| Objective: The effect of COMT Val158 Met polymorphism on brain structure and function has been previously investigated separately, but to date, these methods have not been combined to provide a complete picture of the effect of COMT Val158 Met polymorphism on the brain in healthy individuals. And the interactions between COMT and other dopaminergic system related genes need systematically investigation. Different genotypic combinations of COMT and DRD2 can generate multiple subgroups with different levels of dopamine signaling. Its modulations on brain properties can be investigated by analyzing the combined gene effects of COMT and DRD2. However, the inherent association between modulation patterns of the dopamine system on structural and functional properties of the brain remains unknown. We examined 323 healthy young adults and analyzed both the gray matter volume(GMV) and resting-state functional connectivity(rs FC) differences between genetic groups in a voxel-wise manner throughout the whole brain.Materials and Methods: A total of 323 Chinese Han healthy, young, right-handed subjects were recruited. Resting-state f MRI and high-resolution structural imaging were performed using a GE 3.0T Signa HDX scanner. 1. We genotyped the COMT rs4680(G→A) and DRD2 rs1076560(G→T) in each subject using the PCR and LDR method. 2. All preprocessing steps were carried out based on Matlab. GMV maps were constructed for each subject using the VBM8 implemented in SPM8. The preprocessing of high resolution structural images including segmentation of grey and white matter, spatial normalization and smooth; The f MRI data were preprocessed using DPARSFA, including slice timing, realignment, spatial normalization, resampling, smooth and filter. 3. Using linear regression, we evaluate the main effect of each SNP and their interactions for the demographic and psychological data.4. We used GMV as a measure of brain structural properties and investigated the modulation of the dopamine signaling on GMV by analyzing COMT × DRD2 interactions. And then, we used rs FC as a measure of brain functional properties. We investigated nonlinear modulation of the dopamine signaling on these functional connections by analyzing COMT × DRD2 interactions. Only rs FCs of brain regions with significant interaction effects on GMV were included to maintain the regional consistency between the structural and functional analyses. 5. Finally, a direct correlation between GMV and rs FC in any of brain regions with significant interactions on both measures was assessed in the total population of subjects. 6. We used quadratic regression to test the significance of the fitting curve that modeling the modulation of the presumed dopamine signaling on the GMV and rs FC of brain regions with a significant interaction effect. Different sorting schemes were tested. 7. The Gaussian Random Field(GRF) or Family Wise Error(FWE) method was applied for multiple comparison correction.Results: 1. Neither significant main effects of any SNP nor significant interactions between the two SNPs(P > 0.05) were found for any of the cognitive(memory and execution) and psychological variables(depression, anxiety and personality). 2. The main effects of COMT genotypes on GMV(GRF correction at voxel level P < 0.005 and cluster level P < 0.005) were found in the right anterior cingulate cortex(ACC), the right precentral gyrus, the right inferior frontal operculum(IFop), and the right mid-cingulate cortex(MCC). Post-hoc testing showed that A-allele carriers(AA and GA) exhibited significantly smaller GMV in the four brain regions than the GG homozygotes. 3. There was no significant main effect of DRD2 on the GMV under the same statistical threshold. 4. The GMV analysis revealed a significant non-additive COMT × DRD2 interaction in the right dorsal anterior cingulate cortex(d ACC) with a GRF correction for multiple comparisons(voxel level P < 0.005 and cluster level P < 0.005). Thedistribution of the GMV of this cluster in these genotypic subgroups(which reflected the presumed dopamine signaling) was displayed as an inverted U-shape. By sorting according to COMT and DRD2, the fitting curves tested by quadratic regression were both significant. 5. For the rs FC analysis, we defined the seed region as the cluster of the right d ACC that showed a significant COMT × DRD2 interaction on GMV. A one-sample t-test(FWE, P < 0.05) in the total population revealed that the right d ACC was positively correlated with brain regions of the salience network(SN). These findings suggest that the right d ACC is an important node of the SN. 6. We did not find any significant main effect of COMT or DRD2 polymorphism on the rs FC of the right d ACC. 7. There was a significant non-additive COMT × DRD2 interaction on the rs FC between the right d ACC and the right precuneus. The distribution of the rs FCs of these genotypic subgroups(which reflected the presumed dopamine signaling) was fitted into a U-shaped model. By sorting according to COMT and DRD2, the fitting curves were both significant. 8. We tested correlation between GMV of the right d ACC and rs FC between the right d ACC and the right precuneus and found a significant negative correlation between structural and functional measures of the right d ACC. 9. Although we did not find any significant additive interaction under the same statistical threshold, we found a trend towards significant additive effects(P < 0.005, uncorrected) of the two SNPs on the GMV in the right inferior frontal gyrus(IFG). Post-hoc testing revealed a linear modulation pattern: the GMV of right IFG decreased with increasing dopamine signaling. 10. We then extracted the right IFG as seed regions to perform rs FC analyses. A one-sample t-test(FWE, P < 0.05) in the total population revealed that the right IFG was positively correlated with brain regions of the bilateral temporal and frontal lobes. Voxel-based comparisons of rs FCs were then performed using a one-way ANOVA(P<0.005, uncorrected) to identify brain regions with group differences. We found a significant group differences in the rs FC between the right IFG and the right superior temporal gyrus(STG). Post-hoc testing revealedthat the rs FC between the right IFG and STG increased with increasing dopamine signaling. 11. Similarly, we tested correlation between GMV of the right IFG and rs FC between the right IFG and STG. We found a significant negative correlation between structural and functional measures of the right IFG.Conclusion: 1. No genotypic differences were detected in any assessments of the cognition, mood and personality. 2. The inverted U-shaped modulation of the dopamine signaling on structural property may be explained by the inverted U-shaped model of the dependence of neuronal survival and growth on dopamine signaling. 3. The U-shaped modulation of the functional property may indicate a functional compensatory mechanism through which healthy young adults with structural deficits could maintain their normal behavioral performance. 4. Modulatory effects of COMT and DRD2 on the brain structural and functional property are not independent with each other, which showed an inverse modulation in healthy young adults. |
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