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The emerging molecular architecture of schizophrenia, polygenic risk scores and the clinical implications for GxE research

Abstract

Schizophrenia is a devastating mental disorder. The level of risk in the general population is sustained by the persistence of social, environmental and biological factors, as well as their interactions. Socio-environmental risk factors for schizophrenia are well established and robust. The same can belatedly be said of genetic risk factors for the disorder. Recent progress in schizophrenia genetics is primarily fuelled by genome-wide association, which is able to leverage substantial proportions of additional explained variance previously classified as ‘missing’. Here, we provide an outline of the emerging genetic landscape of schizophrenia and demonstrate how this knowledge can be turned into a simple empirical measure of genetic risk, known as a polygenic risk score. We highlight the statistical framework used to assess the clinical potential of the new score and finally, draw relevance to and discuss the clinical implications for the study of gene–environment interaction.

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References

  1. 1.

    Harrison G, Hopper K, Craig T et al (2001) Recovery from psychotic illness: a 15- and 25-year international follow-up study. Br J Psychiatry 178:506–517

  2. 2.

    Saha S, Chant D, Welham J, McGrath J (2005) A systematic review of the prevalence of schizophrenia. PLoS Med 2(5):e141

  3. 3.

    O’Malley AJ, Frank RG, Normand SL (2011) Estimating cost-offsets of new medications: use of new antipsychotics and mental health costs for schizophrenia. Stat Med 30(16):1971–1988

  4. 4.

    Awad AG, Voruganti LN (2008) The burden of schizophrenia on caregivers: a review. Pharmacoeconomics 26(2):149–162

  5. 5.

    Chan SW (2011) Global perspective of burden of family caregivers for persons with schizophrenia. Arch Psychiatr Nurs 25(5):339–349

  6. 6.

    Kirkbride J, Coid JW, Morgan C et al (2010) Translating the epidemiology of psychosis into public mental health: evidence, challenges and future prospects. J Public Ment Health 9(2):4–14

  7. 7.

    Wray NR, Yang J, Goddard ME, Visscher PM (2010) The genetic interpretation of area under the ROC curve in genomic profiling. PLoS Genet 6(2):e1000864

  8. 8.

    Cardno AG, Marshall EJ, Coid B et al (1999) Heritability estimates for psychotic disorders: the Maudsley twin psychosis series. Arch Gen Psychiatry 56(2):162–168

  9. 9.

    Lander ES, Linton LM, Birren B et al (2001) Initial sequencing and analysis of the human genome. Nature 409(6822):860–921

  10. 10.

    Yang J, Lee SH, Goddard ME, Visscher PM (2011) GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet 88(1):76–82

  11. 11.

    Wray NR, Visscher PM (2010) Narrowing the boundaries of the genetic architecture of schizophrenia. Schizophr Bull 36(1):14–23

  12. 12.

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

  13. 13.

    Lichtenstein P, Yip BH, Bjork C et al (2009) Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 373(9659):234–239

  14. 14.

    Visscher PM, Goddard ME, Derks EM, Wray NR (2012) Evidence-based psychiatric genetics, AKA the false dichotomy between common and rare variant hypotheses. Mol Psychiatry 17(5):474–485

  15. 15.

    Vassos E, Collier DA, Holden S et al (2010) Penetrance for copy number variants associated with schizophrenia. Hum Mol Genet 19(17):3477–3481

  16. 16.

    Heinz A, Deserno L, Reininghaus U (2013) Urbanicity, social adversity and psychosis. World Psychiatry 12(3):187–197

  17. 17.

    Kelly BD, O’Callaghan E, Waddington JL et al (2010) Schizophrenia and the city: a review of literature and prospective study of psychosis and urbanicity in Ireland. Schizophr Res 116(1):75–89

  18. 18.

    Vassos E, Pedersen CB, Murray RM, Collier DA, Lewis CM (2012) Meta-analysis of the association of urbanicity with schizophrenia. Schizophr Bull 38(6):1118–1123

  19. 19.

    Brown AS (2011) The environment and susceptibility to schizophrenia. Prog Neurobiol 93(1):23–58

  20. 20.

    Veling W, Susser E (2011) Migration and psychotic disorders. Expert Rev Neurother 11(1):65–76

  21. 21.

    Allardyce J, Boydell J (2006) Review: the wider social environment and schizophrenia. Schizophr Bull 32(4):592–598

  22. 22.

