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Gene–environment interplay in the etiology of psychosis

Published online by Cambridge University Press:  15 January 2018

Alyson Zwicker ,
Eileen M. Denovan-Wright  and
Rudolf Uher
Alyson Zwicker
Affiliation:
Department of Pathology, Dalhousie University, Halifax, NS, Canada Department of Psychiatry, Dalhousie University, Halifax, NS, Canada Nova Scotia Health Authority, Halifax, NS, Canada
Eileen M. Denovan-Wright
Affiliation:
Department of Pharmacology, Dalhousie University, Halifax, NS, Canada
Rudolf Uher*
Affiliation:
Department of Pathology, Dalhousie University, Halifax, NS, Canada Department of Psychiatry, Dalhousie University, Halifax, NS, Canada Nova Scotia Health Authority, Halifax, NS, Canada Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK
*
Author for correspondence: Rudolf Uher, E-mail: [email protected]
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Abstract

Schizophrenia and other types of psychosis incur suffering, high health care costs and loss of human potential, due to the combination of early onset and poor response to treatment. Our ability to prevent or cure psychosis depends on knowledge of causal mechanisms. Molecular genetic studies show that thousands of common and rare variants contribute to the genetic risk for psychosis. Epidemiological studies have identified many environmental factors associated with increased risk of psychosis. However, no single genetic or environmental factor is sufficient to cause psychosis on its own. The risk of developing psychosis increases with the accumulation of many genetic risk variants and exposures to multiple adverse environmental factors. Additionally, the impact of environmental exposures likely depends on genetic factors, through gene–environment interactions. Only a few specific gene–environment combinations that lead to increased risk of psychosis have been identified to date. An example of replicable gene–environment interaction is a common polymorphism in the AKT1 gene that makes its carriers sensitive to developing psychosis with regular cannabis use. A synthesis of results from twin studies, molecular genetics, and epidemiological research outlines the many genetic and environmental factors contributing to psychosis. The interplay between these factors needs to be considered to draw a complete picture of etiology. To reach a more complete explanation of psychosis that can inform preventive strategies, future research should focus on longitudinal assessments of multiple environmental exposures within large, genotyped cohorts beginning early in life.

Keywords

environmental risk factorsgene–environment interactionsgeneticspsychosisschizophrenia
Type
Invited Review
Information
Psychological Medicine , Volume 48 , Issue 12 , September 2018 , pp. 1925 - 1936
Copyright
Copyright © Cambridge University Press 2018 

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References

Adler, N, Boyce, T, Chesney, M, Cohen, S, Folkman, S, Kahn, R et al. (1994) Socioeconomic status and health. The challenge of the gradient. The American Psychologist 49, 15–24.Google Scholar
Agerbo, E, Sullivan, PF, Vilhjálmsson, BJ, Pedersen, CB, Mors, O, Børglum, AD et al. (2015) Polygenic risk score, parental socioeconomic status, family history of psychiatric disorders, and the risk for schizophrenia. JAMA Psychiatry 72, 635.Google Scholar
Ahn, K, An, SS, Shugart, YY and Rapoport, JL (2016) Common polygenic variation and risk for childhood-onset schizophrenia. Molecular Psychiatry 21, 94–96.Google Scholar
Ahn, K, Gotay, N, Andersen, TM, Anvari, AA, Gochman, P, Lee, Y et al. (2014) High rate of disease-related copy number variations in childhood onset schizophrenia. Molecular Psychiatry 19, 568–572.Google Scholar
Alemany, S, Arias, B, Aguilera, M, Villa, H, Moya, J, Ibanez, MI et al. (2011) Childhood abuse, the BDNF-Val66Met polymorphism and adult psychotic-like experiences. The British Journal of Psychiatry 199, 38–42.Google Scholar
Alemany, S, Arias, B, Fatjó-Vilas, M, Villa, H, Moya, J, Ibáñez, MI et al. (2014) Psychosis-inducing effects of cannabis are related to both childhood abuse and COMT genotypes. Acta Psychiatrica Scandinavica 129, 54–62.Google Scholar
