Serotonergic gene-to-gene interaction is associated with mood and GABA concentrations but not with pain-related cerebral processing in fibromyalgia subjects and healthy controls

Abstract

The neurotransmitter serotonin, involved in the regulation of pain and emotion, is critically regulated by the 5-HT_1A autoreceptor and the serotonin transporter (5-HTT). Polymorphisms of these genes affect mood and endogenous pain modulation, both demonstrated to be altered in fibromyalgia subjects (FMS). Here, we tested the effects of genetic variants of the 5-HT_1A receptor (CC/G-carriers) and 5-HTT (high/intermediate/low expression) on mood, pain sensitivity, cerebral processing of evoked pain (functional MRI) and concentrations of GABA and glutamate (MR spectroscopy) in rostral anterior cingulate cortex (rACC) and thalamus in FMS and healthy controls (HC). Interactions between serotonin-relevant genes were found in affective characteristics, with genetically inferred high serotonergic signalling (5-HT_1A CC/5-HTT_high genotypes) being more favourable across groups. Additionally, 5-HT_1A CC homozygotes displayed higher pain thresholds than G-carriers in HC but not in FMS. Cerebral processing of evoked pressure pain differed between groups in thalamus with HC showing more deactivation than FMS, but was not influenced by serotonin-relevant genotypes. In thalamus, we observed a 5-HT_1A-by-5-HTT and group-by-5-HTT interaction in GABA concentrations, with the 5-HTT high expressing genotype differing between groups and 5-HT_1A genotypes. No significant effects were seen for glutamate or in rACC. To our knowledge, this is the first report of this serotonergic gene-to-gene interaction associated with mood, both among FMS (depression) and across groups (anxiety). Additionally, our findings provide evidence of an association between the serotonergic system and thalamic GABA concentrations, with individuals possessing genetically inferred high serotonergic signalling exhibiting the highest GABA concentrations, possibly enhancing GABAergic inhibitory effects via 5-HT.

Keywords: 5‐HT1A; Fibromyalgia; GABA; Genetic polymorphisms; Mood; Serotonin; Serotonin transporter.

Fig. 1

Gene-by-gene interaction in measures of depression in fibromyalgia subjects (FMS) (n = 81) and anxiety in all participants (n = 120). a FMS displayed a significant 5‐HT_1A-by-5-HTT interaction in HAD-D (Hospital Anxiety and Depression Scale, Depression subscale) scores and b BDI (Beck’s depression inventory) with 5‐HT_1A CC paired with the 5-HTT high expressing genotype resulting in lowest depression values. c A similar pattern was observed in STAI (State-trait anxiety inventory) data obtained from all participants (FMS and healthy controls) with both STAI-S (state subscale) and d STAI-T (trait subscale) displaying serotonin-relevant gene–gene interactions in addition to significant group differences (see Additional file 3: Fig. S1). Plotted are black circles, triangles and squares representing estimated marginal means with 95% confidence interval combined with colored boxplots, with the line representing the median, the upper and lower box representing the 25th (Q1) and 75th (Q3) percentile, i.e. the interquartile range (IQR), and whiskers represent Q1− and Q3 + 1.5*IQR. Raw data is plotted in the background

Fig. 2

Extracted BOLD-signal and GABA concentration. Fibromyalgia subjects (FMS) (n = 68) showed a similar pattern of lower pain-evoked BOLD-signal as healthy controls (HC) (n = 33) in a right rACC and b bilateral thalamus. This effect, however, was only significant in thalamus. c In thalamic GABA concentrations (FMS = 74, HC = 42), there was a significant 5‐HT_1A-by-5-HTT interaction, as well as a significant group-by-5-HTT interaction. A comparable pattern was observed in both relative (upper row) and absolute GABA (lower row) concentrations. Plotted are black circles, triangles and squares representing estimated marginal means with the associated black vertical lines being 95% confidence intervals. In the colored boxplots, the horizontal line represents the median, the upper and lower box representing the 25th (Q1) and 75th (Q3) percentile, i.e. the interquartile range (IQR), and whiskers represent Q1− and Q3 + 1.5*IQR. Raw data is plotted in the background. a.u. arbitrary units, mM millimole, L left, R right