Serotonin transporter gene moderates childhood maltreatment's effects on persistent but not single-episode depression: Replications and implications for resolving inconsistent results

Abstract

Background

Genetic and environmental factors shape life-long vulnerability to depression, but most gene–environment interaction (G × E) research has focused on cross-sectional assessments rather than life-course phenotypes. This study tests the hypothesis that the G × E involving the length polymorphism in the serotonin-transporter-gene-linked-promoter-region (5-HTTLPR) and childhood maltreatment is specific to depression that runs a persistent course in adulthood.

Methods

The hypothesis is tested in two cohorts. Men and women in the Dunedin Study (N = 847), New Zealand, followed to age 32 years with 96% retention and women in the E-Risk Study (N = 930), England, followed to age 40 years with 96% retention. Diagnoses of past-year major depressive episode were established at four separate assessments. Depression diagnosed on two or more occasions was considered persistent.

Results

In both cohorts, statistical tests of gene–environment interactions showed positive results for persistent depression but not single-episode depression. Individuals with two short 5-HTTLPR alleles and childhood maltreatment had elevated risk of persistent but not single-episode depression.

Limitations

Some cases of recurrent depression may have been misclassified as single-episode due to non-contiguous assessment windows, but this would have a conservative effect on the findings. Chronic and recurrent depression could not be reliably distinguished due to non-contiguous periods of assessment. Therefore, the term persistent depression is used to describe either chronic or recurrent course.

Conclusions

The specific effect on persistent depression increases the significance of this G × E for public health. Research that does not distinguish persistent course may underestimate G × E effects and account for some replication failures in G × E research.

Introduction

There is growing appreciation that chronic diseases in adulthood have their roots in early experiences during childhood (Ben-Shlomo and Kuh, 2002, Hertzman, 1999). This is also true for depression, one of the most disabling diseases globally (Danese et al., 2008, Murray and Lopez, 1997). Although adversity at every stage of life contributes to the risk of depression, the effects of childhood experiences are most profound and enduring (Brown et al., 2008, Cicchetti and Rogosch, 2009). Childhood maltreatment, in the form of abuse or neglect, is unfortunately a common experience (Hussey et al., 2006, May-Chahal and Cawson, 2005), and is associated with a 50% increase in the odds of depression in adult life (Widom et al., 2007, Wise et al., 2001). Although childhood maltreatment is a potent risk factor, there are substantial individual differences in outcome and many individuals who experienced maltreatment during childhood remain healthy (Caspi et al., 2010, Cicchetti and Rogosch, 2009).

It has been proposed that individual differences in vulnerability to maltreatment are partially genetically mediated by a common functional length polymorphism in the promoter sequence of the serotonin transporter gene (5-HTTLPR) (Caspi et al., 2003). This hypothesis was supported in a number of studies focusing on threatening events in which physical, sexual, or relational harm against children was carried out or intended (Aguilera et al., 2009, Aslund et al., 2009, Benjet et al., 2010, Cicchetti et al., 2007, Kaufman et al., 2004, Kumsta et al., 2010, Sugden et al., 2010), but inconsistent results have also been reported, especially in studies of childhood adversities other than maltreatment (Araya et al., 2009, Ritchie et al., 2009, Surtees et al., 2006, Wichers et al., 2008). Although the most recent and complete meta-analysis has confirmed that the 5-HTTLPR significantly moderates the depressogenic effects of childhood maltreatment (Karg et al., 2011), these inconsistent results require explanation.

One source of discrepant results may be cross-study inconsistency in the measurement of depression. While the liability to developing depression resulting from childhood maltreatment is life-long, the manifestations of depression are often episodic and their duration and course vary between individuals (Eaton et al., 2008, Judd, 1997, Rhebergen et al., 2009, Solomon et al., 1997). Chronic or recurrent depression is more heritable (Foley et al., 1998, McGuffin et al., 1996) and is more strongly associated with childhood maltreatment (Wiersma et al., 2009) than depression diagnosed at a single time point. Moreover, the influence of childhood maltreatment on depression persistence is direct and cannot be accounted for by more proximal circumstances (Brown et al., 2008). These observations led Brown and Harris (2008) to hypothesize that genetic sensitivity to childhood maltreatment should be specific to depression that is chronic or recurrent.

The present article reports the first test of this hypothesis. Because retrospective assessment of depression is unreliable (Moffitt et al., 2010, Schraedley et al., 2002), a valid test requires longitudinal datasets with repeated assessments. We use data from two population-based cohorts, where depression was assessed on four separate occasions in adulthood with the same diagnostic instrument. The first cohort provides analyses of new data from the Dunedin longitudinal study and the second cohort offers an opportunity to replicate findings in a new dataset. We examine genetic sensitivity to childhood maltreatment in relation to (a) persistent depression, (b) single-episode depression and (c) past-year depression diagnosed at each of the four separate assessment occasions. Comparisons of G × E results for single-episode versus persistent depression test the hypothesis proposed by Brown and Harris (2008). Analyses of past-year depression are comparable to G × E studies that have focused on cross-sectional measurements rather than longitudinal phenotypes. Comparisons of G × E results for depression diagnosed on any given occasion versus persistent depression allow us to gauge the possible contribution of cross-sectional measurement to inconsistencies in the literature.