The Journal of Neuroscience, May 4, 2011 • 31(18):6692– 6698

Gianluca Ursini,1,2 Valentina Bollati,3,4 Leonardo Fazio,1 Annamaria Porcelli,1 Luisa Iacovelli,5 Assia Catalani,Lorenzo Sinibaldi,2Barbara Gelao,1 Raffaella Romano,1 Antonio Rampino,1 Paolo Taurisano,1 Marina Mancini,Annabella Di Giorgio,1,6 Teresa Popolizio,6 Andrea Baccarelli,3,4,7 Antonio De Blasi,8 Giuseppe Blasi1 and Alessandro Bertolino1,6

1Psychiatric Neuroscience Group, Department of Neurological and Psychiatric Sciences, University “Aldo Moro”, 71024 Bari, Italy,

2Mendel Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy,
3Center for Molecular and Genetic Epidemiology, Department of Environmental and Occupational Health, University of Milan, Milan, Italy,
4Istituto Di Ricovero e Cura a Carattere Scientifico Maggiore Hospital, Mangiagalli and Regina Elena Foundation, 20122 Milan, Italy,
5Department of Physiology and Pharmacology “V. Erspamer”, University of Rome “Sapienza”, 00185 Rome, Italy,
6Department of Neuroradiology, IRCCS “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy,
7Exposure, Epidemiology, and Risk Program, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts 02115-
8Department of Molecular Medicine, University of Rome “Sapienza”, 00185 Rome, Italy


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 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 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.