Linking the serotonin transporter gene, family environments, hippocampal volume and depression onset: A prospective imaging gene × environment analysis.

Abstract

A single imaging gene-environment (IGxE) framework that is able to simultaneously model genetic, neurobiological, and environmental influences on psychopathology outcomes is needed to improve understanding of how complex interrelationships between allelic variation, differences in neuroanatomy or neuroactivity, and environmental experience affect risk for psychiatric disorder. In a longitudinal study of adolescent development we demonstrate the utility of such an IGxE framework by testing whether variation in parental behavior at age 12 altered the strength of an imaging genetics pathway, involving an indirect association between allelic variation in the serotonin transporter gene to variation in hippocampal volume and consequent onset of major depressive disorder by age 18. 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 parental aggression 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 because of the effects of these environments on a neurobiological pathway from the serotonin transporter gene to depression onset that proceeds through variation in hippocampal volume.

Hippocampal Volume as an Amplifier of the Effect of Social Context on Adolescent Depression

“…For example, adolescent girls at heightened risk for developing depression due to maternal history of recurrent depression showed smaller hippocampal volumes than girls with no such history (Chen, Hamilton, & Gotlib, 2010). Adding consideration of social context, a more recent study suggested that genetic vulnerability to adolescent depression, as conferred by allelic variation in the serotonin transporter gene, was mediated by smaller bilateral hippocampal volumes and expressed only in conditions of high parental aggression and/or low positive parenting (Little et al, 2015). Thus, there may be multiple paths to depression that involve interplay between hippocampal volume and the environment, with one weighted more by direct genetic risk for depression and another by greater sensitivity to positive and negative environments and the learning they engender (e.g., that one is safe and valued vs. unprotected and unimportant, with implications for depression).…”

Adiposity is inversely associated with hippocampal volume in African Americans and European Americans with diabetes

“…One longitudinal study (Chan et al, 2016) suggested that reductions in hippocampal volume were “neural markers” for depression. They postulated this could relate to the effects of an adverse environment on neurobiological pathways from the serotonin transporter gene proceeding through variation in hippocampal volume to produce depression (Little et al, 2015). In a recent genome-wide-association analysis including 339,224 individuals, a pathway analysis provided strong support for an important role of the central nervous system in susceptibility to obesity (Locke et al, 2015).…”

Sometimes It's Good to be Short: The Serotonin Transporter Gene, Positive Parenting, and Adolescent Depression

“…It is possible that the degree of threat or adversity captured by the negative parenting measures in both the current and some other studies with null findings were not severe enough to reveal the interaction. We have identified, however, in the ADS sample that inclusion of hippocampal volume as an intermediate phenotype in a pathway from the serotonin transporter gene to MDD onset during the adolescent period reveals potential S carrier vulnerability to depression in the context of negative parenting (Little et al., ). Specifically, possession of a greater number of S alleles was associated with smaller hippocampal volume, and the specific variance in hippocampal volume accounted for by genotype was in turn associated with increased risk for MDD onset, but only in the context of more negative, punitive maternal behavior.…”