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

  23. 23.

    Morgan C, Charalambides M, Hutchinson G, Murray RM (2010) Migration, ethnicity, and psychosis: toward a sociodevelopmental model. Schizophr Bull 36(4):655–664

  24. 24.

    Dealberto MJ (2010) Ethnic origin and increased risk for schizophrenia in immigrants to countries of recent and longstanding immigration. Acta Psychiatr Scand 121(5):325–339

  25. 25.

    Henquet C, Murray R, Linszen D, van Os J (2005) The environment and schizophrenia: the role of cannabis use. Schizophr Bull 31(3):608–612

  26. 26.

    Semple DM, McIntosh AM, Lawrie SM (2005) Cannabis as a risk factor for psychosis: systematic review. J Psychopharmacol 19(2):187–194

  27. 27.

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

  28. 28.

    Moore TH, Zammit S, Lingford-Hughes A et al (2007) Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet 370(9584):319–328

  29. 29.

    Parakh P, Basu D (2013) Cannabis and psychosis: have we found the missing links? Asian J Psychiatr 6(4):281–287

  30. 30.

    Schafer I, Fisher HL (2011) Childhood trauma and psychosis—what is the evidence? Dialogues Clin Neurosci 13(3):360–365

  31. 31.

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

  32. 32.

    Varese F, Smeets F, Drukker M et al (2012) Childhood adversities increase the risk of psychosis: a meta-analysis of patient-control, prospective- and cross-sectional cohort studies. Schizophr Bull 38(4):661–671

  33. 33.

    Miller B, Pihlajamaa J, Haukka J et al (2010) Paternal age and mortality in nonaffective psychosis. Schizophr Res 121(1–3):218–226

  34. 34.

    Miller B, Messias E, Miettunen J et al (2011) Meta-analysis of paternal age and schizophrenia risk in male versus female offspring. Schizophr Bull 37(5):1039–1047

  35. 35.

    Davies G, Welham J, Chant D, Torrey EF, McGrath J (2003) A systematic review and meta-analysis of Northern Hemisphere season of birth studies in schizophrenia. Schizophr Bull 29(3):587–593

  36. 36.

    Palmer CG (2010) Evidence for maternal-fetal genotype incompatibility as a risk factor for schizophrenia. J Biomed Biotechnol 2010:576318

  37. 37.

    Scott J, McNeill Y, Cavanagh J, Cannon M, Murray R (2006) Exposure to obstetric complications and subsequent development of bipolar disorder: systematic review. Br J Psychiatry 189:3–11

  38. 38.

    McGrath JJ, Eyles DW, Pedersen CB et al (2010) Neonatal vitamin D status and risk of schizophrenia: a population-based case-control study. Arch Gen Psychiatry 67(9):889–894

  39. 39.

    Khandaker GM, Zimbron J, Lewis G, Jones PB (2013) Prenatal maternal infection, neurodevelopment and adult schizophrenia: a systematic review of population-based studies. Psychol Med 43(2):239–257

  40. 40.

    Brown AS (2012) Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism. Dev Neurobiol 72(10):1272–1276

  41. 41.

    Cohen A, Patel V, Thara R, Gureje O (2008) Questioning an axiom: better prognosis for schizophrenia in the developing world? Schizophr Bull 34(2):229–244

  42. 42.

    Aleman A, Kahn RS, Selten JP (2003) Sex differences in the risk of schizophrenia: evidence from meta-analysis. Arch Gen Psychiatry 60(6):565–571

  43. 43.

    McGrath J, Saha S, Welham J, El Saadi O, MacCauley C, Chant D (2004) A systematic review of the incidence of schizophrenia: the distribution of rates and the influence of sex, urbanicity, migrant status and methodology. BMC Med 2:13

  44. 44.

    Tandon R, Keshavan MS, Nasrallah HA (2008) Schizophrenia, “just the facts” what we know in 2008. 2. Epidemiology and etiology. Schizophr Res 102(1–3):1–18

  45. 45.

    Gunderson KL, Steemers FJ, Lee G, Mendoza LG, Chee MS (2005) A genome-wide scalable SNP genotyping assay using microarray technology. Nat Genet 37(5):549–554

  46. 46.

    Wang DG, Fan JB, Siao CJ et al (1998) Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome. Science 280(5366):1077–1082

  47. 47.

