Modulation Of COMT Val158Met Polymorphism On Brain Structure And Function:a Multi-modeling MRI Study

Objective:The effect of COMT Val158Met polymorphism on brain structure and function has been previously investigated separately and regionally. The interactions between COMT and gender or between COMT and other dopaminergic system related genes need systematically investigation. We examined a large sample size of healthy young adults and analyzed both the GMV, rsFC, and FCD differences between genetic groups in a voxel-wise manner throughout the whole brain.Subjects and Methods:A total of323healthy, young, right-handed subjects were recruited. Resting-state fMRI and high-resolution structural imaging were performed using a GE3.0T Signa HDX scanner.1. We genotyped the COMT rs4680and DRD2rs1076560in each subject using the PCR and LDR method.2. All preprocessing steps were carried out based on Matlab. The preprocessing of high resolution structural images including segmentation of grey and white matter, spatial normalization and smooth; while the preprocessing of resting-state fMRI data including slice timing, realignment, spatial normalization, resampling and smooth. Individual FCD maps were generated by calculating FCD before smoothing. The obtained local and long-range FCD were grand mean scaled to increase the normal distribution. Finally, the FCD maps were smoothed.3. VBM analysis of structural MRI data was performed to investigate group differences of GMV. Then we extracted these brain regions with GMV differences as seeds to compute rsFC with the rest of the brain.4. Considering the possible influence of gender, age, and education leval, we explored the impact of COMT and DRD2polymorphisms on the FCDs.5. A two-way analysis of variance (ANOVA) was used to evaluate the main effects and interactions, with multiple comparisons corrected.Results:1. The genotype distributions of the SNPs were in Hardy-Weinberg equilibrium. 2. ANOVA revealed a significant main effect of COMT on GMV in the right posterior cingulate cortex (PCC). Post-hoc testing showed that Val homozygotes exhibited significantly smaller GMV in the right PCC. The interaction between COMT and gender in GMV was shown in the left medial superior frontal gyrus (mSFG). The post-hoc comparison showed that only male Val homozygotes exhibited significantly smaller GMV than male Met allele carriers.3. PCC and mSFG showed similar rsFC patterns and that they were positively correlated with brain regions of the default-mode network (DMN).4. When the PCC and mSFG was respectively treated as the seed region, there was only significant main effect of COMT on the rsFC between seed regions and the left frontal pole (FP). Post-hoc testing showed that Val homozygotes always exhibited decreased rsFC.5. We repeated the rsFC analysis while controlling for the GMV of the seed region; however, we did not find any significant changes between results.6. Significant COMT×DRD2interaction effects were found in the local FCDs of the superior portion of the right temporal pole (sTP) and left lingual gyrus (LG) and in the long-range FCDs of the right putamen and left medial prefrontal cortex (MPFC). Post-hoc tests showed functional system-dependent nonlinear relationships between the genotypic subgroups and FCD.Conclusion:1. COMT Val158Met polymorphism modulates anatomical morphology and related rsFCs within the DMN; it may be explained by the different levels of COMT activity and DA availability between the genotypic groups.2. Modulatory effects of COMT Val158Met on the structural and functional characteristics of the DMN are independent with each other.3. The effect of COMT Vall58Met on prefrontal morphology is gender-dependent.4. Our findings suggest an interaction between COMT and DRD2genotypes and show a functional system-dependent modulation of dopamine signaling.