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Epigenetic Epidemiology of Psychiatric Disorders

  • Bart P. F. RuttenEmail author
  • Jim van Os
Chapter

Abstract

Exciting developments in the field of epigenetics have generated great interest within psychiatric epidemiology to focus on direct and indirect evidence for epigenetic involvement in behavior, mental health, and complex psychiatric disorders. Epidemiologic evidence on epigenetics in psychiatry, however, is currently very sparsely available. With the aim to address the current status of the literature on evidence indicative of involvement of epigenetic mechanisms in psychiatric disorders, we describe a clear role for epigenetic mechanisms in development and aging of the brain, with experiences and environmental exposures particularly during early life having considerable impact on the development of functional abilities of the brain. Besides the psychiatric consequences of classical syndromes of genetic imprinting in humans, findings of twin discordance, parent-of-origin effects, paternal age effects, and sex differences in psychiatric disorders suggest epigenetic involvement in the etiology of psychiatric disorders. The evidence is further strengthened by observations of endurable effects of various environmental exposures during life on risk of psychiatric disorders, and preliminary epigenetic studies showing differential epigenetic profiles in patients with several psychiatric disorders. Findings of these first (and preliminary) epigenetic studies should be interpreted with caution because of small samples sizes, lack of replication, limitations in the etiologic validity of psychiatric diagnoses, and in accessibility of the regions and cell types of the brain at “appropriate” periods during life. Despite the sparse availability, the current evidence for epigenetic involvement in (particularly early) brain development, mental health, and psychiatric disorders appears very promising, and may be used in bringing together inherited and acquired risk factors into a neurodevelopmental etiological model of psychiatric disorders with epigenetics as a plausible key mediating mechanism. Given the dynamic nature of epigenetic regulation of gene expression and the potential reversibility of epigenetic modifications, future well-designed multidisciplinary and translational studies will be of key importance in order to identify new targets for prevention and therapeutic strategies.

Keywords

Attention Deficit Hyperactivity Disorder Psychiatric Disorder Epigenetic Mechanism Angelman Syndrome Social Defeat Stress 
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.

