Stress-Related Methylation of the Catechol-O-Methyltransferase Val(158) Allele Predicts Human Prefrontal Cognition and Activity

andit is inversely related to mRNA expression and protein levels, potentially explaining the in vivo effects. Finally, methylation of COMT inprefrontal cortex and that in PBMCs of rats are correlated. The relationship of methylation of the COMT Val158 allele with stress, geneexpression,WMperformance, and related brain activity suggests that stress-related methylation is associated with silencing of the gene,which partially compensates the physiological role of the high-activity Val allele in prefrontal cognition and activity. Moreover, theseresults demonstrate how stress-related DNA methylation of specific functional alleles impacts directly on human brain physiologybeyond sequence variation.; DNAmethylation at CpG dinucleotides is associated with gene silencing, stress, and memory. The catechol-O-methyltransferase (COMT)Val158 allele in rs4680 is associated with differential enzyme activity, stress responsivity, and prefrontal activity during working memory(WM), and it creates a CpG dinucleotide. We report that methylation of the Val158 allele measured from peripheral blood mononuclearcells (PBMCs) of Val/Val humans is associated negatively with lifetime stress and positively withWMperformance; it interacts with stressto modulate prefrontal activity during WM, such that greater stress and lower methylation are related to reduced cortical efficiency