The role of the serotonin transporter gene, brain structure and family environment in the emergence of depression during adolescence

Abstract

© 2017 Dr. Keriann LittleRecent findings suggest that complex interrelations between genetics, brain structure and environmental contexts, including stressors and family processes, may have a role in the development of depressive disorders. The role of a functional variant in the 5-HT transporter promoter region polymorphism (5-HTTLPR) and its potential interaction with adverse, stressful life events in predicting depression has been the focus of considerable research attention. The validity of this gene-environment interaction, however, has been queried due to inconsistent findings. The current thesis aims to enhance current understanding of this interaction by considering how two different dimensions of environmental experience (threat versus deprivation) might interact with the serotonin transporter gene during adolescence, while also investigating potential underlying neurobiological mechanisms. Three interconnected studies were conducted that examined the interplay between the serotonin transporter gene, family environment, brain regions of interest and depression. Study 1 examined whether 5-HTTLPR moderated associations between (1) high levels of negative, harsh, critical parenting behaviours (as an index of more threatening environments) and subsequent depression and (2) low levels of positive, supportive parenting behaviours (as an index of more deprived environments) and subsequent depression during adolescence. These GxE interactions were tested in adolescents from two independent longitudinal studies, the Australian Temperament Study (ATP, n=681) a population based sample that relied on questionnaire measures of environment and depression, and the Orygen Adolescent Development Study (ADS, n=174) a sample enhanced for temperamental risk and resilience factors for internalising conditions, that drew on observational measures of the environment and semi-standardised clinical interview measures of depression. In both studies, adolescents carrying at least one copy of the S-allele appeared to be buffered against risk for depression in the context of low positive parenting, whilst adolescents in the L-homozygous group were at greater risk for depression with decreasing levels of positive parenting. Negative parenting did not interact with serotonin transporter genotype in either study. Study 2 was based on the ADS and examined the extent to which variation in hippocampus, amygdala, orbitofrontal cortex (OFC) and anterior cingulate cortex (ACC) volumes in early adolescence mediated a putative association between 5-HTTLPR genotype and first onset of Major Depressive Disorder (MDD) over a six year period. Increasing copies of S-alleles predicted smaller left hippocampal volume, which in turn was associated with increased risk of experiencing a first onset of MDD. Increasing copies of S-alleles also predicted both smaller left and right medial OFC volumes, although neither left nor right medial OFC volumes was prospectively associated with a first episode of MDD during adolescence. Study 3 was also based on the ADS and employed an imaging-gene x environment (IGxE) framework to investigate whether the strength of the imaging genetics pathway involving the hippocampus that was identified in Study 2 differed as a function of parenting behaviour. Results were consistent with the presence of an indirect effect of the serotonin transporter S-allele on depression onset via smaller left and right hippocampal volumes that was significant only in family environments involving either higher levels of negative parenting or lower levels of positive parenting. The previously reported finding of S-allele carriers’ increased risk of depression in adverse environments may therefore be partly due to the effects of these environments on a neurobiological pathway from the serotonin transporter gene to depression onset that proceeds through variation in hippocampal volume. It is hoped that approaches that aim to integrate genetic, environmental and neurobiological factors such as those utilised in this thesis will improve the likelihood of developing more targeted prevention and intervention opportunities for individuals at risk of or already experiencing clinical depression