Alemany, S, Moya, J, Ibáñez, MI, Villa, H, Mezquita, L, Ortet, G et al. (2016) Research letter: childhood trauma and the rs1360780 SNP of FKBP5 gene in psychosis: a replication in two general population samples. Psychological Medicine 46, 221–223.Google Scholar
Allswede, DM, Buka, SL, Yolken, RH, Torrey, EF and Cannon, TD (2016) Elevated maternal cytokine levels at birth and risk for psychosis in adult offspring. Schizophrenia Research 172, 41–45.Google Scholar
Arseneault, L, Cannon, M, Poulton, R, Murray, R, Caspi, A and Moffitt, TE (2002) Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study. BMJ 325, 1212–1213.Google Scholar
Attademo, L, Bernardini, F, Garinella, R and Compton, MT (2017) Environmental pollution and risk of psychotic disorders: a review of the science to date. Schizophrenia Research 181, 55–59.Google Scholar
Avramopoulos, D, Pearce, BD, McGrath, J, Wolyniec, P, Wang, R, Eckart, N et al. (2015) Infection and inflammation in schizophrenia and bipolar disorder: a genome wide study for interactions with genetic variation. PLOS ONE 10, e0116696.Google Scholar
Baumeister, D, Akhtar, R, Ciufolini, S, Pariante, CM and Mondelli, V (2016) Childhood trauma and adulthood inflammation: a meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-α. Molecular Psychiatry 21, 642–649.Google Scholar
Belsky, J and Pluess, M (2009) Beyond diathesis stress: differential susceptibility to environmental influences. Psychological Bulletin 135, 885–908.Google Scholar
Bigdeli, TB, Ripke, S, Bacanu, SA, Lee, SH, Wray, NR, Gejman, PV et al. (2016) Genome-wide association study reveals greater polygenic loading for schizophrenia in cases with a family history of illness. American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics 171, 276–289.Google Scholar
Børglum, A, Demontis, D, Grove, J, Pallesen, J, Hollegaard, M, Pedersen, C et al. (2013) Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci. Molecular Psychiatry 19, 325–333.Google Scholar
Brown, A, Schaefer, C, Wyatt, R, Goetz, R, Begg, M, Gorman, J et al. (2000) Maternal exposure to respiratory infections and adult schizophrenia spectrum disorders: a prospective birth cohort study. Schizophrenia Bulletin 26, 287–295.Google Scholar
Brown, AS, Cohen, P, Harkavy-Friedman, J, Babulas, V, Malaspina, D, Gorman, JM et al. (2001) Prenatal rubella, premorbid abnormalities, and adult schizophrenia. Biological Psychiatry 49, 473–486.Google Scholar
Brown, AS and Patterson, PH (2011) Maternal infection and schizophrenia: implications for prevention. Schizophrenia Bulletin 37, 284–290.Google Scholar
Buka, SL, Cannon, TD, Torrey, EF and Yolken, RH (2008) Maternal exposure to herpes simplex virus and risk of psychosis Among adult offspring. Biological Psychiatry 63, 809–815.Google Scholar
Burns, JK, Tomita, A and Kapadia, AS (2014) Income inequality and schizophrenia: increased schizophrenia incidence in countries with high levels of income inequality. International Journal of Social Psychiatry 60, 185–196.Google Scholar
Byrne, M, Agerbo, E, Bennedsen, B, Eaton, WW and Mortensen, PB (2007) Obstetric conditions and risk of first admission with schizophrenia: a Danish national register based study. Schizophrenia Research 97, 51–59.Google Scholar
Canetta, S and Sourander, A (2014) Elevated maternal C-reactive protein and increased risk of schizophrenia in a national birth cohort. American Journal of Psychiatry 171, 960–968.Google Scholar
Cantor-Graae, E (2005) Schizophrenia and migration: a meta-analysis and review. American Journal of Psychiatry 162, 12–24.Google Scholar
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. Biological Psychiatry 57, 1117–1127.Google Scholar
Clarke, MC, Tanskanen, A, Huttunen, M, Whittaker, JC and Cannon, M (2009) Evidence for an interaction between familial liability and prenatal exposure to infection in the causation of schizophrenia. American Journal of Psychiatry 166, 1025–1030.Google Scholar
Collins, AL, Kim, Y, Sklar, P, O'Donovan, MC and Sullivan, PF (2012) Hypothesis-driven candidate genes for schizophrenia compared to genome-wide association results. Psychological Medicine 42, 607–616.Google Scholar
Collip, D, Myin-Germeys, I, Wichers, M, Jacobs, N, Derom, C, Thiery, E et al. (2013) FKBP5 as a possible moderator of the psychosis-inducing effects of childhood trauma. British Journal of Psychiatry 202, 261–268.Google Scholar