Abbreviations

5-mC

5-methyl cytidine

AD

Alzheimer’s disease

ADHD

Attention deficit hyperactivity disorder

AKT1

v-akt murine thymoma viral oncogene homolog 1

APOE

Apolipoprotein E

APP

Amyloid precursor protein

BDNF

Brain derived neurotrophic factor

CB1

Cannabis-1

CDH1

Cadherin 1

Cdk5

Cyclin-dependent kinase 5

COMT

Catechol-O-methyltransferase

DC-MZ

Dichorionic monozygotic

DNMT

DNA methyl transferase

DRD2

Dopamine D2 receptor

DSM-IV

Diagnostic and Statistical Manual of Mental Disorders 4th edition

DZ

Dizygotic

GABA

Gamma-aminobutyric acid

GAD

Glutamic-acid decarboxylase

H4K12

Histone H4 lysine 12

H4K16

Histone H4 lysine 16

HIST1H2AG

Histone cluster 1, H2ag

HIST1H2AH

Histone cluster 1, H2ah

HIST1H2BJ

Histone cluster 1, H2bj

HIST1H2BK

Histone cluster 1, H2bk

HIST1H4I

Histone cluster 1, H4i

HTERT

Telomerase reverse transcriptase

MAPT

Microtubule-associated protein tau

MC-MZ

Monochorionic monozygotic

MeCP2

Methyl CpG binding protein 2

MS

Multiple sclerosis

MTHFR

Methylenetetrahydrofolate reductase

MZ

Monozygotic

NPAS3

Neuronal PAS domain protein 3

NR3C1

Glucocorticoid receptor

OCM

One-carbon metabolism

PBCs

Pregnancy and birth complications

PCR

Polymerase chain reaction

PPIEL

Peptidylprolyl isomerae E-like

PSEN1

Presenilin 1

PTSD

Post-traumatic stress disorder

RELN

Reelin

SIRT3

Sirtuin 3

SMARCA5

SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 5

SMS

Spermine synthase

SNP

Single nucleotide polymorphism

THC

Δ9-tetrahydrocannabinol

TRKB

Neurotrophic tyrosine kinase, receptor, type 2

UBE3A

Ubiquitin protein ligase E3A

WHO

World Health Organization

References

  1. 1.
    Epigenetics MG (2010) The seductive allure of behavioral epigenetics. Science 329:24–27CrossRefGoogle Scholar
  2. 2.
    Petronis A (2010) Epigenetics as a unifying principle in the aetiology of complex traits and diseases. Nature 465:721–727PubMedCrossRefGoogle Scholar
  3. 3.
    Feinberg AP (2007) Phenotypic plasticity and the epigenetics of human disease. Nature 447:433–440PubMedCrossRefGoogle Scholar
  4. 4.
    Weaver JR, Susiarjo M, Bartolomei MS (2009) Imprinting and epigenetic changes in the early embryo. Mamm Genome 20:532–543PubMedCrossRefGoogle Scholar
  5. 5.
    Hsieh J, Eisch AJ (2010) Epigenetics, hippocampal neurogenesis, and neuropsychiatric disorders: unraveling the genome to understand the mind. Neurobiol Dis 39:73–84PubMedCrossRefGoogle Scholar
  6. 6.
    Yu Y, Casaccia P, Lu QR (2010) Shaping the oligodendrocyte identity by epigenetic control. Epigenetics 5:124–128PubMedCrossRefGoogle Scholar
  7. 7.
    Hsieh J, Gage FH (2005) Chromatin remodeling in neural development and plasticity. Curr Opin Cell Biol 17:664–671PubMedCrossRefGoogle Scholar
  8. 8.
    Levenson JM, Sweatt JD (2006) Epigenetic mechanisms: a common theme in vertebrate and invertebrate memory formation. Cell Mol Life Sci 63:1009–1016PubMedCrossRefGoogle Scholar
  9. 9.
    Renthal W, Nestler EJ (2008) Epigenetic mechanisms in drug addiction. Trends Mol Med 14:341–350PubMedCrossRefGoogle Scholar
  10. 10.
    Day JJ, Sweatt JD (2010) DNA methylation and memory formation. Nat Neurosci 13:1319–1323PubMedCrossRefGoogle Scholar
  11. 11.
    Feng J, Zhou Y, Campbell SL, Le T, Li E, Sweatt JD et al (2010) Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat Neurosci 13:423–430PubMedCrossRefGoogle Scholar
  12. 12.
    Flavell SW, Greenberg ME (2008) Signaling mechanisms linking neuronal activity to gene expression and plasticity of the nervous system. Annu Rev Neurosci 31:563–590PubMedCrossRefGoogle Scholar
  13. 13.
    MacDonald JL, Roskams AJ (2009) Epigenetic regulation of nervous system development by DNA methylation and histone deacetylation. Prog Neurobiol 88:170–183PubMedCrossRefGoogle Scholar
  14. 14.
    Bale TL, Baram TZ, Brown AS, Goldstein JM, Insel TR, McCarthy MM et al (2010) Early life programming and neurodevelopmental disorders. Biol Psychiatry 68:314–319PubMedCrossRefGoogle Scholar
  15. 15.
    Fraga MF, Esteller M (2007) Epigenetics and aging: the targets and the marks. Trends Genet 23:413–418PubMedCrossRefGoogle Scholar
  16. 16.
    Chouliaras L, Rutten BP, Kenis G, Peerbooms O, Visser PJ, Verhey F et al (2010) Epigenetic regulation in the pathophysiology of Alzheimer’s disease. Prog Neurobiol 90:498–510PubMedCrossRefGoogle Scholar
  17. 17.
    Christensen BC, Houseman EA, Marsit CJ, Zheng S, Wrensch MR, Wiemels JL et al (2009) Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context. PLoS Genet 5:e1000602PubMedCrossRefGoogle Scholar
  18. 18.
    Hernandez DG, Nalls MA, Gibbs JR, Arepalli S, van der Brug M, Chong S et al (2011) Distinct DNA methylation changes highly correlated with chronological age in the human brain. Hum Mol Genet 20(6):1164–1172PubMedCrossRefGoogle Scholar
  19. 19.
    Chouliaras L, van den Hove DL, Kenis G, Cruz JD, Lemmens MA, van Os J et al (2011) Caloric restriction attenuates age-related changes of DNA methyltransferase 3a in mouse hippocampus. Brain Behav Immun 25(4):616–623PubMedCrossRefGoogle Scholar
  20. 20.
    Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM et al (2009) Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325:201–204PubMedCrossRefGoogle Scholar
  21. 21.
    Mattson MP, Duan W, Chan SL, Cheng A, Haughey N, Gary DS et al (2002) Neuroprotective and neurorestorative signal transduction mechanisms in brain aging: modification by genes, diet and behavior. Neurobiol Aging 23:695–705PubMedCrossRefGoogle Scholar
  22. 22.
    Sohal RS, Weindruch R (1996) Oxidative stress, caloric restriction, and aging. Science 273:59–63PubMedCrossRefGoogle Scholar
  23. 23.
    Rutten BP, Brasnjevic I, Steinbusch HW, Schmitz C (2010) Caloric restriction and aging but not overexpression of SOD1 affect hippocampal volumes in mice. Mech Ageing Dev 131:574–579PubMedCrossRefGoogle Scholar
  24. 24.
    Liu L, van Groen T, Kadish I, Tollefsbol TO (2009) DNA methylation impacts on learning and memory in aging. Neurobiol Aging 30:549–560PubMedCrossRefGoogle Scholar
  25. 25.
    Peleg S, Sananbenesi F, Zovoilis A, Burkhardt S, Bahari-Javan S, Agis-Balboa RC et al (2010) Altered histone acetylation is associated with age-dependent memory impairment in mice. Science 328:753–756PubMedCrossRefGoogle Scholar
  26. 26.
    Longo VD, Kennedy BK (2006) Sirtuins in aging and age-related disease. Cell 126:257–268PubMedCrossRefGoogle Scholar
  27. 27.
    Mehler MF (2008) Epigenetic principles and mechanisms underlying nervous system functions in health and disease. Prog Neurobiol 86:305–341PubMedCrossRefGoogle Scholar
  28. 28.
    Khan NL, Wood NW (1999) Prader-Willi and Angelman syndromes: update on genetic mechanisms and diagnostic complexities. Curr Opin Neurol 12:149–154PubMedCrossRefGoogle Scholar
  29. 29.
    Lalande M, Calciano MA (2007) Molecular epigenetics of Angelman syndrome. Cell Mol Life Sci 64:947–960PubMedCrossRefGoogle Scholar
  30. 30.
    Christodoulou J, Weaving LS (2003) MECP2 and beyond: phenotype-genotype correlations in Rett syndrome. J Child Neurol 18:669–674PubMedCrossRefGoogle Scholar
  31. 31.
    Dimitropoulos A, Schultz RT (2007) Autistic-like symptomatology in Prader-Willi syndrome: a review of recent findings. Curr Psychiatry Rep 9:159–164PubMedCrossRefGoogle Scholar
  32. 32.
    van Os J, Rutten BP, Poulton R (2008) Gene-environment interactions in schizophrenia: review of epidemiological findings and future directions. Schizophr Bull 34:1066–1082PubMedCrossRefGoogle Scholar
  33. 33.
    Petronis A, Gottesman II, Kan P, Kennedy JL, Basile VS, Paterson AD et al (2003) Monozygotic twins exhibit numerous epigenetic differences: clues to twin discordance? Schizophr Bull 29:169–178PubMedGoogle Scholar
  34. 34.
    Zwijnenburg PJ, Meijers-Heijboer H, Boomsma DI (2010) Identical but not the same: the value of discordant monozygotic twins in genetic research. Am J Med Genet B Neuropsychiatr Genet 153B:1134–1149PubMedGoogle Scholar
