Elsevier

Biological Psychiatry

Volume 57, Issue 10, 15 May 2005, Pages 1117-1127
Biological Psychiatry

Original article
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

https://doi.org/10.1016/j.biopsych.2005.01.026Get rights and content

Background

Recent evidence documents that cannabis use by young people is a modest statistical risk factor for psychotic symptoms in adulthood, such as hallucinations and delusions, as well as clinically significant schizophrenia. The vast majority of cannabis users do not develop psychosis, however, prompting us to hypothesize that some people are genetically vulnerable to the deleterious effects of cannabis.

Methods

In a longitudinal study of a representative birth cohort followed to adulthood, we tested why cannabis use is associated with the emergence of psychosis in a minority of users, but not in others.

Results

A functional polymorphism in the catechol-O-methyltransferase (COMT) gene moderated the influence of adolescent cannabis use on developing adult psychosis. Carriers of the COMT valine158 allele were most likely to exhibit psychotic symptoms and to develop schizophreniform disorder if they used cannabis. Cannabis use had no such adverse influence on individuals with two copies of the methionine allele.

Conclusions

These findings provide evidence of a gene × environment interaction and suggest that a role of some susceptibility genes is to influence vulnerability to environmental pathogens.

Section snippets

Participants

Participants were members of the Dunedin Multidisciplinary Health and Development Study. The birth cohort of 1,037 children (52% male children) was established at age 3 when the investigators enrolled 91% of consecutive births between April 1972 and March 1973 in Dunedin, New Zealand. Cohort families represent the full range of socioeconomic status in the general population of New Zealand’s South Island. Follow-ups have been carried out at ages 3, 5, 7, 9, 11, 13, 15, 18, 21, and most recently

Results

Figure 1A shows the percentage of individuals meeting diagnostic criteria for schizophreniform disorder at age 26, as a function of COMT genotype and adolescent-onset cannabis use. In a hierarchical logistic regression model, the main effect of genotype was not significant, b = .05, SE = .27, z = .17, p = .87, the main effect of adolescent cannabis exposure was significant, b = 1.13, SE = .38, z = 2.96, p = .003, and the interaction between genotype and adolescent cannabis exposure was

Discussion

This study provides evidence that a functional polymorphism in the COMT gene interacted with adolescent-onset cannabis use to predict the emergence of adult psychosis. An alternative causal hypothesis must be considered. It is possible that preexisting early behavior or cognitive problems lead psychosis-prone carriers of the Val allele to take up cannabis use as teenagers. There was no main-effect risk for developing psychosis among carriers of the Val allele, however, and Val allele carriers

References (63)

  • H.G. Pope et al.

    Early-onset cannabis use and cognitive deficitsWhat is the nature of the association?

    Drug Alcohol Depend

    (2003)
  • S. Shifman et al.

    A highly-significant association between a COMT haplotype and schizophrenia

    Am J Hum Genet

    (2002)
  • L.N.P. Voruganti et al.

    Cannabis induced dopamine releaseAn in-vivo SPECT study

    Psychiatr Res

    (2001)
  • D.R. Weinberger et al.

    Prefrontal neurons and the genetics of schizophrenia

    Biol Psychiatry

    (2001)
  • M. Akil et al.

    Catechol-O-methyltransferase genotype and dopamine regulation in the human brain

    J Neuroscience

    (2003)
  • Diagnostic and Statistical Manual of Mental Disorders

    (1994)
  • L. Arseneault et al.

    Causal association between cannabis and psychosisExamination of the evidence

    Br J Psychiatry

    (2004)
  • H. Ashton

    Cannabis or health?

    Curr Opin Psychiatry

    (2002)
  • R.M. Bilder et al.

    The catechol-O-methyltransferase polymorphismRelations to the tonic-phasic dopamine hypothesis and neuropsychiatric phenotypes

    Neuropsychopharmacology

    (2004)
  • A. Blumstein

    Youth violence, guns, and the illicit-drug industry

    J Crim Law Criminol

    (1995)
  • M. Cannon et al.

    Evidence for early-childhood, pan-developmental impairment specific to adult schizophreniform disorderResults from a longitudinal birth cohort

    Arch Gen Psychiatry

    (2002)
  • A. Carlsson et al.

    Interactions between monoamines, glutomate, and GABA in schizophreniaNew evidence

    Ann Rev Pharmacol Toxicol

    (2001)
  • A. Caspi et al.

    Role of genotype in the cycle of violence in maltreated children

    Science

    (2002)
  • A. Caspi et al.

    Influence of life stress on depressionModeration by a polymorphism in the 5-HTT gene

    Science

    (2003)
  • R.A. Chambers et al.

    Developmental neurocircuitry of motivation in adolescenceA critical period of additional vulnerability

    Am. J Psychiatry

    (2003)
  • J. Cohen et al.

    Applied multiple regression/correlation analysis for the behavioral sciences

    (2003)
  • C. Di Maggio et al.

    Evidence of a cohort effect for age at onset of schizophrenia

    Am J Psychiatry

    (2001)
  • M.F. Egan et al.

    Effect of COMT val 108/158 genotype on frontal lobe function and risk for schizophrenia

    PNAS

    (2001)
  • H. Erhrenreich et al.

    Specific attentional dysfunction in adults following early start of cannabis use

    Psychopharmacology

    (1999)
  • D.L. Foley et al.

    Childhood adversity, monoamine oxidase A genotype, and risk for conduct disorder

    Arch Gen Psychiatry

    (2004)
  • S.J. Glatt et al.

    Association between a functional catechol-O-methyltransferase gene polymorphism and schizophreniaMeta-analysis of case-control and family-based studies

    Am J Psychiatry

    (2003)
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