    Purcell SM, Wray NR, Stone JL et al (2009) Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460(7256):748–752

  48. 48.

    Walsh T, McClellan JM, McCarthy SE et al (2008) Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320(5875):539–543

  49. 49.

    Ripke S, O’Dushlaine C, Chambert K et al (2013) Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet 45(10):1150–1159

  50. 50.

    Psychiatric Genetics Consortium (2014) in preparation

  51. 51.

    Sullivan PF, Neale MC, Kendler KS (2000) Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry 157(10):1552–1562

  52. 52.

    Abecasis GR, Altshuler D, Auton A et al (2010) A map of human genome variation from population-scale sequencing. Nature 467(7319):1061–1073

  53. 53.

    Sebat J, Lakshmi B, Troge J et al (2004) Large-scale copy number polymorphism in the human genome. Science 305(5683):525–528

  54. 54.

    Iafrate AJ, Feuk L, Rivera MN et al (2004) Detection of large-scale variation in the human genome. Nat Genet 36(9):949–951

  55. 55.

    Uher R (2009) The role of genetic variation in the causation of mental illness: an evolution-informed framework. Mol Psychiatry 14(12):1072–1082

  56. 56.

    Xu B, Roos JL, Levy S, van Rensburg EJ, Gogos JA, Karayiorgou M (2008) Strong association of de novo copy number mutations with sporadic schizophrenia. Nat Genet 40(7):880–885

  57. 57.

    Jaffe AE, Eaton WW, Straub RE, Marenco S, Weinberger DR (2013) Paternal age, de novo mutations and schizophrenia. Mol Psychiatry [Epub ahead of print]

  58. 58.

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

  59. 59.

    Stefansson H, Sigurdsson E, Steinthorsdottir V et al (2002) Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 71(4):877–892

  60. 60.

    Blackwood DH, Fordyce A, Walker MT, St Clair DM, Porteous DJ, Muir WJ (2001) Schizophrenia and affective disorders—cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am J Hum Genet 69(2):428–433

  61. 61.

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

  62. 62.

    Ng MY, Levinson DF, Faraone SV et al (2009) Meta-analysis of 32 genome-wide linkage studies of schizophrenia. Mol Psychiatry 14(8):774–785

  63. 63.

    Magri C, Sacchetti E, Traversa M et al (2010) New copy number variations in schizophrenia. PLoS One 5(10):e13422

  64. 64.

    Rees E, Walters JT, Georgieva L et al (2013) Analysis of copy number variations at 15 schizophrenia-associated loci. Br J Psychiatry [Epub ahead of print]

  65. 65.

    International Schizophrenia Consortium (2008) Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455(7210):237–241

  66. 66.

    Levinson DF, Duan J, Oh S et al (2011) Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. Am J Psychiatry 168(3):302–316

  67. 67.

    Mulle JG, Dodd AF, McGrath JA et al (2010) Microdeletions of 3q29 confer high risk for schizophrenia. Am J Hum Genet 87(2):229–236

  68. 68.

    Shifman S, Johannesson M, Bronstein M et al (2008) Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women. PLoS Genet 4(2):e28

  69. 69.

    O’Donovan MC, Craddock N, Norton N et al (2008) Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nat Genet 40(9):1053–1055

  70. 70.

    Maher B (2008) Personal genomes: the case of the missing heritability. Nature 456(7218):18–21

  71. 71.

    Derks EM, Vorstman JA, Ripke S, Kahn RS, Ophoff RA (2012) Investigation of the genetic association between quantitative measures of psychosis and schizophrenia: a polygenic risk score analysis. PLoS One 7(6):e37852

  72. 72.

    Terwisscha van Scheltinga AF, Bakker SC, van Haren NE et al (2013) Genetic schizophrenia risk variants jointly modulate total brain and white matter volume. Biol Psychiatry 73(6):525–531

  73. 73.

    Evans DM, Visscher PM, Wray NR (2009) Harnessing the information contained within genome-wide association studies to improve individual prediction of complex disease risk. Hum Mol Genet 18(18):3525–3531

  74. 74.

    Dudbridge F (2013) Power and predictive accuracy of polygenic risk scores. PLoS Genet 9(3):e1003348

  75. 75.

    Lee SH, DeCandia TR, Ripke S et al (2012) Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs. Nat Genet 44(3):247–250

  76. 76.

