title: 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.
authors.affiliation: Psychiatric Neuroscience Group, Department of Neurological and Psychiatric Sciences, University Aldo Moro, 71024 Bari, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Ursini
authors.forename: Valentina
authors.initials: V
authors.lastname: Bollati
authors.forename: Leonardo
authors.initials: L
authors.lastname: Fazio
authors.forename: Annamaria
authors.initials: A
authors.lastname: Porcelli
authors.forename: Luisa
authors.initials: L
authors.lastname: Iacovelli
authors.forename: Assia
authors.initials: A
authors.lastname: Catalani
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Sinibaldi
authors.forename: Barbara
authors.initials: B
authors.lastname: Gelao
authors.forename: Raffaella
authors.initials: R
authors.lastname: Romano
authors.forename: Antonio
authors.initials: A
authors.lastname: Rampino
authors.forename: Paolo
authors.initials: P
authors.lastname: Taurisano
authors.forename: Marina
authors.initials: M
authors.lastname: Mancini
authors.forename: Annabella
authors.initials: A
authors.lastname: Di Giorgio
authors.forename: Teresa
authors.initials: T
authors.lastname: Popolizio
authors.forename: Andrea
authors.initials: A
authors.lastname: Baccarelli
authors.forename: Antonio
authors.initials: A
authors.lastname: De Blasi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Blasi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bertolino
mesh_terms: D000328:Adult; D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D002394:Catechol O-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D003071:Cognition / Q000502:physiology*; D019175:DNA Methylation; D005260:Female; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D009483:Neuropsychological Tests; D011110:Polymorphism, Genetic; D017397:Prefrontal Cortex / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013315:Stress, Psychological / Q000503:physiopathology*; D011795:Surveys and Questionnaires
chemical_list: D002394:Catechol O-Methyltransferase