Abstract
Imaging genetic studies showed exaggerated blood oxygenation level-dependent response in limbic structures in carriers of low activity alleles of serotonin transporter-linked promoter region (5-HTTLPR) as well as catechol O-methyltransferase (COMT) genes. This was suggested to underlie the vulnerability to mood disorders. To better understand the mechanisms of vulnerability, it is important to investigate the genetic modulation of frontal-limbic connectivity that underlies emotional regulation and control. In this study, we have examined the interaction of 5-HTTLPR and COMT genetic markers on effective connectivity within neural circuitry for emotional facial expressions. A total of 91 healthy Caucasian adults underwent functional magnetic resonance imaging experiments with a task presenting dynamic emotional facial expressions of fear, sadness, happiness and anger. The effective connectivity within the facial processing circuitry was assessed with Granger causality method. We have demonstrated that in fear processing condition, an interaction between 5-HTTLPR (S) and COMT (met) low activity alleles was associated with reduced reciprocal connectivity within the circuitry including bilateral fusiform/inferior occipital regions, right superior temporal gyrus/superior temporal sulcus, bilateral inferior/middle prefrontal cortex and right amygdala. We suggest that the epistatic effect of reduced effective connectivity may underlie an inefficient emotion regulation that places these individuals at greater risk for depressive disorders.
Highlights
The last decade has seen the emergence of imaging genetics, as a research strategy to elucidate relationships between genotypic markers and neural structures or processes, that can help to identify pathophysiological processes predisposing to psychiatric disorders.[1]
The aim of the present study was to examine the joint effect of catechol O-methyltransferase (COMT) and 5-HTTLPR functional polymorphisms upon the effective connectivity in neural circuitry, supporting facial emotion processing in healthy volunteers
The polymorphism val158met was considered for COMT genotyping, in line with the suggestions[33] based on direct comparisons of the effects of single COMT val158met single nucleotide polymorphism (SNP) vs the haplotypes employed in previous studies.[34,35]
Summary
The last decade has seen the emergence of imaging genetics, as a research strategy to elucidate relationships between genotypic markers and neural structures or processes, that can help to identify pathophysiological processes predisposing to psychiatric disorders.[1] One consistent finding is exaggerated amygdala response to threat-related stimuli in carriers of low activity short (S) allele of the serotonin transporter-linked promoter region (5-HTTLPR) gene (see review[2]). Imaging genetic studies have reported that met carriers overactivated subcortical limbic regions in response to negative emotional stimuli.[4,5,6] These results suggest a role for the met allele in predisposing to greater stress reactivity[7] and a negative emotion attentional bias that may confer risk for affective disorders. The investigators, emphasized the importance of gene–gene interaction (epistasis) in predisposing toward complex syndromes, such as MDD, that may occur even in the absence of main effects of single genes.[9,10] This is supported by the evidence of interactive effects of COMT and 5-HTTLPR genotypes in predisposing toward development of MDD in individuals with a history of stressful life events.[11]
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