Translational perspectives in addiction psychiatry

Abstract

Background

Heritable factors account for approximately 50–60% of the risk for alcohol dependence. However, which genes confer this risk remains to elucidate. Moreover, genetic association studies are hampered by non-replication. Several strategies can be applied to approach this issue. One option is the application of intermediate phenotypes. Neurobiological measures that are closely related to the addiction phenotype may be more directly related to genetic variation. Intermediate phenotypes related to dopamine function seem particularly suitable, given the strong dopamine hypothesis in addiction. Another strategy is to include environmental factors, such as childhood adverse experience, in genetic association studies. We tested the effect of COMT Val158Met and DRD2 Taq1A genotypes, as modulators of brain dopamine function in the context of self-reported environmental factors, like childhood adverse experience.

Methods

Alcohol-dependent patients (n = 110) and healthy controls (n = 99) were genotyped for the COMT Val158Met and DRD2 Taq1A genotypes. Childhood adversity was measured using self-report questionnaires. Dopamine sensitivity was assessed using an apomorphine challenge with cognitive performance and plasma growth hormone levels as main outcome measures.

Results

COMT genotype modulated the effect of apomorphine on cognitive performance, but was not directly associated with alcohol dependence. Yet, the interaction between childhood adversity and COMT genotype did predict alcohol dependence. DRD2 genotype modulated the effect of apomorphine on plasma growth hormone levels and was also not directly associated with alcohol dependence. Yet, the interaction between parental rule setting and DRD2 genotype did predict alcohol use in a separate population-based sample of adolescents.

Conclusion

This study provides evidence for a role of COMT and DRD2 genotypes in alcohol dependence using both the GxE and intermediate phenotype approach. This confirms that both an intermediate phenotype approach and GxE interaction analyses can be useful tools in understanding mechanisms mediating addiction vulnerability. The clinical relevance of dopamine genes and intermediate phenotypes for staging and profiling of alcohol use disorders remains to be investigated.

Disclosure of interest

The author has not supplied his declaration of competing interest.