Honey G, Jones PB, Bullmore ET, Robbins TW, Fletcher PC. (2008). How dopamine dysregulation leads to psychotic symptoms? Abnormal mesolimbic and mesostriatal prediction error signalling in psychosis. Mol Psychiatry 13:239.PubMedCrossRefGoogle Scholar
  92. Myin-Germeys I, Marcelis M, Krabbendam L, Delespaul P, van Os J. (2005). Subtle fluctuations in psychotic phenomena as functional states of abnormal dopamine reactivity in individuals at risk. Biol Psychiatry 58:105–10.PubMedCrossRefGoogle Scholar
  93. Myin-Germeys I, Van Os J, Schwartz JE, Stone AA, Delespaul PA. (2001). Emotional reactivity to daily life stress in psychosis. Arch Gen Psychiatry 58:1137–44.PubMedCrossRefGoogle Scholar
  94. Nicodemus KK, Marenco S, Batten AJ, Vakkalanka R, Egan MF, Straub RE, Weinberger DR. (2008). Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk. Mol Psychiatry 13:873–7.Google Scholar
  95. Nikulina EM, Covington HE, 3rd, Ganschow L, Hammer RP, Jr, Miczek KA. (2004). Long-term behavioral and neuronal cross-sensitization to amphetamine induced by repeated brief social defeat stress: Fos in the ventral tegmental area and amygdala. Neuroscience 123:857–65.PubMedCrossRefGoogle Scholar
  96. Nimgaonkar VL, Wessely S, Murray RM. (1988). Prevalence of familiality, obstetric complications, and structural brain damage in schizophrenic patients. Br J Psychiatry 153:191–7.PubMedCrossRefGoogle Scholar
  97. Norton N, Williams HJ, Owen MJ. (2006). An update on the genetics of schizophrenia. Curr Opin Psychiatry 19:158–64.PubMedCrossRefGoogle Scholar
  98. O’Callaghan E, Gibson T, Colohan HA, Buckley P, Walshe DG, Larkin C, Waddington JL. (1992). Risk of schizophrenia in adults born after obstetric complications and their association with early onset of illness: a controlled study [see comments]. BMJ 305:1256–9.PubMedCrossRefGoogle Scholar
  99. O’Donovan MC, Craddock N, Owen MJ. (2008). Schizophrenia: complex genetics, not fairy tales. Psychol Med 1–3.Google Scholar
  100. Ottman R. (1990). An epidemiologic approach to gene–environment interaction. Genet Epidemiol 7:177–85.PubMedCrossRefGoogle Scholar
  101. Ottman R. (1996). Gene–environment interaction: definitions and study designs. Prev Med 25:764–70.PubMedCrossRefGoogle Scholar
  102. Ozawa K, Hashimoto K, Kishimoto T, Shimizu E, Ishikura H, Iyo M. (2006). Immune activation during pregnancy in mice leads to dopaminergic hyperfunction and cognitive impairment in the offspring: a neurodevelopmental animal model of schizophrenia. Biol Psychiatry 59:546–54.PubMedCrossRefGoogle Scholar
  103. Pedersen CB, Mortensen PB. (2001). Evidence of a dose–response relationship between urbanicity during upbringing and schizophrenia risk. Arch Gen Psychiatry 58:1039–46.PubMedCrossRefGoogle Scholar
  104. Pedersen CB, Mortensen PB. (2006). Are the cause(s) responsible for urban–rural differences in schizophrenia risk rooted in families or in individuals? Am J Epidemiol 163:971–8.PubMedCrossRefGoogle Scholar
  105. Plomin R, DeFries JC, Loehlin JC. (1977). Genotype–environment interaction and correlation in the analysis of human behavior. Psychol Bull 84:309–22.PubMedCrossRefGoogle Scholar