    International HapMap Consortium (2005) A haplotype map of the human genome. Nature 437(7063):1299–1320

  77. 77.

    de Candia TR, Lee SH, Yang J et al (2013) Additive genetic variation in schizophrenia risk is shared by populations of African and European descent. Am J Hum Genet 93(3):463–470

  78. 78.

    Abel KM, Drake R, Goldstein JM (2010) Sex differences in schizophrenia. Int Rev Psychiatry 22(5):417–428

  79. 79.

    Avshalom Caspi RMH, Belsky DW et al (2013) The p factor: one general psychopathology factor in the structure of psychiatric disorders? Clin Psychol Sci [Epub ahead of print]

  80. 80.

    Lee SH, Ripke S, Neale BM et al (2013) Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet 45(9):984–994

  81. 81.

    Smoller JW, Craddock N, Kendler K et al (2013) Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 381(9875):1371–1379

  82. 82.

    Craddock N, O’Donovan MC, Owen MJ (2006) Genes for schizophrenia and bipolar disorder? Implications for psychiatric nosology. Schizophr Bull 32(1):9–16

  83. 83.

    Chatterjee N, Wheeler B, Sampson J, Hartge P, Chanock SJ, Park JH (2013) Projecting the performance of risk prediction based on polygenic analyses of genome-wide association studies. Nat Genet 45(4):400–405 (pp 405e401–403)

  84. 84.

    So HC, Sham PC (2010) A unifying framework for evaluating the predictive power of genetic variants based on the level of heritability explained. PLoS Genet 6(12):e1001230

  85. 85.

    Janssens AC, Moonesinghe R, Yang Q, Steyerberg EW, van Duijn CM, Khoury MJ (2007) The impact of genotype frequencies on the clinical validity of genomic profiling for predicting common chronic diseases. Genet Med 9(8):528–535

  86. 86.

    Machiela MJ, Chen CY, Chen C, Chanock SJ, Hunter DJ, Kraft P (2011) Evaluation of polygenic risk scores for predicting breast and prostate cancer risk. Genet Epidemiol 35(6):506–514

  87. 87.

    Harris JR, Burton P, Knoppers BM et al (2012) Toward a roadmap in global biobanking for health. Eur J Hum Genet 20(11):1105–1111

  88. 88.

    Iyegbe C, Modinos G, Rivera M (2012) Old obstacles on new horizons: The challenge of implementing gene X environment discoveries in schizophrenia research. In: Maddock J (ed) Public Health: Methodology, Environmental and Systems Issues, vol 1. InTech, Croatia, pp 77–106

  89. 89.

    Bhangale TR, Rieder MJ, Nickerson DA (2008) Estimating coverage and power for genetic association studies using near-complete variation data. Nat Genet 40(7):841–843

  90. 90.

    Kendler KS (1987) Sporadic vs familial classification given etiologic heterogeneity: I. Sensitivity, specificity, and positive and negative predictive value. Genet Epidemiol 4(5):313–330

  91. 91.

    Belsky DW, Moffitt TE, Baker TB et al (2013) Polygenic risk and the developmental progression to heavy, persistent smoking and nicotine dependence: evidence from a 4-decade longitudinal study. JAMA Psychiatry 70(5):534–542

  92. 92.

    McGuire PK, Jones P, Harvey I, Williams M, McGuffin P, Murray RM (1995) Morbid risk of schizophrenia for relatives of patients with cannabis-associated psychosis. Schizophr Res 15(3):277–281

  93. 93.

    Arendt M, Mortensen PB, Rosenberg R, Pedersen CB, Waltoft BL (2008) Familial predisposition for psychiatric disorder: comparison of subjects treated for cannabis-induced psychosis and schizophrenia. Arch Gen Psychiatry 65(11):1269–1274

  94. 94.

    van Os J, Hanssen M, Bak M, Bijl RV, Vollebergh W (2003) Do urbanicity and familial liability coparticipate in causing psychosis? Am J Psychiatry 160(3):477–482

  95. 95.

    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(9):1025–1030

  96. 96.

    Margari F, Petruzzelli MG, Lecce PA et al (2011) Familial liability, obstetric complications and childhood development abnormalities in early onset schizophrenia: a case control study. BMC Psychiatry 11:60

  97. 97.

