Catechol-O-methyltransferase Val158Met polymorphism modulates gray matter volume and functional connectivity of the default mode network

Abstract

The effect of catechol-O-methyltransferase (COMT) Val158Met polymorphism on brain structure and function has been previously investigated separately and regionally; this prevents us from obtaining a full picture of the effect of this gene variant. Additionally, gender difference must not be overlooked because estrogen exerts an interfering effect on COMT activity. We examined 323 young healthy Chinese Han subjects and analyzed the gray matter volume (GMV) differences between Val/Val individuals and Met carriers in a voxel-wise manner throughout the whole brain. We were interested in genotype effects and genotype × gender interactions. We then extracted these brain regions with GMV differences as seeds to compute resting-state functional connectivity (rsFC) with the rest of the brain; we also tested the genotypic differences and gender interactions in the rsFCs. Val/Val individuals showed decreased GMV in the posterior cingulate cortex (PCC) compared with Met carriers; decreased GMV in the medial superior frontal gyrus (mSFG) was found only in male Val/Val subjects. The rsFC analysis revealed that both the PCC and mSFG were functionally correlated with brain regions of the default mode network (DMN). Both of these regions showed decreased rsFCs with different parts of the frontopolar cortex of the DMN in Val/Val individuals than Met carriers. Our findings suggest that the COMT Val158Met polymorphism modulates both the structure and functional connectivity within the DMN and that gender interactions should be considered in studies of the effect of this genetic variant, especially those involving prefrontal morphology.

Figure 1. Significant GMV differences between genotypes.

Val homozygotes exhibit significantly (P < 0.05, corrected) smaller GMV in the right PCC than Met allele carriers. GMV, gray matter volume; L, left; PCC, posterior cingulate cortex; R, right.

Figure 2. The interaction between genotype and gender in GMV.

A significant (P < 0.05, corrected) genotype × gender interaction effect is observed in the left mSFG. Only male Val homozygotes exhibit significantly smaller GMV than male Met allele carriers. GMV, gray matter volume; L, left; mSFG, medial superior frontal gyrus; R, right.

Figure 3. The rsFC maps of the right PCC and left mSFG.

One-sample t-test (FWE, P < 0.05) reveals that the right PCC is positively correlated with brain regions of the DMN (A). The left mSFG shows a similar rsFC pattern (B), although the right PCC and left mSFG differed in rsFC strengths. DMN, default mode network; FWE, Family Wise Error; L, left; mSFG, medial superior frontal gyrus; PCC, posterior cingulate cortex; R, right; rsFC, resting-state functional connectivity.

Figure 4. Genotypic differences in the rsFCs of the right PCC.

There is only a significant (P < 0.05, corrected) main effect of genotype in the rsFC between the right PCC and the left medial FP. Val homozygotes exhibit decreased rsFC when compared with Met allele carriers. FP, frontal pole; L, left; PCC, posterior cingulate cortex; R, right; rsFC, resting-state functional connectivity.

Figure 5. Genotypic differences in the rsFCs of the left mSFG.

There is only a significant (P < 0.05, corrected) main effect of genotype in the rsFC between the left mSFG and the left FP. Val homozygotes exhibit decreased rsFC when compared with Met allele carriers. FP, frontal pole; L, left; mSFG, medial superior frontal gyrus; R, right; rsFC, resting-state functional connectivity.

Figure 6. Illustration of the nonlinear curve model explaining the GMV and rsFC differences among different subgroups.

Both COMT genotype and gender affect DA availability in the brain. Different DA levels may explain the GMV and rsFC differences that were observed among different subgroups. The left column shows the mean and 95% CI of imaging phenotypes of the four subgroups, whereas the right column shows the location of each imaging phenotype on the curve. Arrows represent significant group differences (P < 0.05, corrected). CI, confidence interval; COMT, catechol-O-methyltransferase; DA, dopamine; DMN, default mode network; FP, frontal pole; GMV, gray matter volume; mSFG, medial superior frontal gyrus; PCC, posterior cingulate cortex; rsFC, resting-state functional connectivity.