Although a recent study failed to find any GMV SU5416 VEGFR/PDGFR inhibitor differences between genotypes, most studies have reported GMV differences across genotypes in the temporal cortex, hippocampus and frontal cortex. Although Honea et al. had found significant GMV differences in the left hippocampal region after multiple comparisons corrected at the whole-brain level, the other three studies found genotype differences in GMV using only a small volume correction or a ROI analysis. Even with these liberal statistical methods, several studies have reported no effects of COMT genotype on frontal or hippocampal volume. This discrepancy may be caused by 
differences in demographic characteristics, sample size, environmental background, and statistical methods. In the present study, we recruited a large sample of 299 healthy young Chinese Han subjects, performed GMV analysis at the whole-brain level, and considered both the effect of the genotype, gender and their interactions. We found that Val/Val males showed smaller GMV in the left mSFG than the other three groups, PF-4217903 956905-27-4 suggesting that COMT Val158Met effects on prefrontal morphology is genderdependent. As the key enzyme of DA degradation, COMT may account for more than 60% of the DA degradation in the PFC; it thus plays a unique role in regulating DA levels of the PFC because prefrontal DA transporters are scarce. The Met variant results in a fourfold decrease in enzymatic activity at body temperature, resulting that Val/Val individuals have greater COMT activity and lower DA availability in the PFC compared with Met carriers. Additionally, estrogen may inhibit COMT activity; this effect is more prominent in the PFC. Males who have lower level of estrogen may have greater COMT activity and lower DA availability relative to females. Consequently, both the Val/Val and male statuses may result in lowest DA availability in the PFC, which may contribute to the smallest GMV in the left mSFG in the Val/Val male group. Using VBM analysis of the whole brain, we found significantly reduced GMV in the PCC of Val/Val individuals when compared with Met carriers. Although no studies have reported structural differences between COMT genotypes, functional differences between genotypes in the PCC have been frequently demonstrated. GMV differences in the PCC between genotypes may also be explained by the different levels of COMT activity and DA availability between the two genotypic groups. Of course, this speculation must be validated in future studies because of the relatively low COMT expression in the PCC compared with that in the PFC. In the present study, we also found a main effect of gender on the GMV of the PCC. Although the underlying mechanism is unclear, the effect of estrogen on the COMT activity and DA availability may be one of the possible candidates. In the rsFC analyses, we found significant main effects of genotypes on the rsFCs between the right PCC and the left medial FP and between the left mSFG and the left FP. These findings may be also explained by the different levels of COMT activity and DA availability between the two genotypic groups. However, the significant main effect of gender on the rsFC was only present in the rsFC between the right PCC and the left medial FP, suggesting gender plays a different role in these two rsFCs. Although the effect of estrogen on the COMT activity may partly explain for the gender difference in the rsFC between the right PCC and the left medial FP, this mechanism cannot explain for the lack of gender difference in the rsFC between the left mSFG and the left FP. Thus, other mechanisms may be implicated in gender differences in rsFCs and need to be further studied. One intriguing finding in this study was that modulatory effects of COMT Val158Met were found in both structural and functional characteristics of the DMN.