Interaction of early environment, gender and genes of monoamine neurotransmission in the aetiology of depression in a large population-based Finnish birth cohort

Abstract

Objectives

Depression is a worldwide leading cause of morbidity and disability. Genetic studies have recently begun to elucidate its molecular aetiology. The authors investigated candidate genes of monoamine neurotransmission and early environmental risk factors for depressiveness in the genetically isolated population-based Northern Finland Birth Cohort 1966 (12 058 live births).

Design

The authors ascertained and subdivided the study sample (n=5225) based on measures of early development and of social environment, and examined candidate genes of monoamine neurotransmission, many of which have shown prior evidence of a gene–environment interaction for affective disorders, namely SLC6A4, TPH2, COMT, MAOA and the dopamine receptor genes DRD1–DRD5.

Results and conclusion

The authors observed no major genetic effects of the analysed variants on depressiveness. However, when measures of early development and of social environment were considered, some evidence of interaction was observed. Allelic variants of COMT interacted with high early developmental risk (p=0.005 for rs2239393 and p=0.02 for rs4680) so that the association with depression was detected only in individuals at high developmental risk group (p=0.0046 and β=0.056 for rs5993883–rs2239393–rs4680 risk haplotype CGG including Val158), particularly in males (p=0.0053 and β=0.083 for the haplotype CGG). Rs4274224 from DRD2 interacted with gender (p=0.017) showing a significant association with depressiveness in males (p=0.0006 and β=0.0023; p=0.00005 and β=0.069 for rs4648318–rs4274224 haplotype GG). The results support the role of genes of monoamine neurotransmission in the aetiology of depression conditional on environmental risk and sex, but not direct major effects of monoaminergic genes in this unselected population.

Article summary

Article focus

• Impact on depression of monoaminergic candidate genes with prior evidence of gene–environment interaction for affective disorders, and of dopamine receptor genes.

• Gene–environment and gene–gender interactions in the aetiology of depression.

• Effect of measures of early development and of social environment on depression.

Key messages

• Genes of monoamine neurotransmission play a role in the aetiology of depression conditional on environmental risk, especially in males and in individuals at high early developmental risk group; in particular, there is evidence of an interaction with a COMT high-risk haplotype including Val158.

• Gender-specific mechanisms and responses to environmental effectors are evident in the regulation of mood.

Strengths and limitations of this study

• Depression as defined does not necessarily imply clinical diagnosis of major depression but is based on a self-report or Hopkins Symptom Check List-25 score. Despite this, the prevalence of depressed mood was in the same range as that in earlier reports.

• There was a notable drop-out rate of about half of the original cohort members.

• The choice of measures of early development and of social environment was limited by the availability of variables collected.

• Advantages include the availability of longitudinal follow-up data starting antenatally, enabling inclusion of the environmental dimension without recall bias.

• The cohort’s unique genetic structure with isolation and more genetic homogeneity permits identification of genetic-risk loci that may be missed when using more heterogeneous populations.

• The subjects are representative of the population, with all cohort members born in the same year and within a geographically defined area.

• The study sample’s size is sufficient for identifying genetic variants of moderate impact.

• Both genders are represented in almost equal amounts; gender differences exist in both depression and temperament traits such as harm avoidance.

• As the sample is a 1-year birth cohort, genetic effects may be isolated from the effects of ageing; some psychiatric traits such as harm avoidance are age-dependent.