Elsevier

Schizophrenia Research

Volume 189, November 2017, Pages 196-203
Schizophrenia Research

Gene-environment interaction as a predictor of early adjustment in first episode psychosis

https://doi.org/10.1016/j.schres.2017.02.021Get rights and content

Abstract

Background

This study aims to explore the gene-environment interaction hypothesis applied to pre-symptomatic neurodevelopmental phenotypes of first episode psychosis (FEP), that is, genetic factors might increase vulnerability to the effects of environmental adverse conditions occurring at later stages of development.

Methods

We constructed a schematic ‘two-hit’ model, with Val/Val homozygosity for the catechol-O-methyltransferase (COMT) Val158Met polymorphism as the ‘first hit’ and history of obstetric complications and parental socioeconomic status as ‘second hits’. Early adjustment, measured using the Premorbid Adjustment Scale, was considered the main outcome. The study population comprised 221 adolescents and adults with FEP and 191 sex- and age-matched controls.

Results

The interaction between the Val/Val COMT genotype and a positive history of obstetric complications plus low parental socioeconomic status was significantly associated with poorer early adjustment. These results were observed both in FEP individuals and in controls, and remained significant after controlling for age, sex, and diagnosis.

Conclusions

Individuals carrying Val/Val seem to be more sensitive to the synergistic effect of environmental factors acting early in neurodevelopment, which leads to vulnerability phenotypes such as impaired early adjustment.

Introduction

The ‘two hit’ hypothesis of psychosis proposes that individual genetic factors affecting the earliest stages of neurodevelopment (‘first hit’) might increase vulnerability to the pathological effects of environmental adverse conditions (‘second hits’) occurring at later stages of development (Giovanoli et al., 2013, Niwa et al., 2013). This increased vulnerability would in turn impact the neurodevelopmental mechanisms involved in the pathogenesis of psychosis, thus increasing the risk of developing a psychotic disorder (Arango et al., 2014). Of course, the development of psychosis is likely to be more complex than the binary ‘two hit’ model (Davis et al., 2016). It appears influenced by manifold process involving genetic risk interfacing with multiple environmental hits occurring at key periods of neurodevelopmental activity (Marin, 2016).

The ‘two hit’ (or rather, ‘multi-hit’) effect might be expressed before the emergence of psychotic symptoms in the form of neurodevelopmental phenotypes, such as impaired adjustment early in life. Poor adjustment in childhood and adolescence may be a marker of vulnerability to psychosis (Arango et al., 2014) or a manifestation of the underlying processes of the neurodevelopmental disturbances related to psychosis (Cuesta et al., 2015).

Within this framework, gene variants involved in the pathophysiology of psychosis might act as ‘first hits’ (Schizophrenia-Working-Group-of-the-Psychiatric-Genomics-Consortium, 2014), while environmental factors considered to increase risk for psychosis, such as history of obstetric complications (OCs) (Moreno et al., 2009) and low parental socio-economic status (SES) (Agerbo et al., 2015), might act as ‘second hits’. Although the role of the catechol-O-methyltransferase (COMT) gene psychosis is controversial (Costas et al., 2011, Farrell et al., 2015), polymorphisms within the COMT gene have been reported to interact with psychosocial stress in the development of psychosis (Caspi et al., 2005). The COMT gene, which encodes COMT, the enzyme responsible for degradation of extracellular dopamine in the brain, contains a functional polymorphism (Val158Met). The Val variant is associated with increased COMT activity, which results in reduced dopamine neurotransmission in the prefrontal cortex (Meyer-Lindenberg et al., 2006) and greater predisposition to the stress-related hyperactivity of the mesolimbic dopaminergic system (Ira et al., 2014). These processes may leave Val carriers of the Val158Met polymorphism more sensitive to the effects of environmental factors (Caspi et al., 2005).

Both genetic and early environmental factors have been independently related to outcome in patients with psychosis (Collip et al., 2013, van Dam et al., 2015). However, to our knowledge, no previous studies have analyzed the effect of their potential interaction on early (and premorbid) adjustment. Here, we explore the effect of the interaction between genetic risk factors (COMT Val158Met polymorphism) and early environmental risk factors (history of OC and parental SES) on social and academic adjustment during childhood and early adolescence in subjects with first episode psychosis (FEP) and healthy controls. We hypothesized that participants with a higher number of ‘hits’ would be more impaired than participants with no or only one hit (Feigenson et al., 2014).

Section snippets

Participants

All the participants were from the “Phenotype–genotype and environmental interaction. Application of a predictive model in first psychotic episodes” (PEPs) study. PEPs is a multicenter, naturalistic, longitudinal, 2-year follow-up study designed to evaluate clinical, neuropsychological, neuroimaging, biochemical and genetic variables in adolescents and adults with FEP in Spain. Patients were age- and sex-matched with healthy controls. Recruitment took place between April 2009 and April 2011.

Clinical and demographic characteristics

No differences were found in demographic data (age, sex, and ethnicity), distribution of COMT Val158Met polymorphism, environmental factors (history of OC and parental SES), or early adjustment (PAS-C and PAS-EA) between the FEP patients included (n = 221, 66.0%) and excluded (n = 114, 34.0%) or between the controls included (n = 191, 75.5%) and excluded (n = 62, 24.5%), except for age (as expected due to the inclusion criteria for this specific study; see Supplementary Table 3).