  106. Pulver AE, Liang KY, Brown CH, Wolyniec P, McGrath J, Adler L, Tam D, Carpenter WT, Childs B. (1992). Risk factors in schizophrenia. Season of birth, gender, and familial risk [see comments]. Br J Psychiatry 160:65–71.PubMedCrossRefGoogle Scholar
  107. Read J, van Os J, Morrison AP, Ross CA. (2005). Childhood trauma, psychosis and schizophrenia: a literature review with theoretical and clinical implications. Acta Psychiatr Scand 112:330–50.PubMedCrossRefGoogle Scholar
  108. Rutter M, Moffitt TE, Caspi A. (2006). Gene–environment interplay and psychopathology: multiple varieties but real effects. J Child Psychol Psychiatry 47:226–61.PubMedCrossRefGoogle Scholar
  109. Rutter M. (2005). How the environment affects mental health. Br J Psychiatry 186:4–6.PubMedCrossRefGoogle Scholar
  110. Rutter M. (2006). Genes and Behaviour: Nature-Nurture Interplay Explained. Malden, MA, USA: Blackwell Publishing.Google Scholar
  111. Schmidt-Kastner R, van Os J, Steinbusch HWMS, Schmitz C. (2006). Gene regulation by hypoxia and the neurodevelopmental origin of schizophrenia. Schizophr Res 84:253–71.PubMedCrossRefGoogle Scholar
  112. Schurhoff F, Szoke A, Chevalier F, Roy I, Meary A, Bellivier F, Giros B, Leboyer M. (2007). Schizotypal dimensions: an intermediate phenotype associated with the COMT high activity allele. Am J Med Genet B Neuropsychiatr Genet 144:64–8.Google Scholar
  113. Schurhoff F, Szoke A, Meary A, Bellivier F, Rouillon F, Pauls D, Leboyer M. (2003). Familial aggregation of delusional proneness in schizophrenia and bipolar pedigrees. Am J Psychiatry 160:1313–9.PubMedCrossRefGoogle Scholar
  114. Selten JP, Cantor-Graae E, Kahn RS. (2007). Migration and schizophrenia. Curr Opin Psychiatry 20:111–5.PubMedCrossRefGoogle Scholar
  115. Sham P. (1996). Genetic epidemiology. Br Med Bull 52:408–33.PubMedGoogle Scholar
  116. Shur E. (1982). Season of birth in high and low genetic risk schizophrenics. Br J Psychiatry 140:410–5.PubMedCrossRefGoogle Scholar
  117. Sipos A, Rasmussen F, Harrison G, Tynelius P, Lewis G, Leon DA, Gunnell D. (2004). Paternal age and schizophrenia: a population based cohort study. BMJ 329:1070.PubMedCrossRefGoogle Scholar
  118. Smits L, Pedersen C, Mortensen P, Van Os J. (2004). Association between short birth intervals and schizophrenia in the offspring. Schizophr Res 70:49–56.PubMedCrossRefGoogle Scholar
  119. Spauwen J, Krabbendam L, Lieb R, Wittchen HU, Van Os J. (2006a). Evidence that the outcome of developmental expression of psychosis is worse for adolescents growing up in an urban environment. Psychol Med 407–15.Google Scholar
  120. Spauwen J, Krabbendam L, Lieb R, Wittchen HU, van Os J. (2006b). Impact of psychological trauma on the development of psychotic symptoms: relationship with psychosis proneness. Br J Psychiatry 188:527–33.Google Scholar
  121. Stefanis NC, Henquet C, Avramopoulos D, Smyrnis N, Evdokimidis I, Myin-Germeys I, Stefanis CN, Van Os J. (2007). COMT Val158Met moderation of stress-induced psychosis. Psychol Med 37:1651–6.PubMedCrossRefGoogle Scholar
  122. Stefanis NC, Van Os J, Avramopoulos D, Smyrnis N, Evdokimidis I, Hantoumi I, Stefanis CN. (2004). Variation in catechol-o-methyltransferase val158 met genotype associated with schizotypy but not cognition: a population study in 543 young men. Biol Psychiatry 56:510–5.PubMedCrossRefGoogle Scholar
