We investigated genetic and environmental risk factors for depression in a genetically isolated Finnish birth cohort by assessing the relative impacts of monoaminergic candidate genes for depression in groups of contrasting (high and low) early developmental and social risk. We did not observe any robust genetic effects of the analysed variants on depressiveness. However, when measures of early development and social environment were considered, some signals for association were observed, although none of them survive correction for multiple testing. Our study sample provided modest evidence of an interaction of COMT with the measure of high early developmental risk, particularly in males, and a contribution of an allelic variant of DRD2 to genetic risk for depressiveness particularly in males ().
gene encoding for catechol-O
-methyltransferase enzyme is among the most investigated genes in psychiatric genetics. The enzyme degrades catecholamine neurotransmitters such as dopamine, norepinephrine and epinephrine by catalysing the transfer of a methyl group from S
-adenosylmethionine to the catecholamines. Its enzymatic activity varies according to a G-to-A transition at codon 158 in the COMT
gene, resulting in a valine-to-methionine substitution (Val158Met) on the protein level.31
The enzyme encoded by the Val158 allele has a three- to four-fold higher activity than that encoded by the Met158 allele. Here, we found an association of the haplotype comprising rs5993883 between LD blocks 1 and 2 of COMT
, as well as rs2239393 and rs4680, which are two variants in virtually complete linkage disequilbrium in block 2, with depressive symptoms in high-developmental-risk males (p=0.0053). The high-risk haplotype included the high-activity variant Val158 of COMT
, the allele G of rs4680. This allele has repeatedly been found to be associated with a poor response to pharmacological treatment of depression,32 33
and a European multicentre study identified an association between that allele and early-onset major depression.34
The Val158 allele has already been found earlier to associate with cognitive deficits including poor performance in tasks related to higher-order components of processing35
and perseverative errors, less efficient physiological responses in the prefrontal cortex36
and even schizophrenia based on a meta-analysis,37
although the effect was not significant when studies with allele frequencies deviating from the Hardy–Weinberg equilibrium were excluded.
In our study we observed evidence for an interaction between COMT
and a measure of early developmental risk on depressive symptoms. This interaction could not be explained through gene–environment correlations. Nor were we able to detect a significant correlation of the measure of early developmental risk with depressive symptoms, despite prior evidence for the role of its markers, which were low birth weight21 27
and late motor or verbal development,28
in decreased psychiatric health and well-being, including depression. This finding may reflect the presence of other environmental risk indicators which were not examined in our study. However, they may also reflect individual variability in response to the risk environment and presence of genetic factors (such as the COMT
haplotype containing Met158) that may relate to resilience, adaptive changes in regulation of emotion reactivity and successful coping with stress.38
The observed risk also seemed to arise from an aggregation of the environmental indicators, as none of the risk items separately gave evidence of G×E with the risk variants from COMT
(data not shown). This could reflect a cumulative nature of these environmental influences, such that the effect of one marker may be weak, but the accumulated effect of multiple markers, together with genetic susceptibility, would be strong enough to increase the risk for a deviant development of emotional regulation and thus depressiveness.39
There is some prior evidence of interaction of COMT
with a risk environment on psychosis, antisocial behaviour and dissociation. A study on children with ADHD showed a gene–environment interaction between the Val/Val genotype and low birth weight on early-onset antisocial behaviour,40
and the Val158 allele was also found to associate with cannabis use and psychotic symptoms41
and with increasing levels of dissociation in those exposed to higher levels of childhood trauma.42
Interestingly, a recent report43
revealed an impact of that polymorphism on gender-related patterns of regulation of emotions (activation in limbic and paralimbic regions) in line with findings of the present study.
Another main finding of the present study, and statistically the strongest one, was observed in the dopamine receptor D2 gene DRD2
, where a haplotype comprising the intronic variants rs4648318 in LD block 2 and rs4274224 in block 3 was found to associate with depressive symptoms particularly in males, regardless of their early environment (p=0.00005). Dopamine receptors have key roles in a variety of processes in the vertebrate central nervous system, and dysfunction in dopaminergic neurotransmission may therefore predispose to a variety of neuropsychiatric disorders. Among the receptor genes, DRD2
has attracted the most attention and has been implied to have a role in the aetiology of several psychiatric disorders. However, there are only a few previous reports on unipolar depression, including positive,44
and negative46 47
findings, and for results on depression conditional on risk environment.44 46 48
Our varying results for males and females in general imply different mechanisms of mood regulation and possible gender-specific responses to environmental effectors. Gender differences in depression2 49
as well as in temperament traits49
have previously been reported in various populations, including the current one,50
and the prevalence of depression is higher in women.51
A true gender-specific effect of genetic variants on depressiveness would not be surprising, as there is evidence of gender differences in dopaminergic function52
that may be oestrogen-dependent.