Demographic and

Discussion

This retrospective study assessing the influence of the interaction between COMT Val158Met polymorphism genotype as a ‘first hit’ and two well-known risk factors for psychosis (history of OC and low parental SES) as ‘second hits’ on early adjustment during childhood and adolescence in patients with FEP and healthy controls, shows that Val/Val patients with ‘two second hits’ (positive history of OC plus low parental SES) have poorer early adjustment. The interaction between the Val/Val genotype

Conflict of interest

David Fraguas has been a consultant and/or advisor to or has received honoraria from Eisai, Janssen, Lundbeck, and Otsuka.

Covadonga Díaz-Caneja has previously held a Río Hortega grant, ISCIII, Spanish Ministry of Economy and Competitiveness, and a grant from Fundación Alicia Koplowitz.

Iluminada Corripio has been a consultant for, received honoraria from and/or been on speakers/advisory boards of Ferrer, Lilly, and Otsuka.

Ana Gonzalez-Pinto has received grants and served as consultant, advisor

Contributors

Iluminada Corripio, Ana Gonzalez-Pinto, Antonio Lobo, Miquel Bioque, Manuel J Cuesta, Julio Sanjuán, Salvador Sarró, Bibiana Cabrera, Antoni Bulbena, Josefina Castro-Fornirles, Mara Parellada, Eduard Vieta, Celso Arango, and Miquel Bernardo designed the study and wrote the protocol. David Fraguas, Covadonga Díaz-Caneja, Elisa Rodríguez-Toscano and Barbara Arias managed the literature searches and analyses. David Fraguas undertook the statistical analysis. David Fraguas and Covadonga Díaz-Caneja

Funding source

This study was funded by the following: Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III, CIBERSAM; Madrid Regional Government (S2010/BMD-2422 AGES); Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement (2014SGR1573 and 2014SGR1636); European Union Structural Funds and European Union Seventh Framework Programme under grant agreements FP7-HEALTH-2009-2.2.1-2-241909 (Project EU-GEI), FP7-HEALTH-2009-2.2.1-3-242114 (Project OPTiMISE), FP7-

Acknowledgements

This study was supported by the following: Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III, CIBERSAM; Madrid Regional Government (S2010/BMD-2422 AGES); Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement (2014SGR1573 and 2014SGR1636); European Union Structural Funds and European Union Seventh Framework Programme under grant agreements FP7-HEALTH-2009-2.2.1-2-241909 (Project EU-GEI), FP7-HEALTH-2009-2.2.1-3-242114 (Project OPTiMISE), FP7-

References (56)

  • M. Walshe et al.

    Long-term maternal recall of obstetric complications in schizophrenia research

    Psychiatry Res.

    (2011)
  • E. Agerbo et al.

    Polygenic risk score, parental socioeconomic status, family history of psychiatric disorders, and the risk for schizophrenia: a Danish population-based study and meta-analysis

    JAMA Psychiatry

    (2015)
  • S. Alemany et al.

    Psychosis-inducing effects of cannabis are related to both childhood abuse and COMT genotypes

    Acta Psychiatr. Scand.

    (2014)
  • C. Arango et al.

    Differential neurodevelopmental trajectories in patients with early-onset bipolar and schizophrenia disorders

    Schizophr. Bull.

    (2014)
  • D. Armbruster et al.

    Children under stress - COMT genotype and stressful life events predict cortisol increase in an acute social stress paradigm

    Int. J. Neuropsychopharmacol.

    (2012)
  • R.M. Bilder et al.

    The catechol-O-methyltransferase polymorphism: relations to the tonic-phasic dopamine hypothesis and neuropsychiatric phenotypes

    Neuropsychopharmacology

    (2004)
  • N. Brill et al.

    Validity of the premorbid adjustment scale

    Schizophr. Bull.

    (2008)
  • M. Cannon et al.

    Premorbid social functioning in schizophrenia and bipolar disorder: similarities and differences

    Am. J. Psychiatry

    (1997)
  • H.E. Cannon-Spoor et al.

    Measurement of premorbid adjustment in chronic schizophrenia

    Schizophr. Bull.

    (1982)
  • D. Collip et al.

    FKBP5 as a possible moderator of the psychosis-inducing effects of childhood trauma

    Br. J. Psychiatry

    (2013)
  • A. del Rey-Mejias et al.

    Functional deterioration from the premorbid period to 2 years after the first episode of psychosis in early-onset psychosis

    Eur Child Adolesc Psychiatry

    (2015)
  • C.M. Díaz-Caneja et al.

    Predictors of outcome in early-onset psychosis: a systematic review

    Npj Schizophrenia

    (2015)
  • D.M. Erceg-Hurn et al.

    Modern robust statistical methods: an easy way to maximize the accuracy and power of your research

    Am Psychol

    (2008)
  • M.S. Farrell et al.

    Evaluating historical candidate genes for schizophrenia

    Mol. Psychiatry

    (2015)
  • M. First et al.

    Structured Clinical Interview for DSM-IV Axis II Disorders (SCID-II)

    (1997)
  • M. First et al.

    Structured Clinical Interviewfor DSM-IV Axis I Disorders (SCID-I)

    (1997)
  • S.B. Floresco et al.

    Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission

    Nat. Neurosci.

    (2003)
  • J.K. Forsyth et al.

    Genetic risk for schizophrenia, obstetric complications, and adolescent school outcome: evidence for gene-environment interaction

    Schizophr. Bull.

    (2013)
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