Collip, D, van Winkel, R, Peerbooms, O, Lataster, T, Thewissen, V, Lardinois, M et al. (2011) COMT Val158Met-stress interaction in psychosis: role of background psychosis risk. CNS Neuroscience and Therapeutics 17, 612–619.Google Scholar
Collishaw, S, Pickles, A, Messer, J, Rutter, M, Shearer, C and Maughan, B (2007) Resilience to adult psychopathology following childhood maltreatment: evidence from a community sample. Child Abuse and Neglect 31, 211–229.Google Scholar
Cross-Disorder Group of the Psychiatric Genomics Consortium (2013a) Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nature Genetics 45, 984–994.Google Scholar
Cross-Disorder Group of the Psychiatric Genomics Consortium (2013b) Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. The Lancet 381, 1371–1379.Google Scholar
Curran, C, Byrappa, N and Mcbride, A (2004) Stimulant psychosis: systematic review. British Journal of Psychiatry 185, 196–204.Google Scholar
de Castro-Catala, M, van Nierop, M, Barrantes-Vidal, N, Cristóbal-Narváez, P, Sheinbaum, T, Kwapil, TR et al. (2016) Childhood trauma, BDNF Val66Met and subclinical psychotic experiences. Attempt at replication in two independent samples. Journal of Psychiatric Research 83, 121–129.Google Scholar
Deverman, BE and Patterson, PH (2009) Cytokines and CNS development. Neuron 64, 61–78.Google Scholar
Di Forti, M, Iyegbe, C, Sallis, H, Kolliakou, A, Falcone, MA, Paparelli, A et al. (2012) Confirmation that the AKT1 (rs2494732) genotype influences the risk of psychosis in cannabis users. Biological Psychiatry 72, 811–816.Google Scholar
Dragt, S, Nieman, DH, Veltman, D, Becker, HE, van de Fliert, R, de Haan, L et al. (2011) Environmental factors and social adjustment as predictors of a first psychosis in subjects at ultra high risk. Schizophrenia Research 125, 69–76.Google Scholar
Farrell, MS, Werge, T, Sklar, P, Owen, MJ, Ophoff, RA, O'Donovan, MC et al. (2015) Evaluating historical candidate genes for schizophrenia. Molecular Psychiatry 20, 555–562.Google Scholar
Fearon, P, Kirkbride, JB, Morgan, C, Dazzan, P, Morgan, K, Lloyd, T et al. (2006) Incidence of schizophrenia and other psychoses in ethnic minority groups: results from the MRC AESOP study. Psychological Medicine 36, 1541–1550.Google Scholar
Fineberg, AM, Ellman, LM, Schaefer, CA, Maxwell, SD, Shen, L, Chaudhury, NH et al. (2016) Fetal exposure to maternal stress and risk for schizophrenia spectrum disorders among offspring: differential influences of fetal sex. Psychiatry Research 236, 91–97.Google Scholar
Fisher, H, Caspi, A, Poulton, R, Meier, M, Houts, R, Harrington, H et al. (2013) Specificity of childhood psychotic symptoms for predicting schizophrenia by 38 years of age: a birth cohort study. Psychological Medicine 43, 2077–2086.Google Scholar
Fisher, HL, McGuffin, P, Boydell, J, Fearon, P, Craig, TK, Dazzan, P et al. (2014) Interplay between childhood physical abuse and familial risk in the onset of psychotic disorders. Schizophrenia Bulletin 40, 1443–1451.Google Scholar
Gage, SH, Hickman, M, Heron, J, Munafò, MR, Lewis, G, Macleod, J et al. (2014) Associations of cannabis and cigarette use with psychotic experiences at age 18: findings from the Avon longitudinal study of parents and children. Psychological Medicine 44, 3435–3444.Google Scholar
Gage, SH, Hickman, M and Zammit, S (2015) Association between cannabis and psychosis: epidemiologic evidence. Biological Psychiatry 18, 1–8.Google Scholar
Genovese, G, Fromer, M, Stahl, EA, Ruderfer, DM, Chambert, K, Landén, M et al. (2016) Increased burden of ultra-rare protein-altering variants among 4877 individuals with schizophrenia. Nature Neuroscience 19, 1433–1441.Google Scholar
Girard, SL, Dion, PA, Bourassa, CV, Geoffroy, S, Lachance-Touchette, P, Barhdadi, A et al. (2015) Mutation burden of rare variants in schizophrenia candidate genes. PLOS ONE 10, 1–11.Google Scholar
Gottesman, II, Laursen, TM, Bertelsen, A and Mortensen, PB (2010) Severe mental disorders in offspring with 2 psychiatrically ill parents. Archives of General Psychiatry 67, 252–257.Google Scholar
Green, MJ, Chia, TY, Cairns, MJ, Wu, J, Tooney, PA, Scott, RJ et al. (2014) Catechol-O-methyltransferase (COMT) genotype moderates the effects of childhood trauma on cognition and symptoms in schizophrenia. Journal of Psychiatric Research 49, 43–50.Google Scholar
