AUTHOR=Elton Amanda , Smith Christopher T. , Parrish Michael H. , Boettiger Charlotte A. 

TITLE=COMT Val158Met Polymorphism Exerts Sex-Dependent Effects on fMRI Measures of Brain Function

JOURNAL=Frontiers in Human Neuroscience

VOLUME=11

YEAR=2017

URL=https://www.frontiersin.org/journals/human-neuroscience/articles/10.3389/fnhum.2017.00578

DOI=10.3389/fnhum.2017.00578

ISSN=1662-5161

ABSTRACT=<p>Evidence suggests that dopamine levels in the prefrontal cortex (PFC) modulate executive functions. A key regulator of PFC dopamine is catechol-<italic>O</italic>-methyltransferase (COMT). The activity level of the COMT enzyme are influenced by sex and the Val<sup>158</sup>Met polymorphism (rs4680) of the <italic>COMT</italic> gene, with male sex and Val alleles both being associated with higher bulk enzyme activity, and presumably lower PFC dopamine. <italic>COMT</italic> genotype has not only been associated with individual differences in frontal dopamine-mediated behaviors, but also with variations in neuroimaging measures of brain activity and functional connectivity. In this study, we investigated whether <italic>COMT</italic> genotype predicts individual differences in neural activity and connectivity, and whether such effects are sex-dependent. We tested 93 healthy adults (48 females), genotyped for the Val<sup>158</sup>Met polymorphism, in a delay discounting task and at rest during fMRI. Delay discounting behavior was predicted by an interaction of <italic>COMT</italic> genotype and sex, consistent with a U-shaped relationship with enzyme activity. <italic>COMT</italic> genotype and sex similarly exhibited U-shaped relationships with individual differences in neural activation, particularly among networks that were most engaged by the task, including the default-mode network. Effects of <italic>COMT</italic> genotype and sex on functional connectivity during rest were also U-shaped. In contrast, flexible reorganization of network connections across task conditions varied linearly with <italic>COMT</italic> among both sexes. These data provide insight into the potential influences of COMT-regulated variations in catecholamine levels on brain function, which may represent endophenotypes for disorders of impulsivity.</p>