Interaction of Catechol-O-methyltransferase Val158 Met polymorphism and sex influences association of parietal intrinsic functional connectivity and immediate verbal memory

Abstract

Introduction: Sex differences modulate catechol-O-methyltransferase (COMT) genotype effect at a synaptic dopamine level, which influences brain function as well as cognitive performance. In this study, we investigated how COMT Val¹⁵⁸ Met polymorphism and sex affect intrinsic functional connectivity and memory.

Methods: Intrinsic functional networks were extracted using independent component analysis of resting-state functional magnetic resonance imaging data from 186 healthy young COMT-genotyped participants. The association of these functional networks and memory function was tested to investigate whether the effect of COMT × sex interaction influences the association of intrinsic functional connectivity and memory performance. Quadratic curve fit estimation was used to examine the relationship between functional connectivity and speculative dopamine level among groups.

Results: COMT MM/MV carriers, relative to VV carriers, showed increased functional connectivity in left superior parietal lobule and right inferior frontal gyrus. Further, male MM/MV carriers showed significant higher mean functional connectivity in left inferior parietal lobule relative to male VV carriers and female MM/MV carriers, which was associated with worse immediate verbal recall performance. Additionally, the relationship between inferior parietal lobule functional connectivity and speculative dopamine level among groups fits the quadratic curve.

Conclusions: These findings suggest that the interaction of COMT genotype and sex might regulate synaptic dopaminergic concentrations and influence the association of intrinsic functional connectivity and immediate verbal memory in left inferior parietal lobule.

Keywords: COMT Val158Met; dopamine; functional connectivity; immediate verbal memory; parietal lobule; resting-state fMRI; sex.

FIGURE 1

Cortical representation of the DMN (a), ECN (b), LFPN (c), and RFPN (d) identified by independent component analysis in our study group. Data are displayed on the lateral and medial surfaces of the left and right hemispheres of a brain surface map. The color scale represents the t values in each RSN. DMN, default mode network; ECN, executive control network; LFPN, left fronto‐parietal network; RFPN, right fronto‐parietal network

FIGURE 2

Effect of COMT Val¹⁵⁸Met polymorphism on DMN, ECN, LFPN, and RFPN. (a) Increased functional connectivity for MM/MV relative to VV group in left superior parietal lobule and right inferior frontal gyrus (red) are rendered on a template brain. For illustration purposes, height threshold p < .001 uncorrected, >30 voxels. (b and c) Mean functional connectivity (across subjects’ mean ± SEM) for DMN, ECN, LFPN, and RFPN networks in MM/MV and VV groups at the peak MNI coordinates of (b) left superior parietal lobule (x = −42, y = −62, z = 56, Z = 5.3) and (c) right inferior frontal gyrus (x = 50, y = 18, z = 28, Z = 4.5) in LFPN. Error bars denote one SEM. COMT, catechol‐O‐methyltransferase; DMN, default mode network; ECN, executive control network; LFPN, left fronto‐parietal network; RFPN, right fronto‐parietal network; MM/MV, Met/Met and Met/Val; VV, Val/Val; SEM, standard error of mean

FIGURE 3

Effect of COMT Val¹⁵⁸Met polymorphism and sex on DMN, ECN, LFPN, and RFPN. (a) Significant COMT × sex interaction on FC in left inferior parietal lobule (red) are rendered on a template brain. For illustration purposes, height threshold p < .001 uncorrected, >30 voxels. (b) Mean FC (across subjects’ mean ± SEM) for DMN, ECN, LFPN, and RFPN networks in four groups based on COMT genotype and sex at the peak MNI coordinates of left inferior parietal lobule (x = −30, y = −66, z = 40, Z = 4.4). Male MM/MV carriers showed significantly higher FC relative to male VV carriers (Z = 4.8) and female MM/MV carriers (Z = 7.0). Error bars denote one SEM. COMT, catechol‐O‐methyltransferase; DMN, default mode network; ECN, executive control network; LFPN, left fronto‐parietal network; RFPN, right fronto‐parietal network; MM/MV, Met/Met and Met/Val; VV, Val/Val; FC, functional connectivity; SEM, standard error of mean