  123. Sugarman PA, Craufurd D. (1994). Schizophrenia in the Afro-Caribbean community. Br J Psychiatry 164:474–80.PubMedCrossRefGoogle Scholar
  124. Sullivan PF. (2008). The dice are rolling for schizophrenia genetics. Psychol Med 1–4.Google Scholar
  125. Susser E, Neugebauer R, Hoek HW, Brown AS, Lin S, Labovitz D, Gorman JM. (1996). Schizophrenia after prenatal famine. Further evidence [see comments]. Arch Gen Psychiatry 53:25–31.PubMedGoogle Scholar
  126. Susser E, Susser M. (1989). Familial aggregation studies. A note on their epidemiologic properties. Am J Epidemiol 129:23–30.PubMedGoogle Scholar
  127. Talkowski ME, Kirov G, Bamne M, Georgieva L, Torres G, Mansour H, Chowdari KV, Milanova V, Wood J, McClain L, Prasad K, Shirts B, Zhang J, O’Donovan MC, Owen MJ, Devlin B, Nimgaonkar VL. (2008). A network of dopaminergic gene variations implicated as risk factors for schizophrenia. Hum Mol Genet 17:747–58.PubMedCrossRefGoogle Scholar
  128. Tenn CC, Fletcher PJ, Kapur S. (2005). A putative animal model of the “prodromal” state of schizophrenia. Biol Psychiatry 57:586–93.PubMedCrossRefGoogle Scholar
  129. Tidey JW, Miczek KA. (1996). Social defeat stress selectively alters medocorticolimbic release: an in vivo microdialysis study. Brain Research 721:140–9.PubMedCrossRefGoogle Scholar
  130. Tienari P, Wynne LC, Moring J, Lahti I, Naarala M, Sorri A, Wahlberg KE, Saarento O, Seitamaa M, Kaleva M, et al. (1994). The Finnish adoptive family study of schizophrenia. Implications for family research [see comments]. Br J Psychiatry Suppl:20–6.Google Scholar
  131. Tienari P, Wynne LC, Sorri A, Lahti I, Laksy K, Moring J, Naarala M, Nieminen P, Wahlberg KE. (2004). Genotype–environment interaction in schizophrenia-spectrum disorder. Long-term follow-up study of Finnish adoptees. Br J Psychiatry 184:216–22.PubMedCrossRefGoogle Scholar
  132. Toulopoulou T, Picchioni M, Rijsdijk F, Hua-Hall M, Ettinger U, Sham P, Murray R. (2007). Substantial genetic overlap between neurocognition and schizophrenia: genetic modeling in twin samples. Arch Gen Psychiatry 64:1348–55.PubMedCrossRefGoogle Scholar
  133. van Haren NE, Bakker SC, Kahn RS. (2008). Genes and structural brain imaging in schizophrenia. Curr Opin Psychiatry 21:161–7.PubMedCrossRefGoogle Scholar
  134. Van Os J, Fahy TA, Bebbington P, Jones P, Wilkins S, Sham P, Russell A, Gilvarry K, Lewis S, Toone B, et al. (1994). The influence of life events on the subsequent course of psychotic illness. A prospective follow-up of the Camberwell Collaborative Psychosis Study. Psychol Med 24:503–13.PubMedCrossRefGoogle Scholar
  135. Van Os J, Hanssen M, Bak M, Bijl RV, Vollebergh W. (2003). Do urbanicity and familial liability coparticipate in causing psychosis? Am J Psychiatry 160:477–82.PubMedCrossRefGoogle Scholar
  136. Van Os J, Hanssen M, Bijl R-V, Ravelli A. (2000). Straus (1969) revisited: a psychosis continuum in the general population? Schizophr Res 45:11–20.PubMedCrossRefGoogle Scholar
  137. van Os J, Henquet C, Stefanis N. (2005). Cannabis-related psychosis and the gene–environment interaction: comments on Ferdinand et al. 2005. Addiction 100:874–5.PubMedCrossRefGoogle Scholar