  35. 35.
    Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML et al (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 102:10604–10609PubMedCrossRefGoogle Scholar
  36. 36.
    Kaminsky ZA, Tang T, Wang SC, Ptak C, Oh GH, Wong AH et al (2009) DNA methylation profiles in monozygotic and dizygotic twins. Nat Genet 41:240–245PubMedCrossRefGoogle Scholar
  37. 37.
    Mill J, Dempster E, Caspi A, Williams B, Moffitt T, Craig I (2006) Evidence for monozygotic twin (MZ) discordance in methylation level at two CpG sites in the promoter region of the catechol-O-methyltransferase (COMT) gene. Am J Med Genet B Neuropsychiatr Genet 141:421–425Google Scholar
  38. 38.
    Kuratomi G, Iwamoto K, Bundo M, Kusumi I, Kato N, Iwata N et al (2008) Aberrant DNA methylation associated with bipolar disorder identified from discordant monozygotic twins. Mol Psychiatry 13:429–441PubMedCrossRefGoogle Scholar
  39. 39.
    Kaminsky Z, Petronis A, Wang SC, Levine B, Ghaffar O, Floden D et al (2008) Epigenetics of personality traits: an illustrative study of identical twins discordant for risk-taking behavior. Twin Res Hum Genet 11:1–11PubMedCrossRefGoogle Scholar
  40. 40.
    Baranzini SE, Mudge J, van Velkinburgh JC, Khankhanian P, Khrebtukova I, Miller NA et al (2010) Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis. Nature 464:1351–1356PubMedCrossRefGoogle Scholar
  41. 41.
    Rutten BP, Mill J (2009) Epigenetic mediation of environmental influences in major psychotic disorders. Schizophr Bull 35:1045–1056PubMedCrossRefGoogle Scholar
  42. 42.
    Jirtle RL, Skinner MK (2007) Environmental epigenomics and disease susceptibility. Nat Rev Genet 8:253–262PubMedCrossRefGoogle Scholar
  43. 43.
    Haque FN, Gottesman II, Wong AH (2009) Not really identical: epigenetic differences in monozygotic twins and implications for twin studies in psychiatry. Am J Med Genet C Semin Med Genet 151C:136–141PubMedCrossRefGoogle Scholar
  44. 44.
    Malaspina D, Perrin M, Kleinhaus KR, Opler M, Harlap S (2008) Growth and schizophrenia: aetiology, epidemiology and epigenetics. Novartis Found Symp 289:196–203, discussion 203–197, 238–140PubMedCrossRefGoogle Scholar
  45. 45.
    Delahanty RJ, Kang JQ, Brune CW, Kistner EO, Courchesne E, Cox NJ et al (2011) Maternal transmission of a rare GABRB3 signal peptide variant is associated with autism. Mol Psychiatry 16(1):86–96PubMedCrossRefGoogle Scholar
  46. 46.
    Anney RJ, Hawi Z, Sheehan K, Mulligan A, Pinto C, Brookes KJ et al (2008) Parent of origin effects in attention/deficit hyperactivity disorder (ADHD): analysis of data from the international multicenter ADHD genetics (IMAGE) program. Am J Med Genet B Neuropsychiatr Genet 147B:1495–1500PubMedCrossRefGoogle Scholar
  47. 47.
    De Luca V, Likhodi O, Kennedy JL, Wong AH (2007) Parent-of-origin effect and genomic imprinting of the HTR2A receptor gene T102C polymorphism in psychosis. Psychiatry Res 151:243–248PubMedCrossRefGoogle Scholar
  48. 48.
    De Luca V, Likhodi O, Kennedy JL, Wong AH (2007) Differential expression and parent-of-origin effect of the 5-HT2A receptor gene C102T polymorphism: analysis of suicidality in schizophrenia and bipolar disorder. Am J Med Genet B Neuropsychiatr Genet 144B:370–374PubMedCrossRefGoogle Scholar
  49. 49.
    Goos LM, Ezzatian P, Schachar R (2007) Parent-of-origin effects in attention-deficit hyperactivity disorder. Psychiatry Res 149:1–9PubMedCrossRefGoogle Scholar
  50. 50.
    Bassett SS, Avramopoulos D, Perry RT, Wiener H, Watson B Jr, Go RC et al (2006) Further evidence of a maternal parent-of-origin effect on chromosome 10 in late-onset Alzheimer’s disease. Am J Med Genet B Neuropsychiatr Genet 141B:537–540PubMedCrossRefGoogle Scholar
  51. 51.
    Perrin MC, Brown AS, Malaspina D (2007) Aberrant epigenetic regulation could explain the relationship of paternal age to schizophrenia. Schizophr Bull 33:1270–1273PubMedCrossRefGoogle Scholar
  52. 52.
    Grether JK, Anderson MC, Croen LA, Smith D, Windham GC (2009) Risk of autism and increasing maternal and paternal age in a large north American population. Am J Epidemiol 170:1118–1126PubMedCrossRefGoogle Scholar
  53. 53.
    Reichenberg A, Gross R, Sandin S, Susser ES (2010) Advancing paternal and maternal age are both important for autism risk. Am J Public Health 100:772–773, author reply 773PubMedCrossRefGoogle Scholar
  54. 54.
    Croen LA, Najjar DV, Fireman B, Grether JK (2007) Maternal and paternal age and risk of autism spectrum disorders. Arch Pediatr Adolesc Med 161:334–340PubMedCrossRefGoogle Scholar
  55. 55.
    Reichenberg A, Gross R, Weiser M, Bresnahan M, Silverman J, Harlap S et al (2006) Advancing paternal age and autism. Arch Gen Psychiatry 63:1026–1032PubMedCrossRefGoogle Scholar
  56. 56.
    Miller B, Messias E, Miettunen J, Alaräisänen A, Järvelin MR, Koponen H et al (2010) Meta-analysis of paternal age and schizophrenia risk in male versus female offspring. Schizophr Bull 2011 Sep 37(5):1039–1047Google Scholar
  57. 57.
    Saha S, Barnett AG, Foldi C, Burne TH, Eyles DW, Buka SL et al (2009) Advanced paternal age is associated with impaired neurocognitive outcomes during infancy and childhood. PLoS Med 6:e40PubMedCrossRefGoogle Scholar
  58. 58.
    Saha S, Barnett AG, Buka SL, McGrath JJ (2009) Maternal age and paternal age are associated with distinct childhood behavioural outcomes in a general population birth cohort. Schizophr Res 115:130–135PubMedCrossRefGoogle Scholar
  59. 59.
    Sherazi R, McKeon P, McDonough M, Daly I, Kennedy N (2006) What’s new? The clinical epidemiology of bipolar I disorder. Harv Rev Psychiatry 14:273–284PubMedCrossRefGoogle Scholar
  60. 60.
    Bijl RV, De Graaf R, Ravelli A, Smit F, Vollebergh WA (2002) Gender and age-specific first incidence of DSM-III-R psychiatric disorders in the general population. Results from the Netherlands Mental Health Survey and Incidence Study (NEMESIS). Soc Psychiatry Psychiatr Epidemiol 37:372–379PubMedCrossRefGoogle Scholar
  61. 61.
    Bijl RV, Ravelli A, van Zessen G (1998) Prevalence of psychiatric disorder in the general population: results of The Netherlands Mental Health Survey and Incidence Study (NEMESIS). Soc Psychiatry Psychiatr Epidemiol 33:587–595PubMedCrossRefGoogle Scholar
  62. 62.
    Wittchen HU, Stein MB, Kessler RC (1999) Social fears and social phobia in a community sample of adolescents and young adults: prevalence, risk factors and co-morbidity. Psychol Med 29:309–323PubMedCrossRefGoogle Scholar
  63. 63.
    Polanczyk G, Rohde LA (2007) Epidemiology of attention-deficit/hyperactivity disorder across the lifespan. Curr Opin Psychiatry 20:386–392PubMedCrossRefGoogle Scholar
  64. 64.
    Fombonne E (2009) Epidemiology of pervasive developmental disorders. Pediatr Res 65:591–598PubMedCrossRefGoogle Scholar
  65. 65.
    Fombonne E (1999) The epidemiology of autism: a review. Psychol Med 29:769–786PubMedCrossRefGoogle Scholar
  66. 66.
    Nelson CB, Wittchen HU (1998) DSM-IV alcohol disorders in a general population sample of adolescents and young adults. Addiction 93:1065–1077PubMedCrossRefGoogle Scholar
  67. 67.
    van Os J, Kapur S (2009) Schizophrenia. Lancet 374:635–645PubMedCrossRefGoogle Scholar
  68. 68.
    van Os J, Kenis G, Rutten BP (2010) The environment and schizophrenia. Nature 468:203–212PubMedCrossRefGoogle Scholar
  69. 69.
    McCarthy MM, Auger AP, Bale TL, De Vries GJ, Dunn GA, Forger NG et al (2009) The epigenetics of sex differences in the brain. J Neurosci 29:12815–12823PubMedCrossRefGoogle Scholar
  70. 70.
    Schwarz JM, Nugent BM, McCarthy MM (2010) Developmental and hormone-induced epigenetic changes to estrogen and progesterone receptor genes in brain are dynamic across the life span. Endocrinology 151:4871–4881PubMedCrossRefGoogle Scholar
  71. 71.