GROUP investigators (2011) Evidence that familial liability for psychosis is expressed as differential sensitivity to cannabis. Archives of General Psychiatry 68, 138.Google Scholar
Gurillo, P, Jauhar, S, Murray, RM and MacCabe, JH (2015) Does tobacco use cause psychosis? Systematic review and meta-analysis. The Lancet Psychiatry 2, 718–725.Google Scholar
Hajebi, A, Amini, H, Kashani, L and Sharifi, V (2016) Twelve-month course and outcome of methamphetamine-induced psychosis compared with first episode primary psychotic disorders. Early Intervention in Psychiatry, 1–7.Google Scholar
Han, B, Pouget, JG, Slowikowski, K, Stahl, E, Lee, CH, Diogo, D et al. (2016) A method to decipher pleiotropy by detecting underlying heterogeneity driven by hidden subgroups applied to autoimmune and neuropsychiatric diseases. Nature Genetics 48, 803–810.Google Scholar
Hill, AB (1965) The environment and disease: association or causation? Proceedings of the Royal Society of Medicine 58, 295–300.Google Scholar
Holick, F (1995) Environmental factors that influence the cutaneous production of vitamin D1-3. American Journal of Clinical Nutrition 61, 638S–645S.Google Scholar
Holloway, T, Moreno, JL, Umali, A, Rayannavar, V, Hodes, GE, Russo, SJ et al. (2013) Prenatal stress induces schizophrenia-like alterations of serotonin 2A and metabotropic glutamate 2 receptors in the adult offspring: role of maternal immune system. The Journal of Neuroscience 33, 1088–1098.Google Scholar
Hong Lee, S, Byrne, EM, Hultman, CM, Kahler, A, Vinkhuyzen, AAE, Ripke, S, et al. (2015) New data and an old puzzle: the negative association between schizophrenia and rheumatoid arthritis. International Journal of Epidemiology 44, 1706–1721Google Scholar
Jones, HJ, Stergiakouli, E, Tansey, KE, Hubbard, L, Heron, J, Cannon, M et al. (2016) Phenotypic manifestation of genetic risk for schizophrenia during adolescence in the general population. JAMA Psychiatry 73, 221–228.Google Scholar
Keers, R, Coleman, JRI, Lester, KJ, Roberts, S, Breen, G, Thastum, M et al. (2016) A genome-wide test of the differential susceptibility hypothesis reveals a genetic predictor of differential response to psychological treatments for child anxiety disorders. Psychotherapy and Psychosomatics 85, 146–158.Google Scholar
Kelleher, I, Connor, D, Clarke, MC, Devlin, N, Harley, M and Cannon, M (2012) Prevalence of psychotic symptoms in childhood and adolescence: a systematic review and meta-analysis of population-based studies. Psychological Medicine 42, 1857–1863.Google Scholar
Kelley, ME, Wan, CR, Broussard, B, Crisafio, A, Cristofaro, S, Johnson, S et al. (2016) Marijuana use in the immediate 5-year premorbid period is associated with increased risk of onset of schizophrenia and related psychotic disorders. Schizophrenia Research 171, 62–67.Google Scholar
Kennedy, BP, Kawachi, I, Glass, R and Prothrow-Stith, D (1998) Income distribution, socioeconomic status, and self rated health in the United States: multilevel analysis. BMJ 317, 917–921.Google Scholar
Kety, SS, Wender, PH, Jacobsen, B, Ingraham, LJ, Jansson, L, Faber, B et al. (1994) Mental illness in the biological and adoptive relatives of schizophrenic adoptees. Archives of General Psychiatry 51, 442–455.Google Scholar
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. Archives of General Psychiatry 65, 146–152.Google Scholar
Kooijman, MN, Kruithof, CJ, van Duijn, CM, Duijts, L, Franco, OH, van IJzendoorn, MH et al. (2016) The generation R study: design and cohort update 2017. European Journal of Epidemiology 31, 1243–1264.Google Scholar
Korver, N, Quee, PJ, Boos, HBM, Simons, CJP and de Haan, L (2012) Genetic Risk and Outcome of Psychosis (GROUP), a multi site longitudinal cohort study focused on gene-environment interaction: objectives, sample characteristics, recruitment and assessment methods. International Journal of Methods in Psychiatric Research 21, 205–221.Google Scholar
Li, H, Lu, Q, Xiao, E, Li, Q, He, Z and Mei, X (2014) Methamphetamine enhances the development of schizophrenia in first-degree relatives of patients with schizophrenia. Canadian Journal of Psychiatry 59, 107–113.Google Scholar
MacKenzie, LE, Abidi, S, Fisher, HL, Propper, L, Bagnell, A, Morash-Conway, J et al. (2016) Stimulant medication and psychotic symptoms in offspring of parents with mental illness. Pediatrics 137, e20152486.Google Scholar