  138. Van Os J, Krabbendam L, Myin-Germeys I, Delespaul P. (2005). The schizophrenia envirome. Curr Opin Psychiatry 18:141–5.PubMedCrossRefGoogle Scholar
  139. Van Os J, Marcelis M. (1998). The ecogenetics of schizophrenia: a review. Schizophr Res 32:127–35.PubMedCrossRefGoogle Scholar
  140. van Os J, Pedersen CB, Mortensen PB. (2004). Confirmation of synergy between urbanicity and familial liability in the causation of psychosis. Am J Psychiatry 161:2312–4.PubMedCrossRefGoogle Scholar
  141. Van Os J, Sham P. (2003). Gene–environment interactions. In: Murray RM, Jones PB, Susser E, Van Os J, Cannon M. (eds.), The Epidemiology of Schizophrenia. Cambridge, Cambridge University Press, pp. 235–54.Google Scholar
  142. Van Os J. (2004). Does the urban environment cause psychosis? Br J Psychiatry 184:287–8.PubMedCrossRefGoogle Scholar
  143. van Os J. (2005). Commentary on residential location papers by Whitfield et al. (2005) and Willemsen et al. (2005). Twin Res Hum Genet 8:318–9.PubMedCrossRefGoogle Scholar
  144. Venerosi A, Valanzano A, Cirulli F, Alleva E, Calamandrei G. (2004). Acute global anoxia during C-section birth affects dopamine-mediated behavioural responses and reactivity to stress. Behav Brain Res 154:155–64.PubMedCrossRefGoogle Scholar
  145. Verdoux H, Gindre C, Sorbara F, Tournier M, Swendsen JD. (2003). Effects of cannabis and psychosis vulnerability in daily life: an experience sampling test study. Psychol Med 33:23–32.PubMedCrossRefGoogle Scholar
  146. Verdoux H, Van Os J, Sham P, Jones P, Gilvarry K, Murray R. (1996). Does familiality predispose to both emergence and persistence of psychosis? A follow-up study. Br J Psychiatry 168:620–6.PubMedCrossRefGoogle Scholar
  147. Vollema MG, Sitskoorn MM, Appels MC, Kahn RS. (2002). Does the Schizotypal Personality Questionnaire reflect the biological-genetic vulnerability to schizophrenia? Schizophr Res 54:39–45.PubMedCrossRefGoogle Scholar
  148. Wahlberg KE, Wynne LC, Hakko H, Laksy K, Moring J, Miettunen J, Tienari P. (2004). Interaction of genetic risk and adoptive parent communication deviance: longitudinal prediction of adoptee psychiatric disorders. Psychol Med 34:1531–41.PubMedCrossRefGoogle Scholar
  149. Wahlberg KE, Wynne LC, Oja H, Keskitalo P, Pykalainen L, Lahti I, Moring J, Naarala M, Sorri A, Seitamaa M, Laksy K, Kolassa J, Tienari P. (1997). Gene–environment interaction in vulnerability to schizophrenia: findings from the Finnish Adoptive Family Study of Schizophrenia. Am J Psychiatry 154:355–62.PubMedGoogle Scholar
  150. Walker E. (1981). Attentional and neuromotor functions of schizophrenics, schizoaffectives, and patients with other affective disorders. Arch Gen Psychiatry 38:1355–8.PubMedGoogle Scholar
  151. Weaver IC, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR, Dymov S, Szyf M, Meaney MJ. (2004). Epigenetic programming by maternal behavior. Nat Neurosci 7:847–54.PubMedCrossRefGoogle Scholar
  152. Weiser M, van Os J, Reichenberg A, Rabinowitz J, Nahon D, Kravitz E, Lubin G, Shmushkevitz M, Knobler HY, Noy S, Davidson M. (2007). Social and cognitive functioning, urbanicity and risk for schizophrenia. Br J Psychiatry 191:320–4.PubMedCrossRefGoogle Scholar