    Waggoner D (2007) Mechanisms of disease: epigenesis. Semin Pediatr Neurol 14:7–14PubMedCrossRefGoogle Scholar
  72. 72.
    Monteiro J, Derom C, Vlietinck R, Kohn N, Lesser M, Gregersen PK (1998) Commitment to X inactivation precedes the twinning event in monochorionic MZ twins. Am J Hum Genet 63:339–346PubMedCrossRefGoogle Scholar
  73. 73.
    Manning N (2008) The influence of twinning on cardiac development. Early Hum Dev 84:173–179PubMedCrossRefGoogle Scholar
  74. 74.
    Hall LL, Lawrence JB (2003) The cell biology of a novel chromosomal RNA: chromosome painting by XIST/Xist RNA initiates a remodeling cascade. Semin Cell Dev Biol 14:369–378PubMedCrossRefGoogle Scholar
  75. 75.
    Loat CS, Asbury K, Galsworthy MJ, Plomin R, Craig IW (2004) X inactivation as a source of behavioural differences in monozygotic female twins. Twin Res 7:54–61PubMedCrossRefGoogle Scholar
  76. 76.
    Peerbooms OL, Wichers M, Jacobs N, Kenis G, Derom C, Vlietinck R et al (2010) No major role for X-inactivation in variations of intelligence and behavioral problems at middle childhood. Am J Med Genet B Neuropsychiatr Genet 153B:1311–1317PubMedCrossRefGoogle Scholar
  77. 77.
    Rosa A, Picchioni MM, Kalidindi S, Loat CS, Knight J, Toulopoulou T et al (2008) Differential methylation of the X-chromosome is a possible source of discordance for bipolar disorder female monozygotic twins. Am J Med Genet B Neuropsychiatr Genet 147B:459–462PubMedCrossRefGoogle Scholar
  78. 78.
    Wichers M, Schrijvers D, Geschwind N, Jacobs N, Myin-Germeys I, Thiery E et al (2009) Mechanisms of gene-environment interactions in depression: evidence that genes potentiate multiple sources of adversity. Psychol Med 39:1077–1086PubMedCrossRefGoogle Scholar
  79. 79.
    Wichers MC, Purcell S, Danckaerts M, Derom C, Derom R, Vlietinck R et al (2002) Prenatal life and post-natal psychopathology: evidence for negative gene-birth weight interaction. Psychol Med 32:1165–1174PubMedCrossRefGoogle Scholar
  80. 80.
    Oh G, Petronis A (2008) Environmental studies of schizophrenia through the prism of epigenetics. Schizophr Bull 34:1122–1129PubMedCrossRefGoogle Scholar
  81. 81.
    Crow TJ (2007) How and why genetic linkage has not solved the problem of psychosis: review and hypothesis. Am J Psychiatry 164:13–21PubMedCrossRefGoogle Scholar
  82. 82.
    Wong AH, Gottesman II, Petronis A (2005) Phenotypic differences in genetically identical organisms: the epigenetic perspective. Hum Mol Genet 14(Spec No 1):R11–R18PubMedCrossRefGoogle Scholar
  83. 83.
    Khashan AS, Abel KM, McNamee R, Pedersen MG, Webb RT, Baker PN et al (2008) Higher risk of offspring schizophrenia following antenatal maternal exposure to severe adverse life events. Arch Gen Psychiatry 65:146–152PubMedCrossRefGoogle Scholar
  84. 84.
    Huttunen MO, Niskanen P (1978) Prenatal loss of father and psychiatric disorders. Arch Gen Psychiatry 35:429–431PubMedCrossRefGoogle Scholar
  85. 85.
    Van Os J, Selten J-P (1998) Prenatal exposure to maternal stress and subsequent schizophrenia: the May 1940 invasion of the Netherlands. Br J Psychiatry 172:324–326PubMedCrossRefGoogle Scholar
  86. 86.
    Susser E, Neugebauer R, Hoek HW, Brown AS, Lin S, Labovitz D et al (1996) Schizophrenia after prenatal famine. Further evidence. Arch Gen Psychiatry 53:25–31PubMedCrossRefGoogle Scholar
  87. 87.
    Xu MQ, Sun WS, Liu BX, Feng GY, Yu L, Yang L et al (2009) Prenatal malnutrition and adult schizophrenia: further evidence from the 1959–1961 Chinese famine. Schizophr Bull 35:568–576PubMedCrossRefGoogle Scholar
  88. 88.
    Insel BJ, Schaefer CA, McKeague IW, Susser ES, Brown AS (2008) Maternal iron deficiency and the risk of schizophrenia in offspring. Arch Gen Psychiatry 65:1136–1144PubMedCrossRefGoogle Scholar
  89. 89.
    Opler MG, Buka SL, Groeger J, McKeague I, Wei C, Factor-Litvak P et al (2008) Prenatal exposure to lead, delta-aminolevulinic acid, and schizophrenia: further evidence. Environ Health Perspect 116:1586–1590PubMedCrossRefGoogle Scholar
  90. 90.
    Brown AS, Bottiglieri T, Schaefer CA, Quesenberry CP Jr, Liu L, Bresnahan M et al (2007) Elevated prenatal homocysteine levels as a risk factor for schizophrenia. Arch Gen Psychiatry 64:31–39PubMedCrossRefGoogle Scholar
  91. 91.
    Hollister JM, Laing P, Mednick SA (1996) Rhesus incompatibility as a risk factor for schizophrenia in male adults. Arch Gen Psychiatry 53:19–24PubMedCrossRefGoogle Scholar
  92. 92.
    McGrath JJ, Eyles DW, Pedersen CB, Anderson C, Ko P, Burne TH et al (2010) Neonatal vitamin D status and risk of schizophrenia: a population-based case-control study. Arch Gen Psychiatry 67(9):889–894PubMedCrossRefGoogle Scholar
  93. 93.
    Mortensen PB, Norgaard-Pedersen B, Waltoft BL, Sorensen TL, Hougaard D, Torrey EF et al (2007) Toxoplasma gondii as a risk factor for early-onset schizophrenia: analysis of filter paper blood samples obtained at birth. Biol Psychiatry 61:688–693PubMedCrossRefGoogle Scholar
  94. 94.
    Brown AS, Schaefer CA, Quesenberry CP Jr, Liu L, Babulas VP, Susser ES (2005) Maternal exposure to toxoplasmosis and risk of schizophrenia in adult offspring. Am J Psychiatry 162:767–773PubMedCrossRefGoogle Scholar
  95. 95.
    Brown AS, Derkits EJ (2010) Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry 167:261–280PubMedCrossRefGoogle Scholar
  96. 96.
    Sorensen HJ, Mortensen EL, Reinisch JM, Mednick SA (2009) Association between prenatal exposure to bacterial infection and risk of schizophrenia. Schizophr Bull 35:631–637PubMedCrossRefGoogle Scholar
  97. 97.
    Clarke MC, Tanskanen A, Huttunen M, Whittaker JC, Cannon M (2009) Evidence for an interaction between familial liability and prenatal exposure to infection in the causation of schizophrenia. Am J Psychiatry 166:1025–1030PubMedCrossRefGoogle Scholar
  98. 98.
    Sorensen HJ, Mortensen EL, Reinisch JM, Mednick SA (2003) Do hypertension and diuretic treatment in pregnancy increase the risk of schizophrenia in offspring? Am J Psychiatry 160:464–468PubMedCrossRefGoogle Scholar
  99. 99.
    Sorensen HJ, Mortensen EL, Reinisch JM, Mednick SA (2004) Association between prenatal exposure to analgesics and risk of schizophrenia. Br J Psychiatry 185:366–371PubMedCrossRefGoogle Scholar
  100. 100.
    Oberlander TF, Weinberg J, Papsdorf M, Grunau R, Misri S, Devlin AM (2008) Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics 3:97–106PubMedCrossRefGoogle Scholar
  101. 101.
    Zheng S, Rollet M, Pan YX (2011) Maternal protein restriction during pregnancy induces CCAAT/enhancer-binding protein (C/EBPbeta) expression through the regulation of histone modification at its promoter region in female offspring rat skeletal muscle. Epigenetics 6(2):161–170PubMedCrossRefGoogle Scholar
  102. 102.
    Thornburg KL, Shannon J, Thuillier P, Turker MS (2010) In utero life and epigenetic predisposition for disease. Adv Genet 71:57–78PubMedCrossRefGoogle Scholar
  103. 103.
    Waterland RA, Michels KB (2007) Epigenetic epidemiology of the developmental origins hypothesis. Annu Rev Nutr 27:363–388PubMedCrossRefGoogle Scholar
  104. 104.
    Selten JP, Frissen A, Lensvelt-Mulders G, Morgan VA (2010) Schizophrenia and 1957 pandemic of influenza: meta-analysis. Schizophr Bull 36:219–228PubMedCrossRefGoogle Scholar
  105. 105.
    Selten JP, Cantor-Graae E, Nahon D, Levav I, Aleman A, Kahn RS (2003) No relationship between risk of schizophrenia and prenatal exposure to stress during the Six-Day War or Yom Kippur War in Israel. Schizophr Res 63:131–135PubMedCrossRefGoogle Scholar
  106. 106.
    McGrath J, Eyles D, Mowry B, Yolken R, Buka S (2003) Low maternal vitamin D as a risk factor for schizophrenia: a pilot study using banked sera. Schizophr Res 63:73–78PubMedCrossRefGoogle Scholar
  107. 107.
    Cannon TD, Rosso IM, Bearden CE, Sanchez LE, Hadley T (1999) A prospective cohort study of neurodevelopmental processes in the genesis and epigenesis of schizophrenia. Dev Psychopathol 11:467–485PubMedCrossRefGoogle Scholar