Mäki, P, Riekki, T, Miettunen, J, Isohanni, M, Jones, PB, Murray, GK et al. (2010) Schizophrenia in the offspring of antenatally depressed mothers in the Northern Finland 1966 birth cohort: relationship to family history of psychosis. American Journal of Psychiatry 167, 70–77.Google Scholar
Malaspina, D, Corcoran, C, Kleinhaus, KR, Perrin, MC, Fennig, S, Nahon, D et al. (2008) Acute maternal stress in pregnancy and schizophrenia in offspring: a cohort prospective study. BMC Psychiatry 8, 1–9.Google Scholar
Marconi, A, Di Forti, M, Lewis, C, Murray, RM and Vassos, E (2016) Meta-analysis of the association between the level of cannabis use and risk of psychosis. Schizophrenia Bulletin 42, 1262–1269.Google Scholar
Marshall, C, Howrigan, D, Merico, D, Thiruvahindrapuram, B, Wu, WGreer, D, et al. (2016) Contribution of novel CNVs to schizophrenia from a genome-wide study of 41321 subjects. Nature Genetics 49, 27–38.Google Scholar
Martin, J, Tilling, K, Hubbard, L, Stergiakouli, E, Thapar, A, Davey Smith, G et al. (2016) Association of genetic risk for schizophrenia with nonparticipation over time in a population-based cohort study. American Journal of Epidemiology 183, 1149–1158.Google Scholar
McGrath, J (1999) Hypothesis: is low prenatal vitamin D a risk-modifying factor for schizophrenia? Schizophrenia Research 40, 173–177.Google Scholar
McGrath, J, Saari, K, Hakko, H, Jokelainen, J, Jones, P, Järvelin, MR et al. (2004) Vitamin D supplementation during the first year of life and risk of schizophrenia: a Finnish birth cohort study. Schizophrenia Research 67, 237–245.Google Scholar
McGrath, JJ, Alati, R, Clavarino, A, Williams, GM, Bor, W, Najman, JM et al. (2016) Age at first tobacco use and risk of subsequent psychosis-related outcomes: a birth cohort study. The Australian and New Zealand Journal of Psychiatry 50, 577–583.Google Scholar
McGrath, JJ, Burne, TH, Féron, F, MacKay-Sim, A and Eyles, DW (2010a) Developmental vitamin D deficiency and risk of schizophrenia: a 10-year update. Schizophrenia Bulletin 36, 1073–1078.Google Scholar
McGrath, JJ, Eyles, DW, Pedersen, CB, Anderson, C, Ko, P, Burne, TH et al. (2010b) Neonatal vitamin D status and risk of schizophrenia. Archives of General Psychiatry 67, 889–894.Google Scholar
McKetin, R, Gardner, J, Baker, AL, Dawe, S, Ali, R, Voce, A et al. (2016) Correlates of transient versus persistent psychotic symptoms among dependent methamphetamine users. Psychiatry Research 238, 166–171.Google Scholar
Mednick, SA, Machon, RA, Huttunen, MO and Bonett, D (1988) Adult schizophrenia following prenatal exposure to an influenza epidemic. Archives of General Psychiatry 45, 189–192.Google Scholar
Ménard, C, Pfau, ML, Hodes, GE and Russo, SJ (2017) Immune and neuroendocrine mechanisms of stress vulnerability and resilience. Neuropsychopharmacology Reviews 42, 62–80.Google Scholar
Miller, BJ, Culpepper, N, Rapaport, MH and Buckley, P (2013) Prenatal inflammation and neurodevelopment in schizophrenia: a review of human studies. Progress in Neuro-Psychopharmacology and Biological Psychiatry 42, 92–100.Google Scholar
Moore, THM, Zammit, S, Lingford-hughes, A, Barnes, TRE, Jones, PB, Burke, M et al. (2007) Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. The Lancet 370, 319–328.Google Scholar
Morgan, CJA, Freeman, TP, Powell, J and Curran, HV (2016) AKT1 genotype moderates the acute psychotomimetic effects of naturalistically smoked cannabis in young cannabis smokers. Translational Psychiatry 6, e738.Google Scholar
Mortensen, PB, Pedersen, CB, Westergaard, T, Wohlfahrt, J, Ewald, H, Mors, O et al. (1999) Effects of family history and place and season of birth on the risk of schizophrenia. The New England Journal of Medicine 340, 603–608.Google Scholar
Newbury, J, Arseneault, L, Caspi, A, Moffitt, TE, Odgers, CL and Fisher, HL (2016) Why are children in urban neighborhoods at increased risk for psychotic symptoms? Findings from a UK longitudinal cohort study. Schizophrenia Bulletin 42, 372–383.Google Scholar
Ng, MYM, Levinson, DF, Faraone, SV, Suarez, BK, DeLisi, LE, Arinami, T et al. (2009) Meta-analysis of 32 genome-wide linkage studies of schizophrenia. Molecular Psychiatry 14, 774–785.Google Scholar
Niarchou, M, Zammit, S, Van Goozen, SHM, Thapar, A, Tierling, HM, Owen, MJ et al. (2014) Psychopathology and cognition in children with 22q11.2 deletion syndrome. British Journal of Psychiatry 204, 46–54.Google Scholar