  153. Weisfeld GE, Weisfeld CC. (2002). Marriage: an evolutionary perspective. Neuro Endocrinol Lett 23(Suppl 4):47–54.PubMedGoogle Scholar
  154. Wellman CL, Izquierdo A, Garrett JE, Martin KP, Carroll J, Millstein R, Lesch KP, Murphy DL, Holmes A. (2007). Impaired stress-coping and fear extinction and abnormal corticolimbic morphology in serotonin transporter knock-out mice. J Neurosci 27:684–91.PubMedCrossRefGoogle Scholar
  155. Whitfield JB, Zhu G, Heath AC, Martin NG. (2005). Choice of residential location: chance, family influences, or genes? Twin Res Hum Genet 8:22–6.PubMedCrossRefGoogle Scholar
  156. Wichers M, Myin-Germeys I, Jacobs N, Peeters F, Kenis G, Derom C, Vlietinck R, Delespaul P, Van Os J. (2007a). Genetic risk of depression and stress-induced negative affect in daily life. Br J Psychiatry 191:218–23.Google Scholar
  157. Wichers MC, Myin-Germeys I, Jacobs N, Peeters F, Kenis G, Derom C, Vlietinck R, Delespaul P, van Os J. (2007b). Evidence that moment-to-moment variation in positive emotions buffer genetic risk for depression: a momentary assessment twin study. Acta Psychiatr Scand 115:451–7.Google Scholar
  158. Wilkinson LS, Davies W, Isles AR. (2007). Genomic imprinting effects on brain development and function. Nat Rev Neurosci 8:832–43.PubMedCrossRefGoogle Scholar
  159. Willemsen G, Posthuma D, Boomsma DI. (2005). Environmental factors determine where the Dutch live: results from the Netherlands twin register. Twin Res Hum Genet 8:312–7.PubMedCrossRefGoogle Scholar
  160. Wong MY, Day NE, Luan JA, Chan KP, Wareham NJ. (2003). The detection of gene–environment interaction for continuous traits: should we deal with measurement error by bigger studies or better measurement? Int J Epidemiol 32:51–7.PubMedCrossRefGoogle Scholar
  161. Yui K, Goto K, Ikemoto S, Ishiguro T. (2000). Stress induced spontaneous recurrence of methamphetamine psychosis: the relation between stressful experiences and sensitivity to stress. Drug Alcohol Depend 58:67–75.PubMedCrossRefGoogle Scholar
  162. Zammit S, Allebeck P, Dalman C, Lundberg I, Hemmingson T, Owen MJ, Lewis G. (2003). Paternal age and risk for schizophrenia. Br J Psychiatry 183:405–8.PubMedCrossRefGoogle Scholar
  163. Zammit S, Lewis S, Gunnell D, Smith GD. (2007). Schizophrenia and neural tube defects: comparisons from an epidemiological perspective. Schizophr Bull 33:853–8.PubMedCrossRefGoogle Scholar
  164. Zinkstok J, van Nimwegen L, van Amelsvoort T, de Haan L, Yusuf MA, Baas F, Linszen D. (2008). Catechol-O-methyltransferase gene and obsessive-compulsive symptoms in patients with recent-onset schizophrenia: preliminary results. Psychiatry Res 157:1–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Jim van Os
    • 1
    • 2
  • Bart P.F. Rutten
    • 1
  • Richie Poulton
    • 3
  1. 1.Department of Psychiatry and NeuropsychologySchool of Mental Health and Neuroscience, Maastricht University Medical Centre, EURON, SEARCHMaastrichtThe Netherlands
  2. 2.Division of Psychological MedicineInstitute of PsychiatryLondonUK
  3. 3.Dunedin Multidisciplinary Health & Development Research Unit, Department of Preventive and Social MedicineDunedin School of Medicine, University of OtagoDunedinNew Zealand

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