  108. 108.
    Buka SL, Tsuang MT, Torrey EF, Klebanoff MA, Bernstein D, Yolken RH (2001) Maternal infections and subsequent psychosis among offspring. Arch Gen Psychiatry 58:1032–1037PubMedCrossRefGoogle Scholar
  109. 109.
    Brown AS, Schaefer CA, Quesenberry CP Jr, Shen L, Susser ES (2006) No evidence of relation between maternal exposure to herpes simplex virus type 2 and risk of schizophrenia? Am J Psychiatry 163:2178–2180PubMedCrossRefGoogle Scholar
  110. 110.
    Jaaro-Peled H, Ayhan Y, Pletnikov MV, Sawa A (2010) Review of pathological hallmarks of schizophrenia: comparison of genetic models with patients and nongenetic models. Schizophr Bull 36:301–313PubMedCrossRefGoogle Scholar
  111. 111.
    Ayhan Y, Sawa A, Ross CA, Pletnikov MV (2009) Animal models of gene-environment interactions in schizophrenia. Behav Brain Res 204:274–281PubMedCrossRefGoogle Scholar
  112. 112.
    Heijmans BT, Tobi EW, Stein AD, Putter H, Blauw GJ, Susser ES et al (2008) Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci USA 105:17046–17049PubMedCrossRefGoogle Scholar
  113. 113.
    Brown AS, Susser ES (2008) Prenatal nutritional deficiency and risk of adult schizophrenia. Schizophr Bull 34:1054–1063PubMedCrossRefGoogle Scholar
  114. 114.
    Smits L, Pedersen C, Mortensen P, van Os J (2004) Association between short birth intervals and schizophrenia in the offspring. Schizophr Res 70:49–56PubMedCrossRefGoogle Scholar
  115. 115.
    Mortensen PB, Pedersen MG, Pedersen CB (2010) Psychiatric family history and schizophrenia risk in Denmark: which mental disorders are relevant? Psychol Med 40:201–210PubMedCrossRefGoogle Scholar
  116. 116.
    Cannon M, Jones PB, Murray RM (2002) Obstetric complications and schizophrenia: historical and meta-analytic review. Am J Psychiatry 159:1080–1092PubMedCrossRefGoogle Scholar
  117. 117.
    Byrne M, Agerbo E, Bennedsen B, Eaton WW, Mortensen PB (2007) Obstetric conditions and risk of first admission with schizophrenia: a Danish national register based study. Schizophr Res 97:51–59PubMedCrossRefGoogle Scholar
  118. 118.
    Rutter M (2009) Understanding and testing risk mechanisms for mental disorders. J Child Psychol Psychiatry 50:44–52PubMedCrossRefGoogle Scholar
  119. 119.
    Klaning U (1999) Greater occurrence of schizophrenia in dizygotic but not monozygotic twins. Register-based study. Br J Psychiatry 175:407–409PubMedCrossRefGoogle Scholar
  120. 120.
    Klaning U, Pedersen CB, Mortensen PB, Kyvik KO, Skytthe A (2002) A possible association between the genetic predisposition for dizygotic twinning and schizophrenia. Schizophr Res 58:31–35PubMedCrossRefGoogle Scholar
  121. 121.
    Kendler KS, Pedersen NL, Farahmand BY, Persson PG (1996) The treated incidence of psychotic and affective illness in twins compared with population expectation: a study in the Swedish Twin and Psychiatric Registries. Psychol Med 26:1135–1144PubMedCrossRefGoogle Scholar
  122. 122.
    Spauwen J, Krabbendam L, Lieb R, Wittchen HU, van Os J (2004) Early maternal stress and health behaviours and offspring expression of psychosis in adolescence. Acta Psychiatr Scand 110:356–364PubMedCrossRefGoogle Scholar
  123. 123.
    Bartels-Velthuis AA, Jenner JA, van de Willige G, van Os J, Wiersma D (2010) Prevalence and correlates of auditory vocal hallucinations in middle childhood. Br J Psychiatry 196:41–46PubMedCrossRefGoogle Scholar
  124. 124.
    Zammit S, Odd D, Horwood J, Thompson A, Thomas K, Menezes P et al (2009) Investigating whether adverse prenatal and perinatal events are associated with non-clinical psychotic symptoms at age 12 years in the ALSPAC birth cohort. Psychol Med 39(9):1457–1467PubMedCrossRefGoogle Scholar
  125. 125.
    Mittal VA, Ellman LM, Cannon TD (2008) Gene-environment interaction and covariation in schizophrenia: the role of obstetric complications. Schizophr Bull 34:1083–1094PubMedCrossRefGoogle Scholar
  126. 126.
    Cannon TD (1997) On the nature and mechanisms of obstetric influences in schizophrenia: a review and synthesis of epidemiologic studies. Int Rev Psychiatry 9:387–397CrossRefGoogle Scholar
  127. 127.
    Schmidt-Kastner R, van Os J, Steinbusch HWM, Schmitz C (2006) Gene regulation by hypoxia and the neurodevelopmental origin of schizophrenia. Schizophr Res 84:253–271PubMedCrossRefGoogle Scholar
  128. 128.
    Nicodemus KK, Marenco S, Batten AJ, Vakkalanka R, Egan MF, Straub RE et al (2008) Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk. Mol Psychiatry 13(9):873–877PubMedCrossRefGoogle Scholar
  129. 129.
    Watson JA, Watson CJ, McCann A, Baugh J (2010) Epigenetics, the epicenter of the hypoxic response. Epigenetics 5:293–296PubMedCrossRefGoogle Scholar
  130. 130.
    Tienari P, Wynne LC, Moring J, Lahti I, Naarala M, Sorri A et al (1994) The finnish adoptive family study of schizophrenia. Implications for family research [see comments]. Br J Psychiatry Suppl 20–26Google Scholar
  131. 131.
    Wahlberg KE, Wynne LC, Oja H, Keskitalo P, Pykalainen L, Lahti I et al (1997) Gene-environment interaction in vulnerability to schizophrenia: findings from the Finnish Adoptive Family Study of Schizophrenia. Am J Psychiatry 154:355–362PubMedGoogle Scholar
  132. 132.
    Tienari P, Wynne LC, Sorri A, Lahti I, Laksy K, Moring J et al (2004) Genotype-environment interaction in schizophrenia-spectrum disorder. Long-term follow-up study of Finnish adoptees. Br J Psychiatry 184:216–222PubMedCrossRefGoogle Scholar
  133. 133.
    Wahlberg KE, Wynne LC, Hakko H, Laksy K, Moring J, Miettunen J et al (2004) Interaction of genetic risk and adoptive parent communication deviance: longitudinal prediction of adoptee psychiatric disorders. Psychol Med 34:1531–1541PubMedCrossRefGoogle Scholar
  134. 134.
    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 99:432–440PubMedCrossRefGoogle Scholar
  135. 135.
    Schreier A, Wolke D, Thomas K, Horwood J, Hollis C, Gunnell D et al (2009) Prospective study of peer victimization in childhood and psychotic symptoms in a nonclinical population at age 12 years. Arch Gen Psychiatry 66:527–536PubMedCrossRefGoogle Scholar
  136. 136.
    Kessler RC, McLaughlin KA, Green JG, Gruber MJ, Sampson NA, Zaslavsky AM et al (2010) Childhood adversities and adult psychopathology in the WHO World Mental Health Surveys. Br J Psychiatry 197:378–385PubMedCrossRefGoogle Scholar
  137. 137.
    McLaughlin KA, Green JG, Gruber MJ, Sampson NA, Zaslavsky AM, Kessler RC (2010) Childhood adversities and adult psychiatric disorders in the national comorbidity survey replication II: associations with persistence of DSM-IV disorders. Arch Gen Psychiatry 67:124–132PubMedCrossRefGoogle Scholar
  138. 138.
    Green JG, McLaughlin KA, Berglund PA, Gruber MJ, Sampson NA, Zaslavsky AM et al (2010) Childhood adversities and adult psychiatric disorders in the national comorbidity survey replication I: associations with first onset of DSM-IV disorders. Arch Gen Psychiatry 67:113–123PubMedCrossRefGoogle Scholar
  139. 139.
    Bruffaerts R, Demyttenaere K, Borges G, Haro JM, Chiu WT, Hwang I et al (2010) Childhood adversities as risk factors for onset and persistence of suicidal behaviour. Br J Psychiatry 197:20–27PubMedCrossRefGoogle Scholar
  140. 140.
    Weaver IC, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR et al (2004) Epigenetic programming by maternal behavior. Nat Neurosci 7:847–854PubMedCrossRefGoogle Scholar
  141. 141.
    Weaver IC, Champagne FA, Brown SE, Dymov S, Sharma S, Meaney MJ et al (2005) Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life. J Neurosci 25:11045–11054PubMedCrossRefGoogle Scholar
  142. 142.
    Weaver IC, Meaney MJ, Szyf M (2006) Maternal care effects on the hippocampal transcriptome and anxiety-mediated behaviors in the offspring that are reversible in adulthood. Proc Natl Acad Sci USA 103:3480–3485PubMedCrossRefGoogle Scholar