Nielsen, PR, Meyer, U and Mortensen, PB (2016) Individual and combined effects of maternal anemia and prenatal infection on risk for schizophrenia in offspring. Schizophrenia Research 172, 35–40.Google Scholar
Nosarti, C, Reichenberg, A and Murray, RM (2012) Preterm birth and psychiatric disorders in young adult life. Archives of General Psychiatry 69, E1–E8.Google Scholar
O'Donoghue, B, Lyne, J, Madigan, K, Lane, A, Turner, N, O'Callaghan, E et al. (2015) Environmental factors and the age at onset in first episode psychosis. Schizophrenia Research 168, 106–112.Google Scholar
Orlovska, S, Pedersen, MS, Benros, ME, Mortensen, PB, Agerbo, E and Nordentoft, M (2014) Head injury as risk factor for psychiatric disorders: a nationwide register-based follow-up study of 113906 persons with head injury. American Journal of Psychiatry 171, 463–469.Google Scholar
Owen, MJ and Doherty, JL (2016) What can we learn from the high rates of schizophrenia in people with 22q11.2 deletion syndrome? World Psychiatry 15, 22–23.Google Scholar
Padmanabhan, JL, Shah, JL, Tandon, N and Keshavan, MS (2017) The ‘polyenviromic risk score’: aggregating environmental risk factors predicts conversion to psychosis in familial high-risk subjects. Schizophrenia Research 181, 17–22.Google Scholar
Pedersen, CB and Mortensen, PB (2001) Evidence of a dose-response relationship between urbanicity during upbringing and schizophrenia risk. Archives of General Psychiatry 58, 1039–1046.Google Scholar
Perala, J, Suvisaari, J, Saarni, SI, Kuoppasalmi, K, Isometsa, E, Pirkola, S et al. (2007) Lifetime prevalence of psychotic and bipolar I disorders in a general population. Archives of General Psychiatry 64, 19–28.Google Scholar
Pickrell, JK, Berisa, T, Liu, JZ, Ségurel, L, Tung, JY and Hinds, DA (2016) Detection and interpretation of shared genetic influences on 42 human traits. Nature Genetics 48, 709–717.Google Scholar
Plomin, R, DeFries, JC and Loehlin, JC (1977) Genotype-environment interaction and correlation in the analysis of human behavior. Psychological bulletin 84, 309–322.Google Scholar
Polanczyk, G, Moffitt, TE, Arseneault, L, Cannon, M, Ambler, A, Keefe, RSE et al. (2010) Etiological and clinical features of childhood psychotic symptoms: results from a birth cohort. Archives of General Psychiatry 67, 328–338.Google Scholar
Polderman, TJC, Benyamin, B, de Leeuw, CA, Sullivan, PF, van Bochoven, A, Visscher, PM et al. (2015) Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nature Genetics 47, 702–709.Google Scholar
Poulton, R, Caspi, A, Moffitt, TE, Cannon, M, Murray, RM and Harrington, H (2000) Children's self-reported psychotic symptoms and adult schizophreniform disorder: a 15-year longitudinal study. Archives of General Psychiatry 57, 1053–1058.Google Scholar
Purcell, SM, Moran, JL, Fromer, M, Ruderfer, D, Solovieff, N, Roussos, P et al. (2014) A polygenic burden of rare disruptive mutations in schizophrenia. Nature 506, 185–190.Google Scholar
Ramsay, H, Kelleher, I, Flannery, P, Clarke, MC, Lynch, F, Harley, M et al. (2013) Relationship between the COMT-Val158Met and BDNF-Val66Met polymorphisms, childhood trauma and psychotic experiences in an adolescent general population sample. PLOS ONE 8, e79741.Google Scholar
Reininghaus, U, Dutta, R, Dazzan, P, Doody, GA, Fearon, P, Lappin, J et al. (2015) Mortality in schizophrenia and other psychoses: a 10-year follow-up of the ÆSOP first-episode cohort. Schizophrenia Bulletin 41, 664–673.Google Scholar
Riglin, L, Collishaw, S, Richards, A, Thapar, AK, Maughan, B, O'Donovan, MC et al. (2016) Schizophrenia risk alleles and neurodevelopmental outcomes in childhood: a population-based cohort study. The Lancet Psychiatry 4, 57–62.Google Scholar
Sanders, AR, Duan, J, Levinson, DF, Shi, J, He, D, Hou, C et al. (2008) No significant association of 14 candidate genes to schizophrenia in a large European-ancestry sample: implications for psychiatric genetics. American Journal of Psychiatry 165, 497–506.Google Scholar
Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427.Google Scholar
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. Archives of General Psychiatry 66, 527–536.Google Scholar
Sekar, A, Bialas, AR, de Rivera, H, Davis, A, Hammond, TR, Kamitaki, N et al. (2016) Schizophrenia risk from complex variation of complement component 4. Nature 530, 177–183.Google Scholar
