This study examined the environmentally-mediated impacts of four notable risk factors for depression and fatigue, in Sri Lanka, where some of these risks are especially prevalent. Exposure to early school leaving, poor standard of living (informal structural materials, poor toilet or water facilities, or hunger due to poverty in the past 3 months), stressful life events and poor parental care in childhood were mainly associated with depression (lifetime-ever) and fatigue through environmental mechanisms, although genetic factors also played a role.
For history of depression, we found person-specific environmental effects "uncontaminated" by gene-environment covariation or family-wide exposures, from early school leaving and standard of living, but only in men. In women, these environmental pathways to depression were not found, but the association between life events and depression was partly mediated by genetics. These measured environments partly explain some of the overall aetiological sex difference in depression, which was found to be less heritable in men in this population [27
]. However, we also found a role for genes in depression in men (mediating the link between parenting experiences recalled from childhood and depression). And the association with this same exposure revealed a role for family-wide environmental influences in depression in women. Although these reports might be linked to recall bias rather than experiences in childhood, our findings suggest that there is a genetic component to male depression in this population (which was too small for us to have power to confirm in the previous univariate study) [27
]. It also suggests that there are shared (family) environmental influences on depression (although we cannot be sure of the particular aspect of the environment that is responsible).
For fatigue, we found person-specific environmentally-mediated effects from negative life events (which is consistent with twin findings from Sweden [15
]) and from early school leaving, but not from standard of living or parenting. In addition, there was a role for family-environmental effects on the relationship between all four risk factors and fatigue.
Some specificity of environmental influences on depression and fatigue
There were some similarities in that the exposures that influenced fatigue and history of depression, in particular early school leaving (in men) had environmentally mediated effects on both disorders. Thus early school leaving is a strong candidate as an environmentally-mediated risk factor that leads to both depression and fatigue in men. So although the duration of one's school career was found to be partly heritable (this might operate via intelligence which is itself highly heritable [30
]), the environmental rather than the genetic influences on school duration are connected to depression and fatigue in later life. In contrast, men's standard of living appears to have an environmental impact on depression but not fatigue, despite both these outcomes often occurring in the same individual, and despite the likelihood of (tiring) manual labour among those with poor standards of living.
The results also highlight the contribution of shared (family-wide) environmental factors (C) to fatigue, and to a lesser extent to history of depression, in Sri Lanka. But it is not clear whether the specific measured risk factors measured here are responsible, or whether other aspects of the family environment that could be acting as confounders. Whilst 'C' has generally not been found to be an important determinant in previous (Western) twin studies of depression or fatigue, it is hard to definitively rule out [31
]. Thus the present findings might be representing effects specific to Sri Lanka, or they may reflect small 'C' effects that exist throughout the world that have not been confidently detected elsewhere due to low power to detect 'C' in the classical twin design. This highlights the particular importance of controlling for potential confounders within the family when examining risk factors for fatigue.
Genetic mediation of apparent environmental risks
Where we found genetic mediation ('A') of the association between exposure and disorder, an active or evocative gene-environment correlation (rGE
) is indicated. This means certain characteristics that are partially heritable (e.g. risk taking and other aspects of personality and lifestyle) lead people to seek out or elicit certain environments, which are then associated with the disorder. This was found in relation to life events and history of depression in women, as has been found elsewhere [11
], and supports findings that this type of association is more characteristic of women than men [13
]. There was a lack of genetically-mediated associations of measured exposures with fatigue, despite apparent heritability of this phenotype both in this population (submitted: [28
]) and elsewhere [31
]. This suggests that genetic factors are more likely to have a direct impact on fatigue, rather than an indirect effect through influencing personality and/or lifestyle. For example, the genetic factors influencing fatigue might directly influence sensory perceptions, which has been shown to be heritable.
This study is based on cross-sectional reports, and requires confirmation through longitudinal waves of data. Although the findings are based on correlations, the twin structure of the data does mean we can be confident of ruling out genetic and family-environmental confounds by examining differences within MZ pairs. Nonetheless, this is not an interventional study and thus we cannot definitively pinpoint precise events that eventually resulted in depression or fatigue outcome. For example early school leaving might be a marker of earlier environmental effects such as a bad accident that prevented school attendance in one MZ cotwin but not the other. Also, the environmental exposures correlated with one another to some degree; but rather than appearing to be a generalised effect of poverty, we found evidence of independent environmentally-mediated associations of early school leaving, standard of living and life events with depression in men.
The lifetime-ever status of the depression assessment makes it hard to rule out reverse causality for environmentally-mediated associations because the exposure could be relatively recent. So although an environmentally-mediated association of life events with history of depression was detected in men, it is likely that at least some of this association is driven by prior depression.
Current mood or personality may have affected the retrospective reporting of parental care and recent life events. This dictates caution in interpreting within-person associations of these exposures with depression and fatigue.
Finally, although our analyses examining the overlap between measured exposures and fatigue or depression outcome looked for correlations between genes and environments, our assessment of the heritability of depression and fatigue did not assess potential interactions between genes and environments, due to low power. Studies on other samples have found evidence for such interactions in the aetiology of depressive symptoms [37