  143. 143.
    McGowan PO, Sasaki A, D’Alessio AC, Dymov S, Labonte B, Szyf M et al (2009) Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci 12:342–348PubMedCrossRefGoogle Scholar
  144. 144.
    Arseneault L, Cannon M, Witton J, Murray RM (2004) Causal association between cannabis and psychosis: examination of the evidence. Br J Psychiatry 184:110–117PubMedCrossRefGoogle Scholar
  145. 145.
    Henquet C, Di Forti M, Morrison P, Kuepper R, Murray RM (2008) Gene-environment interplay between cannabis and psychosis. Schizophr Bull 34:1111–1121PubMedCrossRefGoogle Scholar
  146. 146.
    Murray RM, Morrison PD, Henquet C, Di Forti M (2007) Cannabis, the mind and society: the hash realities. Nat Rev Neurosci 8:885–895PubMedCrossRefGoogle Scholar
  147. 147.
    Houston JE, Murphy J, Adamson G, Stringer M, Shevlin M (2008) Childhood sexual abuse, early cannabis use, and psychosis: testing an interaction model based on the National Comorbidity Survey. Schizophr Bull 34:580–585PubMedCrossRefGoogle Scholar
  148. 148.
    Caspi A, Moffitt TE, 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 57:1117–1127PubMedCrossRefGoogle Scholar
  149. 149.
    Henquet C, Rosa A, Delespaul P, Papiol S, Fananas L, van Os J et al (2009) COMT ValMet moderation of cannabis-induced psychosis: a momentary assessment study of ‘switching on’ hallucinations in the flow of daily life. Acta Psychiatr Scand 119:156–160PubMedCrossRefGoogle Scholar
  150. 150.
    van Winkel R (2011) Family-based analysis of genetic variation underlying psychosis-inducing effects of cannabis: sibling analysis and proband follow-up. Arch Gen Psychiatry 68(2):148–157PubMedCrossRefGoogle Scholar
  151. 151.
    De Hert M, Wampers M, Jendricko T, Franic T, Vidovic D, De Vriendt N et al (2011) Effects of cannabis use on age at onset in schizophrenia and bipolar disorder. Schizophr Res 126(1–3):270–276PubMedCrossRefGoogle Scholar
  152. 152.
    Jacobs N, Rijsdijk F, Derom C, Vlietinck R, Delespaul P, van Os J et al (2006) Genes making one feel blue in the flow of daily life: a momentary assessment study of gene-stress interaction. Psychosom Med 68:201–206PubMedCrossRefGoogle Scholar
  153. 153.
    G.R.O.U.P (2010) 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 68(2):138–147Google Scholar
  154. 154.
    Chevaleyre V, Takahashi KA, Castillo PE (2006) Endocannabinoid-mediated synaptic plasticity in the CNS. Annu Rev Neurosci 29:37–76PubMedCrossRefGoogle Scholar
  155. 155.
    Villares J (2007) Chronic use of marijuana decreases cannabinoid receptor binding and mRNA expression in the human brain. Neuroscience 145:323–334PubMedCrossRefGoogle Scholar
  156. 156.
    Ellgren M, Spano SM, Hurd YL (2007) Adolescent cannabis exposure alters opiate intake and opioid limbic neuronal populations in adult rats. Neuropsychopharmacology 32:607–615PubMedCrossRefGoogle Scholar
  157. 157.
    Casu MA, Pisu C, Sanna A, Tambaro S, Spada GP, Mongeau R et al (2005) Effect of delta9-tetrahydrocannabinol on phosphorylated CREB in rat cerebellum: an immunohistochemical study. Brain Res 1048:41–47PubMedCrossRefGoogle Scholar
  158. 158.
    Fernandez-Ruiz J, Gomez M, Hernandez M, de Miguel R, Ramos JA (2004) Cannabinoids and gene expression during brain development. Neurotox Res 6:389–401PubMedCrossRefGoogle Scholar
  159. 159.
    Mato S, Chevaleyre V, Robbe D, Pazos A, Castillo PE, Manzoni OJ (2004) A single in-vivo exposure to delta 9THC blocks endocannabinoid-mediated synaptic plasticity. Nat Neurosci 7:585–586PubMedCrossRefGoogle Scholar
  160. 160.
    Scallet AC (1991) Neurotoxicology of cannabis and THC: a review of chronic exposure studies in animals. Pharmacol Biochem Behav 40:671–676PubMedCrossRefGoogle Scholar
  161. 161.
    Heath RG, Fitzjarrell AT, Fontana CJ, Garey RE (1980) Cannabis sativa: effects on brain function and ultrastructure in rhesus monkeys. Biol Psychiatry 15:657–690PubMedGoogle Scholar
  162. 162.
    Hoffman AF, Oz M, Caulder T, Lupica CR (2003) Functional tolerance and blockade of long-term depression at synapses in the nucleus accumbens after chronic cannabinoid exposure. J Neurosci 23:4815–4820PubMedGoogle Scholar
  163. 163.
    Featherstone RE, Kapur S, Fletcher PJ (2007) The amphetamine-induced sensitized state as a model of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 31:1556–1571PubMedCrossRefGoogle Scholar
  164. 164.
    Castner SA, Williams GV (2007) From vice to virtue: insights from sensitization in the nonhuman primate. Prog Neuropsychopharmacol Biol Psychiatry 31:1572–1592PubMedCrossRefGoogle Scholar
  165. 165.
    Uslaner J, Badiani A, Norton CS, Day HEW, Watson SJ, Akil H et al (2001) Amphetamine and cocaine induce different patterns of c-fos mRNA expression in the striatum and subthalamic nucleus depending on environmental context. Eur J Neurosci 13:1977–1983PubMedCrossRefGoogle Scholar
  166. 166.
    Bibb JA, Chen J, Taylor JR, Svenningsson P, Nishi A, Snyder GL et al (2001) Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5. Nature 410:376–380PubMedCrossRefGoogle Scholar
  167. 167.
    Nestler EJ, Barrot M, Self DW (2001) Delta FosB: a sustained molecular switch for addiction. Proc Natl Acad Sci 98:11042PubMedCrossRefGoogle Scholar
  168. 168.
    Kumar A, Choi KH, Renthal W, Tsankova NM, Theobald DEH, Truong HT et al (2005) Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum. Neuron 48:303–314PubMedCrossRefGoogle Scholar
  169. 169.
    Sekine Y, Iyo M, Ouchi Y, Matsunaga T, Tsukada H, Okada H et al (2001) Methamphetamine-related psychiatric symptoms and reduced brain dopamine transporters studied with PET. Am J Psychiatry 158:1206–1214PubMedCrossRefGoogle Scholar
  170. 170.
    Lehrmann E, Colantuoni C, Deep-Soboslay A, Becker KG, Lowe R, Huestis MA et al (2006) Transcriptional changes common to human cocaine, cannabis and phencyclidine abuse. PLoS One 1:e114PubMedCrossRefGoogle Scholar
  171. 171.
    Greenstein R, Novak G, Seeman P (2007) Amphetamine sensitization elevates CaMKIIbeta mRNA. Synapse 61:827–834PubMedCrossRefGoogle Scholar
  172. 172.
    Iwata SI, Hewlett GH, Ferrell ST, Kantor L, Gnegy ME (1997) Enhanced dopamine release and phosphorylation of synapsin I and neuromodulin in striatal synaptosomes after repeated amphetamine. J Pharmacol Exp Ther 283:1445–1452PubMedGoogle Scholar
  173. 173.
    Cantor-Graae E, Selten JP (2005) Schizophrenia and migration: a meta-analysis and review. Am J Psychiatry 162:12–24PubMedCrossRefGoogle Scholar
  174. 174.
    Bourque F, van der Ven E, Malla A (2010) A meta-analysis of the risk for psychotic disorders among first- and second-generation immigrants. Psychol Med 41(5):1–14Google Scholar
  175. 175.
    Bresnahan M, Begg MD, Brown A, Schaefer C, Sohler N, Insel B et al (2007) Race and risk of schizophrenia in a US birth cohort: another example of health disparity? Int J Epidemiol 36:751–758PubMedCrossRefGoogle Scholar
  176. 176.
    Veling W, Susser E, van Os J, Mackenbach JP, Selten JP, Hoek HW (2008) Ethnic density of neighborhoods and incidence of psychotic disorders among immigrants. Am J Psychiatry 165:66–73PubMedCrossRefGoogle Scholar
  177. 177.
    Boydell J, Van Os J, McKenzie K, Allardyce J, Goel R, McCreadie RG et al (2001) Incidence of schizophrenia in ethnic minorities in London: ecological study into interactions with environment. BMJ 323:1336PubMedCrossRefGoogle Scholar
  178. 178.
    Morgan C, Charalambides M, Hutchinson G, Murray RM (2010) Migration, ethnicity, and psychosis: toward a sociodevelopmental model. Schizophr Bull, Medline EPub. doi: sbq051 [pii]  10.1093/schbul/sbq051
  179. 179.
    Selten JP, Cantor-Graae E (2005) Social defeat: risk factor for schizophrenia? Br J Psychiatry 187:101–102PubMedCrossRefGoogle Scholar
  180. 180.
    Renthal W, Maze I, Krishnan V, Covington HE 3rd, Xiao G, Kumar A et al (2007) Histone deacetylase 5 epigenetically controls behavioral adaptations to chronic emotional stimuli. Neuron 56:517–529PubMedCrossRefGoogle Scholar