Sideli, L, Fisher, HL, Murray, RM, Sallis, H, Russo, M, Stilo, SA et al. (2015) Interaction between cannabis consumption and childhood abuse in psychotic disorders: preliminary findings on the role of different patterns of cannabis use. Early Intervention in Psychiatry, 1–8.Google Scholar
Singh, T, Kurki, MI, Curtis, D, Purcell, SM, Crooks, L, McRae, J et al. (2016) Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders. Nature Neuroscience 19, 571–577.Google Scholar
Smith, K (2011) Trillion-dollar brain drain. Nature 478, 15–15.Google Scholar
Stefanis, NC, Dragovic, M, Power, BD, Jablensky, A, Castle, D and Morgan, VA (2013) Age at initiation of cannabis use predicts age at onset of psychosis: the 7-to 8-year trend. Schizophrenia Bulletin 39, 251–254.Google Scholar
Stefanis, NC, Henquet, C, Avramopoulos, D, Smyrnis, N, Evdokimidis, I, Myin-Germeys, I et al. (2007) COMT valmet moderation of stress-induced psychosis. Psychological Medicine 37, 1651–1656.Google Scholar
Stepniak, B, Papiol, S, Hammer, C, Ramin, A, Everts, S, Hennig, L et al. (2014) Accumulated environmental risk determining age at schizophrenia onset: a deep phenotyping-based study. The Lancet Psychiatry 1, 444–453.Google Scholar
Sullivan, PF, Agrawal, A, Bulik, CM, Andreassen, OA, Borglum, AD, Breen, G et al. (2017) Psychiatric genomics: an update and an agenda. American Journal of Psychiatry, doi: 10.1176/appi.ajp.2017.17030283.Google Scholar
Sullivan, PF, Kendler, KS and Neale, MC (2003) Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Archives of General Psychiatry 60, 1187–1192.Google Scholar
Susser, ES and Lin, SP (1992) Schizophrenia after prenatal exposure to the Dutch Hunger Winter of 1944–1945. Archives of General Psychiatry 49, 983–988.Google Scholar
Taylor, A, Jones, H, Sallis, H, Eusden, J, Stergiakouli, E, Davies, N et al. (2017) The molecular genetics of participation in the Avon Longitudinal Study of Parents and Children. bioRxiv, doi: 10.1101/206698.Google Scholar
Taylor, PJ (2007) The unreliability of high human heritability estimates and small shared effects of growing up in the same family. Biological Theory 2, 387–397.Google Scholar
Thorup, AAE, Jepsen, JR, Ellersgaard, DV, Burton, BK, Christiani, CJ, Hemager, N et al. (2015) The Danish High Risk and Resilience Study – VIA 7 – a cohort study of 520 7-year-old children born of parents diagnosed with either schizophrenia, bipolar disorder or neither of these two mental disorders. BMC Psychiatry 15, 233.Google Scholar
Tienari, P, Ynne, LCW, Sorri, A and Lahti, I (2004) Genotype-environment interaction in schizophrenia-spectrum disorder: long-term follow-up study of Finnish adoptees. British Journal of Psychiatry 184, 216–222.Google Scholar
Torrey, EF, Bartko, JJ and Yolken, RH (2012) Toxoplasma gondii and other risk factors for schizophrenia: an update. Schizophrenia Bulletin 38, 642–647.Google Scholar
Tottenham, N (2013) Risk and developmental heterogeneity in previously institutionalized children. Journal of Adolescent Health 51, S29–S33.Google Scholar
Trotta, A, Di Forti, M, Iyegbe, C, Green, P, Dazzan, P, Mondelli, V et al. (2015) Familial risk and childhood adversity interplay in the onset of psychosis. British Journal of Psychiatry Open 1, 6–13.Google Scholar
Trotta, A, Di Forti, M, Mondelli, V, Dazzan, P, Pariante, C, David, A et al. (2013) Prevalence of bullying victimisation amongst first-episode psychosis patients and unaffected controls. Schizophrenia Research 150, 169–175.Google Scholar
Trotta, A, Iyegbe, C, Di Forti, M, Sham, PC, Campbell, DD, Cherny, SS et al. (2016) Interplay between schizophrenia polygenic risk score and childhood adversity in first-presentation psychotic disorder: a pilot study. PLOS ONE 11, e0163319.Google Scholar
Uher, R, Cumby, J, Mackenzie, LE, Morash-conway, J, Glover, JM, Aylott, A et al. (2014) A familial risk enriched cohort as a platform for testing early interventions to prevent severe mental illness. BMC Psychiatry 14, 344.Google Scholar
Uher, R and Zwicker, A (2017) Etiology in psychiatry: embracing the reality of poly-gene-environmental causation of mental illness. World Psychiatry 16, 121–129.Google Scholar
Van Den Bossche, MJ, Strazisar, M, Cammaerts, S, Liekens, AM, Vandeweyer, G, Depreeuw, V et al. (2013) Identification of rare copy number variants in high burden schizophrenia families. American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics 162, 273–282.Google Scholar
