The 5-HTTLPR Polymorphism Affects Network-Based Functional Connectivity in the Visual-Limbic System in Healthy Adults

Abstract

The serotonin transporter-linked polymorphic region 5-HTTLPR is a key genetic regulator of 5-HTT expression in the human brain where the short allele S has been implicated in emotion dysregulation. However, the neural mechanism underlying the association between this variant and emotion processing is still unclear. Earlier studies suggested an effect of 5-HTTLPR on amygdala activation during emotional face processing. However, this association has been questioned in recent studies employing larger sample sizes and meta-analyses. Here, we examined a sample of 223 healthy subjects with a well-established fMRI emotional face processing task to (1) re-evaluate the association between 5-HTTLPR and amygdala activation, (2) explore potential network-based functional connectivity phenotypes for associations with 5-HTTLPR, and (3) probe the reliability, behavioral significance and potential structural confounds of the identified network phenotype. Our results revealed no significant effect of 5-HTTLPR on amygdala activation (P>0.79). However, the number of S alleles was significantly correlated with functional connectivity of a visual-limbic subnetwork (P_FWE=0.03). The subnetwork cluster included brain regions that are pivotal to emotion regulation such as the hippocampus, orbitofrontal cortex, anterior cingulate gyrus, fusiform gyrus, and subcortex. Notably, individuals with lower subnetwork connectivity had significantly higher emotion suppression scores (P=0.01). Further, the connectivity metrics were test-retest reliable and independent from subnetwork gray matter volume and white matter anisotropy. Our data provide evidence for a functional network-based phenotype linking genetic variation in 5-HTTLPR to emotion regulation, and suggest that further critical evaluations of the association between 5-HTTLPR and amygdala activation are warranted.

Figure 1

The identified subnetwork associated with 5-HTTLPR polymorphism (a). The functional connectivity of this subnetwork significantly decreased in both ls and ss carriers (cluster-level P_FWE=0.03, mean connectivity differences P=7e−15) (b). In contrast, the mean grey matter volumes and mean FA values were not significantly different between genotype groups for the identified nodes (c) and interconnecting visual-limbic white matter tracts (d), respectively. In addition, participants with lower subnetwork connectivity showed higher emotional suppression scores (e). Bars indicate mean values and error bars indicate standard errors.