  181. 181.
    Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ (2006) Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 9:519–525PubMedCrossRefGoogle Scholar
  182. 182.
    Cougnard A, Marcelis M, Myin-Germeys I, De Graaf R, Vollebergh W, Krabbendam L et al (2007) Does normal developmental expression of psychosis combine with environmental risk to cause persistence of psychosis? A psychosis proneness-persistence model. Psychol Med 37:513–527PubMedCrossRefGoogle Scholar
  183. 183.
    Dominguez MD, Wichers M, Lieb R, Wittchen HU, van Os J (2011) Evidence that onset of clinical psychosis is an outcome of progressively more persistent subclinical psychotic experiences: an 8-year cohort study. Schizophr Bull 37(1):84–93PubMedCrossRefGoogle Scholar
  184. 184.
    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 123:857–865PubMedCrossRefGoogle Scholar
  185. 185.
    Kabbaj M, Isgor C, Watson SJ, Akil H (2002) Stress during adolescence alters behavioral sensitization to amphetamine. Neuroscience 113:395–400PubMedCrossRefGoogle Scholar
  186. 186.
    Von Frijtag JC, Reijmers LG, Van der Harst JE, Leus IE, Van den Bos R, Spruijt BM (2000) Defeat followed by individual housing results in long-term impaired reward- and cognition-related behaviours in rats. Behav Brain Res 117:137–146CrossRefGoogle Scholar
  187. 187.
    Sugden C (2006) One-carbon metabolism in psychiatric illness. Nutr Res Rev 19:117–136PubMedCrossRefGoogle Scholar
  188. 188.
    van der Put NM, van Straaten HW, Trijbels FJ, Blom HJ (2001) Folate, homocysteine and neural tube defects: an overview. Exp Biol Med (Maywood) 226:243–270Google Scholar
  189. 189.
    Zhang HY, Luo GA, Liang QL, Wang Y, Yang HH, Wang YM et al (2008) Neural tube defects and disturbed maternal folate- and homocysteine-mediated one-carbon metabolism. Exp Neurol 212:515–521PubMedCrossRefGoogle Scholar
  190. 190.
    Pasca SP, Dronca E, Kaucsar T, Craciun EC, Endreffy E, Ferencz BK et al (2009) One carbon metabolism disturbances and the C677T MTHFR gene polymorphism in children with autism spectrum disorders. J Cell Mol Med 13:4229–4238PubMedCrossRefGoogle Scholar
  191. 191.
    de Jonge R, Tissing WJ, Hooijberg JH, Jansen G, Kaspers GJ, Lindemans J et al (2009) Polymorphisms in folate-related genes and risk of pediatric acute lymphoblastic leukemia. Blood 113:2284–2289PubMedCrossRefGoogle Scholar
  192. 192.
    Wiemels JL, Smith RN, Taylor GM, Eden OB, Alexander FE, Greaves MF (2001) Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia. Proc Natl Acad Sci USA 98:4004–4009PubMedCrossRefGoogle Scholar
  193. 193.
    Kronenberg G, Colla M, Endres M (2009) Folic acid, neurodegenerative and neuropsychiatric disease. Curr Mol Med 9:315–323PubMedCrossRefGoogle Scholar
  194. 194.
    Kim JM, Kim SW, Shin IS, Yang SJ, Park WY, Kim SJ et al (2008) Folate, vitamin b(12), and homocysteine as risk factors for cognitive decline in the elderly. Psychiatry Investig 5:36–40PubMedCrossRefGoogle Scholar
  195. 195.
    Kim YI (1999) Folate and carcinogenesis: evidence, mechanisms, and implications. J Nutr Biochem 10:66–88PubMedCrossRefGoogle Scholar
  196. 196.
    Levine AJ, Figueiredo JC, Lee W, Conti DV, Kennedy K, Duggan DJ et al (2010) A candidate gene study of folate-associated one carbon metabolism genes and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev 19:1812–1821PubMedCrossRefGoogle Scholar
  197. 197.
    Smulders YM, Stehouwer CD (2005) Folate metabolism and cardiovascular disease. Semin Vasc Med 5:87–97PubMedCrossRefGoogle Scholar
  198. 198.
    Carmichael SL, Yang W, Correa A, Olney RS, Shaw GM (2009) Hypospadias and intake of nutrients related to one-carbon metabolism. J Urol 181:315–321, discussion 321PubMedCrossRefGoogle Scholar
  199. 199.
    Wani NA, Hamid A, Kaur J (2008) Folate status in various pathophysiological conditions. IUBMB Life 60:834–842PubMedCrossRefGoogle Scholar
  200. 200.
    Betcheva ET, Mushiroda T, Takahashi A, Kubo M, Karachanak SK, Zaharieva IT et al (2009) Case-control association study of 59 candidate genes reveals the DRD2 SNP rs6277 (C957T) as the only susceptibility factor for schizophrenia in the Bulgarian population. J Hum Genet 54:98–107PubMedCrossRefGoogle Scholar
  201. 201.
    Feng LG, Song ZW, Xin F, Hu J (2009) Association of plasma homocysteine and methy­lenetetrahydrofolate reductase C677T gene variant with schizophrenia: a Chinese Han ­population-based case-control study. Psychiatry Res 168:205–208PubMedCrossRefGoogle Scholar
  202. 202.
    Gaysina D, Cohen S, Craddock N, Farmer A, Hoda F, Korszun A et al (2008) No association with the 5,10-methylenetetrahydrofolate reductase gene and major depressive disorder: results of the depression case control (DeCC) study and a meta-analysis. Am J Med Genet B Neuropsychiatr Genet 147B:699–706PubMedCrossRefGoogle Scholar
  203. 203.
    Gilbody S, Lewis S, Lightfoot T (2007) Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review. Am J Epidemiol 165:1–13PubMedCrossRefGoogle Scholar
  204. 204.
    Pan CC, McQuoid DR, Taylor WD, Payne ME, Ashley-Koch A, Steffens DC (2009) Association analysis of the COMT/MTHFR genes and geriatric depression: an MRI study of the putamen. Int J Geriatr Psychiatry 24:847–855PubMedCrossRefGoogle Scholar
  205. 205.
    Yuan YG, Zhang ZJ, Li JJ (2008) Plasma homocysteine but not MTHFR gene polymorphism is associated with geriatric depression in the Chinese population. Acta Neuropsychiatr 20(5):251–255CrossRefGoogle Scholar
  206. 206.
    Yu L, Li T, Robertson Z, Dean J, Gu NF, Feng GY et al (2004) No association between polymorphisms of methylenetetrahydrofolate reductase gene and schizophrenia in both Chinese and Scottish populations. Mol Psychiatry 9:1063–1065PubMedCrossRefGoogle Scholar
  207. 207.
    del Rio GC, Torres-Sanchez L, Chen J, Schnaas L, Hernandez C, Osorio E et al (2009) Maternal MTHFR 677 C  >  T genotype and dietary intake of folate and vitamin B(12): their impact on child neurodevelopment. Nutr Neurosci 12:13–20CrossRefGoogle Scholar
  208. 208.
    Ueland PM, Hustad S, Schneede J, Refsum H, Vollset SE (2001) Biological and clinical implications of the MTHFR C677T polymorphism. Trends Pharmacol Sci 22:195–201PubMedCrossRefGoogle Scholar
  209. 209.
    McGuffin P, Rijsdijk F, Andrew M, Sham P, Katz R, Cardno A (2003) The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Arch Gen Psychiatry 60:497–502PubMedCrossRefGoogle Scholar
  210. 210.
    Lichtenstein P, Yip BH, Bjork C, Pawitan Y, Cannon TD, Sullivan PF et al (2009) Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 373:234–239PubMedCrossRefGoogle Scholar
  211. 211.
    Van Snellenberg JX, de Candia T (2009) Meta-analytic evidence for familial coaggregation of schizophrenia and bipolar disorder. Arch Gen Psychiatry 66:748–755PubMedCrossRefGoogle Scholar
  212. 212.
    Cardno AG, Rijsdijk FV, Sham PC, Murray RM, McGuffin P (2002) A twin study of genetic relationships between psychotic symptoms. Am J Psychiatry 159:539–545PubMedCrossRefGoogle Scholar
  213. 213.
    Peerbooms OL, van Os J, Drukker M, Kenis G, Hoogveld L, de Hert M et al (2010) Meta-analysis of MTHFR gene variants in schizophrenia, bipolar disorder and unipolar depressive disorder: evidence for a common genetic vulnerability? Brain Behav Immun Dec 24 [Epub ahead of print]Google Scholar
  214. 214.
    Gonzales ML, LaSalle JM (2010) The role of MeCP2 in brain development and neurodevelopmental disorders. Curr Psychiatry Rep 12:127–134PubMedCrossRefGoogle Scholar
  215. 215.
    Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 23:185–188PubMedCrossRefGoogle Scholar
  216. 216.
    Klauck SM, Lindsay S, Beyer KS, Splitt M, Burn J, Poustka A (2002) A mutation hot spot for nonspecific X-linked mental retardation in the MECP2 gene causes the PPM-X syndrome. Am J Hum Genet 70:1034–1037PubMedCrossRefGoogle Scholar