van Gastel, WA, MacCabe, JH, Schubart, CD, Vreeker, A, Tempelaar, W, Kahn, RS et al. (2013) Cigarette smoking and cannabis use are equally strongly associated with psychotic-like experiences: a cross-sectional study in 1929 young adults. Psychological Medicine 43, 2393–2401.Google Scholar
Van Nierop, M, Janssens, M, Bruggeman, R, Cahn, W, De Haan, L, Kahn, RS et al. (2013) Evidence that transition from health to psychotic disorder can be traced to semi-ubiquitous environmental effects operating against background genetic risk. PLOS ONE 8, e76690.Google Scholar
Van Os, J, Hanssen, M, Bak, M, Bijl, RV and Vollebergh, W (2003) Do urbanicity and familial liability coparticipate in causing psychosis? American Journal of Psychiatry 160, 477–482.Google Scholar
Van Os, J, Pedersen, CB and Mortensen, PB (2004) Confirmation of synergy between urbanicity and familial liability in the causation of psychosis. American Journal of Psychiatry 161, 2312–2314.Google Scholar
van Os, J and Selten, J-P (1998) Prenatal exposure to maternal stress and subsequent schizophrenia. The May 1940 invasion of The Netherlands. British Journal of Psychiatry 172, 324–326.Google Scholar
van Winkel, R (2011) Family-based analysis of genetic variation underlying psychosis-inducing effects of cannabis: sibling analysis and proband follow-up. Archives of General Psychiatry 68, 148–157.Google Scholar
van Winkel, R, GROUP investigators (2015) Further evidence that cannabis moderates familial correlation of psychosis-related experiences. PLOS ONE 10, e0137625.Google Scholar
Varese, F, Smeets, F, Drukker, M, Lieverse, R, Lataster, T, Viechtbauer, W et al. (2012) Childhood adversities increase the risk of psychosis: a meta-analysis of patient-control, prospective-and cross-sectional cohort studies. Schizophrenia Bulletin 38, 661–671.Google Scholar
Vassos, E, Di Forti, M, Coleman, J, Iyegbe, C, Prata, D, Euesden, J, et al. (2017) An examination of polygenic score risk prediction in individuals with first episode psychosis. Biological Psychiatry 81, 470–477.Google Scholar
Vassos, E, Pedersen, CB, Murray, RM, Collier, DA and Lewis, CM (2012) Meta-analysis of the association of urbanicity with schizophrenia. Schizophrenia Bulletin 38, 1118–1123.Google Scholar
Vaucher, J, Keating, BJ, Lasserre, AM, Gan, W, Lyall, D, Ward, J et al. (2017) Cannabis use and risk of schizophrenia: a Mendelian randomization study. Molecular Psychiatry, 1–6.Google Scholar
Verweij, KJH, Abdellaoui, A, Nivard, MG, Sainz Cort, A, Ligthart, L, Draisma, HHM et al. (2017) Short communication: genetic association between schizophrenia and cannabis use. Drug and Alcohol Dependence 171, 117–121.Google Scholar
Vinkers, CH, Van Gastel, WA, Schubart, CD, Van Eijk, KR, Luykx, JJ, Van Winkel, R et al. (2013) The effect of childhood maltreatment and cannabis use on adult psychotic symptoms is modified by the COMT Val158Met polymorphism. Schizophrenia Research 150, 303–311.Google Scholar
Walsh, C, MacMillan, H and Jamieson, E (2002) The relationship between parental psychiatric disorder and child physical and sexual abuse: findings from the Ontario health supplement. Child Abuse and Neglect 26, 11–22.Google Scholar
Walsh, T, McClellan, JM, McCarthy, SE, Addington, AM, Pierce, SB, Cooper, GM et al. (2008) Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320, 539–543.Google Scholar
Weber-Stadlbauer, U, Richetto, J, Labouesse, MA, Bohacek, J, Mansuy, IM and Meyer, U (2017) Transgenerational transmission and modification of pathological traits induced by prenatal immune activation. Molecular Psychiatry 22, 102–112.Google Scholar
Wolke, D, Lereya, ST, Fisher, HL, Lewis, G and Zammit, S (2014) Bullying in elementary school and psychotic experiences at 18 years: a longitudinal, population-based cohort study. Psychological Medicine 44, 2199–2211.Google Scholar
Zammit, S, Owen, MJ, Evans, J, Heron, J and Lewis, G (2011) Cannabis, COMT and psychotic experiences. British Journal of Psychiatry 199, 380–385.Google Scholar
Zavos, HMS, Freeman, D, Haworth, CMA, McGuire, P, Plomin, R, Cardno, AG et al. (2014) Consistent etiology of severe, frequent psychotic experiences and milder, less frequent manifestations. JAMA Psychiatry 71, 1049–1057.Google Scholar