    Wicks S, Hjern A, Dalman C (2010) Social risk or genetic liability for psychosis? A study of children born in Sweden and reared by adoptive parents. Am J Psychiatry 167(10):1240–1246

  98. 98.

    Kendler KS, Gardner CO (2010) Interpretation of interactions: guide for the perplexed. Br J Psychiatry 197(3):170–171

  99. 99.

    Zammit S, Lewis G, Dalman C, Allebeck P (2010) Examining interactions between risk factors for psychosis. Br J Psychiatry 197(3):207–211

  100. 100.

    Rothman KJ (1976) Causes. Am J Epidemiol 104(6):587–592

  101. 101.

    Little J, Higgins JP, Ioannidis JP et al (2009) STrengthening the REporting of Genetic Association Studies (STREGA): an extension of the STROBE statement. PLoS Med 6(2):e22

  102. 102.

    Modinos G, Iyegbe C, Prata D et al (2013) Molecular genetic gene-environment studies using candidate genes in schizophrenia: a systematic review. Schizophr Res 150(2–3):356–365

  103. 103.

    Duncan LE, Keller MC (2011) A critical review of the first 10 years of candidate gene-by-environment interaction research in psychiatry. Am J Psychiatry 168(10):1041–1049

  104. 104.

    Zammit S, Owen MJ, Evans J, Heron J, Lewis G (2011) Cannabis, COMT and psychotic experiences. Br J Psychiatry 199:380–385

  105. 105.

    Caspi A, Moffitt TE, Cannon M 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(10):1117–1127

  106. 106.

    Smith PG, Day NE (1984) The design of case-control studies: the influence of confounding and interaction effects. Int J Epidemiol 13(3):356–365

  107. 107.

    Di Forti M, Iyegbe C, Sallis H et al (2012) Confirmation that the AKT1 (rs2494732) genotype influences the risk of psychosis in cannabis users. Biol Psychiatry 72(10):811–816

  108. 108.

    Bhattacharyya S, Atakan Z, Martin-Santos R et al (2012) Preliminary report of biological basis of sensitivity to the effects of cannabis on psychosis: AKT1 and DAT1 genotype modulates the effects of delta-9-tetrahydrocannabinol on midbrain and striatal function. Mol Psychiatry 17(12):1152–1155

  109. 109.

    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):148–157

  110. 110.

    Kantrowitz JT, Nolan KA, Sen S, Simen AA, Lachman HM, Bowers MB Jr (2009) Adolescent cannabis use, psychosis and catechol-O-methyltransferase genotype in African Americans and Caucasians. Psychiatr Q 80(4):213–218

  111. 111.

    Henquet C, Rosa A, Delespaul P 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(2):156–160

  112. 112.

    Zammit S, Spurlock G, Williams H et al (2007) Genotype effects of CHRNA7, CNR1 and COMT in schizophrenia: interactions with tobacco and cannabis use. Br J Psychiatry 191:402–407

  113. 113.

    Henquet C, Rosa A, Krabbendam L et al (2006) An experimental study of catechol-O-methyltransferase Val158Met moderation of delta-9-tetrahydrocannabinol-induced effects on psychosis and cognition. Neuropsychopharmacology 31(12):2748–2757

  114. 114.

    Alemany S, Arias B, Aguilera M et al (2011) Childhood abuse, the BDNF-Val66Met polymorphism and adult psychotic-like experiences. Br J Psychiatry 199(1):38–42

  115. 115.

    Muntjewerff JW, Ophoff RA, Buizer-Voskamp JE, Strengman E, den Heijer M (2011) Effects of season of birth and a common MTHFR gene variant on the risk of schizophrenia. Eur Neuropsychopharmacol 21(4):300–305

  116. 116.

    Chotai J, Serretti A, Lattuada E, Lorenzi C, Lilli R (2003) Gene-environment interaction in psychiatric disorders as indicated by season of birth variations in tryptophan hydroxylase (TPH), serotonin transporter (5-HTTLPR) and dopamine receptor (DRD4) gene polymorphisms. Psychiatry Res 119(1–2):99–111

  117. 117.

    Tochigi M, Ohashi J, Umekage T et al (2002) Human leukocyte antigen-A specificities and its relation with season of birth in Japanese patients with schizophrenia. Neurosci Lett 329(2):201–204

  118. 118.