It is noteworthy that despite previous reports of the 5-HTTLPR variant,13
we did not detect any evidence of an association for SLC6A4
. Similarly, a recent meta-analysis did not find any evidence of an association with depression alone, or in interaction with stressful life events,16
although a current review14
and a meta-analysis of all studies to date15
support the positive association findings and the role of 5-HTTLPR and stress in depression. The SLC6A4
SNPs included in our study tag the 5-HTTLPR well (D′>0.9), as determined using genotypes from a population-based Finnish Health 2000 study.53
Moreover, the LD measure thus obtained is conservative, since in the population under current study, LD has been shown to be stronger than in the general Finnish population, which was represented by the Health 2000 study sample.54
We did not use the Bonferroni correction for multiple testing, owing to limitations of sample size and expected magnitude of gene effects in complex traits. Although none of the results from the primary analyses () survive conservative correction, a neurobiological a priori hypothesis based on previously published studies supports the validity of our most robust findings. It is, however, noteworthy that they were observed only when the sample was conditioned on measures of early development or of social environment, or gender. Still, the strongest association signal, obtained using DRD2′s rs4274224 with HSCL score in males (p=0.0006), remains close to statistical significance, even when taking into account the amount of multiple testing performed. The finding was further supported by results of our haplotype analysis containing rs4274224, which showed a statistically significant association with the HSCL score in males (p=0.00005).
There are some limitations in the present study. First, it is notable that depression as defined here did not necessarily signify a clinical diagnosis of major depression. Instead, it was defined based either on self-report or on the score from HSCL, which as a measure has its limitations. However, the prevalence of depressed mood was in the same range as in earlier reports.1 55
Second, there was a notable drop-out rate among the original material of all cohort members. About half of the original cohort members did not participate in this study. Finally, when the NFBC 1966 study was initiated, it was not possible to predict that an investigation such as the present one would one day be conducted. Therefore, we are limited by the original choice of variables to be collected, and the measures of early development or of social environment may only be indicators or markers of risk rather than risk factors themselves.39
It is also noteworthy that we did not detect any association of our measure of current depression with the measure of high early developmental risk, despite it being formulated based on previous reports of their effects on psychiatric health and well-being.27–30
However, the effect of genetic risk may be modulated by early life stress, even though the direct link between early life environment and current status would be too weak to be detected in our study sample, and this modulating effect may be seen in the results of the G×E analysis.
The current study has several potential advantages, such as the availability of longitudinal follow-up data starting antenatally, enabling us to include the environmental dimension without any risk of recall bias. Another advantage is the unique genetic structure of our study cohort, characterised by isolation, founder effect, multiple bottlenecks and more genetic homogeneity compared with many other isolates,56
allowing us to identify genetic risk loci that may be missed in the screening of other more heterogeneous populations. Furthermore, the subjects were representative, with all cohort members born in the same year and within a geographically defined area.
In addition, the size of the sample is sufficient to identify genetic variants of moderate impact. We also have both genders represented in almost equal amounts (48% males, 52% females), which is notable since gender differences are evident both in depression2 49
and in temperament traits—for example, harm avoidance.49
Furthermore, it is beneficial that the sample is a 1-year birth cohort, as it is well established that some psychiatric traits, such as harm avoidance57
of temperament, are age-dependent. We can therefore isolate genetic effects from the effects of ageing.
Our results support a modest role of COMT and DRD2, two genes of monoamine neurotransmission, in the aetiology of depression conditional on environmental risk, particularly in males, though not direct effects of monoaminergic genes in this unselected population. These findings imply that the nature of the role of monoaminergic genes in depression should be examined further in future studies, and pending replication in other, independent population samples.