  217. 217.
    Couvert P, Bienvenu T, Aquaviva C, Poirier K, Moraine C, Gendrot C et al (2001) MECP2 is highly mutated in X-linked mental retardation. Hum Mol Genet 10:941–946PubMedCrossRefGoogle Scholar
  218. 218.
    Shi J, Levinson DF, Duan J, Sanders AR, Zheng Y, Pe’er I et al (2009) Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 460:753–757PubMedGoogle Scholar
  219. 219.
    Uddin M, Koenen KC, Aiello AE, Wildman DE, de Los SR, Galea S (2011) Epigenetic and inflammatory marker profiles associated with depression in a community-based epidemiologic sample. Psychol Med 41(5):1–11CrossRefGoogle Scholar
  220. 220.
    Uddin M, Aiello AE, Wildman DE, Koenen KC, Pawelec G, de Los Santos R et al (2010) Epigenetic and immune function profiles associated with posttraumatic stress disorder. Proc Natl Acad Sci USA 107:9470–9475PubMedCrossRefGoogle Scholar
  221. 221.
    Ernst C, Chen ES, Turecki G (2009) Histone methylation and decreased expression of TrkB.T1 in orbital frontal cortex of suicide completers. Mol Psychiatry 14:830–832PubMedCrossRefGoogle Scholar
  222. 222.
    Abdolmaleky HM, Cheng KH, Faraone SV, Wilcox M, Glatt SJ, Gao F et al (2006) Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder. Hum Mol Genet 15:3132–3145PubMedCrossRefGoogle Scholar
  223. 223.
    Grayson DR, Jia X, Chen Y, Sharma RP, Mitchell CP, Guidotti A et al (2005) Reelin promoter hypermethylation in schizophrenia. Proc Natl Acad Sci USA 102:9341–9346PubMedCrossRefGoogle Scholar
  224. 224.
    Dempster EL, Mill J, Craig IW, Collier DA (2006) The quantification of COMT mRNA in post mortem cerebellum tissue: diagnosis, genotype, methylation and expression. BMC Med Genet 7:10PubMedCrossRefGoogle Scholar
  225. 225.
    Mill J, Tang T, Kaminsky Z, Khare T, Yazdanpanah S, Bouchard L et al (2008) Epigenomic profiling reveals DNA methylation changes associated with major psychosis. Am J Hum Genet 82:696–711PubMedCrossRefGoogle Scholar
  226. 226.
    Tochigi M, Iwamoto K, Bundo M, Komori A, Sasaki T, Kato N et al (2008) Methylation status of the reelin promoter region in the brain of schizophrenic patients. Biol Psychiatry 63:530–533PubMedCrossRefGoogle Scholar
  227. 227.
    Veldic M, Guidotti A, Maloku E, Davis JM, Costa E (2005) In psychosis, cortical interneurons overexpress DNA-methyltransferase 1. Proc Natl Acad Sci USA 102:2152–2157PubMedCrossRefGoogle Scholar
  228. 228.
    Kuratomi G, Iwamoto K, Bundo M, Kusumi I, Kato N, Iwata N et al (2007) Aberrant DNA methylation associated with bipolar disorder identified from discordant monozygotic twins. Mol Psychiatry 13:429–441PubMedCrossRefGoogle Scholar
  229. 229.
    Mastroeni D, Grover A, Delvaux E, Whiteside C, Coleman PD, Rogers J (2008) Epigenetic changes in Alzheimer’s disease: decrements in DNA methylation. Neurobiol Aging 12:2025–2037Google Scholar
  230. 230.
    Yoshikai S, Sasaki H, Doh-ura K, Furuya H, Sakaki Y (1990) Genomic organization of the human amyloid beta-protein precursor gene. Gene 87:257–263PubMedCrossRefGoogle Scholar
  231. 231.
    Tohgi H, Utsugisawa K, Nagane Y, Yoshimura M, Ukitsu M, Genda Y (1999) The methy­lation status of cytosines in a tau gene promoter region alters with age to downregulate transcriptional activity in human cerebral cortex. Neurosci Lett 275:89–92PubMedCrossRefGoogle Scholar
  232. 232.
    Barrachina M, Ferrer I (2009) DNA methylation of Alzheimer disease and tauopathy-related genes in postmortem brain. J Neuropathol Exp Neurol 68(8):880–891PubMedCrossRefGoogle Scholar
  233. 233.
    Wang SC, Oelze B, Schumacher A (2008) Age-specific epigenetic drift in late-onset Alzheimer’s disease. PLoS One 3:e2698PubMedCrossRefGoogle Scholar
  234. 234.
    Silva PN, Gigek CO, Leal MF, Bertolucci PH, de Labio RW, Payao SL et al (2008) Promoter methylation analysis of SIRT3, SMARCA5, HTERT and CDH1 genes in aging and Alzheimer’s disease. J Alzheimers Dis 13:173–176PubMedGoogle Scholar
  235. 235.
    Michels KB (2010) The promises and challenges of epigenetic epidemiology. Exp Gerontol 45:297–301PubMedCrossRefGoogle Scholar
  236. 236.
    Kessler RC, Ormel J, Petukhova M, McLaughlin KA, Green JG, Russo LJ et al (2011) Development of lifetime comorbidity in the world health organization world mental health surveys. Arch Gen Psychiatry 68:90–100PubMedCrossRefGoogle Scholar
  237. 237.
    McMillan KA, Enns MW, Cox BJ, Sareen J (2009) 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 Psychiatry 54:477–486PubMedGoogle Scholar
  238. 238.
    Hanssen M, Peeters F, Krabbendam L, Radstake S, Verdoux H, Van Os J (2003) How psychotic are individuals with non-psychotic disorders? Soc Psychiatry Psychiatr Epidemiol 38:149–154PubMedCrossRefGoogle Scholar
  239. 239.
    Weiser M, Reichenberg A, Rabinowitz J, Knobler HY, Lubin G, Yazvitzky R et al (2004) Cognitive performance of male adolescents is lower than controls across psychiatric disorders: a population-based study. Acta Psychiatr Scand 110:471–475PubMedCrossRefGoogle Scholar
  240. 240.
    Huang J, Perlis RH, Lee PH, Rush AJ, Fava M, Sachs GS et al (2010) Cross-disorder genomewide analysis of schizophrenia, bipolar disorder, and depression. Am J Psychiatry 167:1254–1263PubMedCrossRefGoogle Scholar
  241. 241.
    Argyropoulos SV, Landau S, Kalidindi S, Toulopoulou T, Castle DJ, Murray RM et al (2008) Twins discordant for schizophrenia: psychopathology of the non-schizophrenic co-twins. Acta Psychiatr Scand 118:214–219PubMedCrossRefGoogle Scholar
  242. 242.
    Bjornsson HT, Fallin MD, Feinberg AP (2004) An integrated epigenetic and genetic approach to common human disease. Trends Genet 20:350–358PubMedCrossRefGoogle Scholar
  243. 243.
    Foley DL, Craig JM, Morley R, Olsson CA, Dwyer T, Smith K et al (2009) Prospects for epigenetic epidemiology. Am J Epidemiol 169:389–400PubMedCrossRefGoogle Scholar
  244. 244.
    Wong CC, Caspi A, Williams B, Craig IW, Houts R, Ambler A et al (2010) A longitudinal study of epigenetic variation in twins. Epigenetics 5(6):516–526PubMedCrossRefGoogle Scholar
  245. 245.
    Pidsley R, Mill J (2011) Epigenetic studies of psychosis: current findings, methodological approaches, and implications for postmortem research. Biol Psychiatry 69:146–156PubMedCrossRefGoogle Scholar
  246. 246.
    Andersen SL, Teicher MH (2008) Stress, sensitive periods and maturational events in adolescent depression. Trends Neurosci 31:183–191PubMedCrossRefGoogle Scholar
  247. 247.
    Davey Smith G, Ebrahim S, Lewis S, Hansell AL, Palmer LJ, Burton PR (2005) Genetic epidemiology and public health: hope, hype, and future prospects. Lancet 366:1484–1498PubMedCrossRefGoogle Scholar
  248. 248.
    McGorry PD, Nelson B, Amminger GP, Bechdolf A, Francey SM, Berger G et al (2009) Intervention in individuals at ultra-high risk for psychosis: a review and future directions. J Clin Psychiatry 70:1206–1212PubMedCrossRefGoogle Scholar
  249. 249.
    Albert MS, Blacker D (2006) Mild cognitive impairment and dementia. Annu Rev Clin Psychol 2:379–388PubMedCrossRefGoogle Scholar
  250. 250.
    Nestler EJ, Hyman SE (2010) Animal models of neuropsychiatric disorders. Nat Neurosci 13:1161–1169PubMedCrossRefGoogle Scholar
  251. 251.
    Chouliaras L, van den Hove DL, Kenis G, Keitel S, Hof PR, van Os J, Steinbusch HW, Schmitz C, Rutten BP (2011) Neurobiol Aging. 2011 Jul 14. [Epub ahead of print]Google Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  1. 1.Department of Psychiatry and Psychology, School for Mental Health and Neuroscience, European Graduate School of Neuroscience (EURON), South Limburg Mental Health Research and Teaching Network (SEARCH)Maastricht University Medical CentreMaastrichtThe Netherlands
  2. 2.Department of Psychosis Studies, Institute of PsychiatryKing’s College London, King’s Health PartnersLondonUK

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