    Narita K, Sasaki T, Akaho R et al (2000) Human leukocyte antigen and season of birth in Japanese patients with schizophrenia. Am J Psychiatry 157(7):1173–1175

  119. 119.

    Nicodemus KK, Marenco S, Batten AJ et al (2008) Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk. Mol Psychiatry 13(9):873–877

  120. 120.

    Peerbooms O, Rutten BP, Collip D et al (2012) Evidence that interactive effects of COMT and MTHFR moderate psychotic response to environmental stress. Acta Psychiatr Scand 125(3):247–256

  121. 121.

    Collip D, van Winkel R, Peerbooms O et al (2011) COMT Val158Met-stress interaction in psychosis: role of background psychosis risk. CNS Neurosci Ther 17(6):612–619

  122. 122.

    Keri S, Kiss I, Seres I, Kelemen O (2009) A polymorphism of the neuregulin 1 gene (SNP8NRG243177/rs6994992) affects reactivity to expressed emotion in schizophrenia. Am J Med Genet B Neuropsychiatr Genet 150B(3):418–420

  123. 123.

    Simons CJ, Wichers M, Derom C et al (2009) Subtle gene-environment interactions driving paranoia in daily life. Genes Brain Behav 8(1):5–12

  124. 124.

    van Winkel R, Henquet C, Rosa A et al (2008) Evidence that the COMT(Val158Met) polymorphism moderates sensitivity to stress in psychosis: an experience-sampling study. Am J Med Genet B Neuropsychiatr Genet 147B(1):10–17

  125. 125.

    Stefanis NC, Henquet C, Avramopoulos D et al (2007) COMT Val158Met moderation of stress-induced psychosis. Psychol Med 37(11):1651–1656

  126. 126.

    Aschard H, Lutz S, Maus B et al (2012) Challenges and opportunities in genome-wide environmental interaction (GWEI) studies. Hum Genet 131(10):1591–1613

  127. 127.

    Clayton D, McKeigue PM (2001) Epidemiological methods for studying genes and environmental factors in complex diseases. Lancet 358(9290):1356–1360

  128. 128.

    Hirschhorn JN, Daly MJ (2005) Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 6(2):95–108

  129. 129.

    Wang WY, Barratt BJ, Clayton DG, Todd JA (2005) Genome-wide association studies: theoretical and practical concerns. Nat Rev Genet 6(2):109–118

  130. 130.

    Kraft P, Yen YC, Stram DO, Morrison J, Gauderman WJ (2007) Exploiting gene-environment interaction to detect genetic associations. Hum Hered 63(2):111–119

  131. 131.

    Ege MJ, Strachan DP (2013) Comparisons of power of statistical methods for gene-environment interaction analyses. Eur J Epidemiol 28(10):785–797

  132. 132.

    Sanders AR, Duan J, Levinson DF et al (2008) No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics. Am J Psychiatry 165(4):497–506

  133. 133.

    Collins AL, Kim Y, Sklar P, O’Donovan MC, Sullivan PF (2012) Hypothesis-driven candidate genes for schizophrenia compared to genome-wide association results. Psychol Med 42(3):607–616

  134. 134.

    Borglum AD, Demontis D, Grove J et al (2013) Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci. Mol Psychiatry. doi:10.1038/mp.2013.2

  135. 135.

    Bermejo JL, Hemminki K (2007) Gene-environment studies: any advantage over environmental studies? Carcinogenesis 28(7):1526–1532

  136. 136.

    Wong MY, Day NE, Luan JA, Wareham NJ (2004) Estimation of magnitude in gene-environment interactions in the presence of measurement error. Stat Med 23(6):987–998

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Acknowledgments

CI is funded by the National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and (Institute of Psychiatry) King’s College London. AB and DC are funded by the European Community Seventh Framework Programme Grant on European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI).

Conflict of interest

The authors declare no conflict of interest.

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Correspondence to Conrad Iyegbe.

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Iyegbe, C., Campbell, D., Butler, A. et al. The emerging molecular architecture of schizophrenia, polygenic risk scores and the clinical implications for GxE research. Soc Psychiatry Psychiatr Epidemiol 49, 169–182 (2014). https://doi.org/10.1007/s00127-014-0823-2

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Keywords

  • Polygenic risk score
  • Schizophrenia
  • Gene–environment interaction
  • Prediction
  • GWAS
  • GWEIS