Objective Imaging genetic studies demonstrated that some genes implicated in emotional processes may have an effect on the brain structure and functioning. The role of serotonin transporter-linked promoter region (5-HTTLPR) marker and catechol O-methyltransferase (COMT) gene was highlighted in separate studies. There is less evidence of a possible interaction (epistasis) of the above genes. In this study we have examined an interaction of 5-HTTLPR and COMT markers on effective connectivity and brain volume within neural circuitry associated with emotion processing.
Method Ninety one healthy Caucasian adults underwent functional MRI (fMRI) and structural MRI. In fMRI study the participants were presented with video clips of dynamic emotional facial expressions of fear, sadness, happiness and anger. The effective connectivity within the emotion processing circuitry was assessed with Granger causality method. This method allows an exploration of temporal relationship between the activity in different regions, which sheds light on possible causality of the brain events. In the structural neuroimaging part of the study we applied diffeomorphic anatomic registration through exponentiated Lie algebra (DARTEL) whole-brain voxel-based morphometry (VBM) which has better sensitivity compared with the earlier VBM methods.
Results We have demonstrated that in the fear processing condition, an interaction between 5-HTTLPR (S) and COMT(met) low activity alleles was associated with reduced effective connectivity within the circuitry including bilateral inferior prefrontal cortex, right superior temporal gyrus, bilateral fusiform/inferior occipital regions, and right amygdala. The results of the structural data analysis showed an interaction of COMT and 5-HTTLPR genotypes with regional grey matter volume in bilateral parahippocampal gyrus, amygdala, hippocampus, cerebellum and right putamen. In particular, the gray matter volume in these regions was smaller in individuals who were both COMT-met and 5-HTTLPR-S carriers, as compared to those carrying either 5-HTTLPR-L/L, or COMT-val/val.
Conclusion The epistatic effect of COMT-met and 5-HTTLPR-S markers impacts on both the brain function and structure and is associated with: (1) reduced effective connectivity within the frontal-limbic emotion processing circuit. (2) reduced volumes of key temporal-limbic regions involved in emotion processing. These genetic effects may underlie an inefficient emotion regulation that places the individuals carrying low activity alleles of both COMT and 5-HTTLPR at greater risk for depressive disorders.