Stress-related methylation of the catechol-O-methyltransferase val158 allele predicts human prefrontal cognition and activity

Gianluca Ursini, Valentina Bollati, Leonardo Fazio, Annamaria Porcelli, Luisa Iacovelli, Assia Catalani, Lorenzo Sinibaldi, Barbara Gelao, Raffaella Romano, Antonio Rampino, Paolo Taurisano, Marina Mancini, Annabella di Giorgio, Teresa Popolizio, Andrea Baccarelli, Antonio de Blasi, Giuseppe Blasi, Alessandro Bertolino

Research output: Contribution to journalArticlepeer-review


DNA methylationatCpG dinucleotides isassociated 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 mononuclear cells (PBMCs)ofVal/Valhumans is associated negatively with life time 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 Val158 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.

Original languageEnglish
Pages (from-to)6692-6698
Number of pages7
JournalJournal of Neuroscience
Issue number18
Publication statusPublished - May 4 2011

ASJC Scopus subject areas

  • Neuroscience(all)


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