Stress-related methylation of the catechol-O-methyltransferase Val 158 allele predicts human prefrontal cognition and activity

Abstract

DNA methylation at CpG dinucleotides is associated with gene silencing, stress, and memory. The catechol-O-methyltransferase (COMT) Val(158) 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 Val(158) allele measured from peripheral blood mononuclear cells (PBMCs) of Val/Val humans is associated negatively with lifetime stress and positively with WM performance; it interacts with stress to modulate prefrontal activity during WM, such that greater stress and lower methylation are related to reduced cortical efficiency; and it is inversely related to mRNA expression and protein levels, potentially explaining the in vivo effects. Finally, methylation of COMT in prefrontal cortex and that in PBMCs of rats are correlated. The relationship of methylation of the COMT Val(158) allele with stress, gene expression, WM performance, 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, these results demonstrate how stress-related DNA methylation of specific functional alleles impacts directly on human brain physiology beyond sequence variation.

Figure 1.

C2 methylation in Val/Val subjects: relationship with stress and WM behavioral performance. A, Mean ± 0.95 confidence interval of the effect of stress on methylation of COMT C2 rs4680 in Val/Val homozygotes—subjects with greater stress scores have reduced methylation. B, Scatter plot of the correlation between methylation of COMT C2 rs4680 and WM accuracy—Val/Val subjects with greater methylation have greater accuracy (see Results for statistics).

Figure 2.

Interaction between C2 methylation, stress scores, and prefrontal activity during WM in Val/Val subjects. A, Coronal section of the interaction between stress scores and C2 methylation on BOLD fMRI response in PFC. B, Scatter plot of the interaction showing that subjects with greater stress scores and lower methylation have greater activity in PFC, i.e., less efficiency (see Results for statistics).

Figure 3.

Scatter plot of the correlation between C2 methylation and t scores of MB-COMT expression levels (transformed −ΔΔCt) in PBMCs of Val/Val subjects; greater methylation is correlated with lower expression (see Results for statistics).

Figure 4.

Scatter plot of the correlation between methylation of COMT in PBMCs and in PFC of a group of 16 rats—methylation analysis on a CpG (chromosome 11: 84,577,576-7) in the COMT region (Leu¹⁵¹) corresponding to the region where the human rs4680 site is found shows a direct correlation between methylation in PBMCs and in PFC (see Results for statistics).