title: Gene-gene effects on central processing of aversive stimuli.
abstract: Emotional reactivity and regulation are fundamental to human behavior. As inter-individual behavioral variation is affected by a multitude of different genes, there is intense interest to investigate gene-gene effects. Functional sequence variation at two genes has been associated with response and resiliency to emotionally unpleasant stimuli. These genes are the catechol-O-methyltransferase gene (COMT Val158Met) and the regulatory region (5-HTTLPR) of the serotonin transporter gene. Recently, it has been proposed that 5-HTT expression is not only affected by the common S/L variant of 5-HTTLPR but also by an A to G substitution. Using functional magnetic resonance imaging, we assessed the effects of COMT Val(158)Met and both 5-HTT genotypes on brain activation by standardized affective visual stimuli (unpleasant, pleasant, and neutral) in 48 healthy subjects. Based on previous studies, the analysis of genotype effects was restricted to limbic brain areas. To determine allele-dose effects, the number of COMT Met158 alleles (i.e., lower activity of COMT) and the number of 5-HTT low expressing alleles (S and G) was correlated with the blood oxygen level-dependent (BOLD) response to pleasant or unpleasant stimuli compared to neutral stimuli. We observed an additive effect of COMT and both 5-HTT polymorphisms, accounting for 40% of the inter-individual variance in the averaged BOLD response of amygdala, hippocampal and limbic cortical regions elicited by unpleasant stimuli. Effects of 5-HTT and COMT genotypes did not affect brain processing of pleasant stimuli. These data indicate that functional brain imaging may be used to assess the interaction of multiple genes on the function of neuronal networks.
authors.affiliation: Department of Psychiatry, Technische Universität Dresden, Dresden, Germany.
authors.forename: M N
authors.initials: MN
authors.lastname: Smolka
authors.forename: M
authors.initials: M
authors.lastname: Bühler
authors.forename: G
authors.initials: G
authors.lastname: Schumann
authors.forename: S
authors.initials: S
authors.lastname: Klein
authors.forename: X-Z
authors.initials: XZ
authors.lastname: Hu
authors.forename: M
authors.initials: M
authors.lastname: Moayer
authors.forename: A
authors.initials: A
authors.lastname: Zimmer
authors.forename: J
authors.initials: J
authors.lastname: Wrase
authors.forename: H
authors.initials: H
authors.lastname: Flor
authors.forename: K
authors.initials: K
authors.lastname: Mann
authors.forename: D F
authors.initials: DF
authors.lastname: Braus
authors.forename: D
authors.initials: D
authors.lastname: Goldman
authors.forename: A
authors.initials: A
authors.lastname: Heinz
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D001931:Brain Mapping; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D004644:Emotions / Q000502:physiology*; D005838:Genotype; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods; D008032:Limbic System / Q000098:blood supply / Q000502:physiology*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008606:Mental Processes; D008715:Methionine / Q000235:genetics; D008875:Middle Aged; D010100:Oxygen / Q000097:blood; D011110:Polymorphism, Genetic; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D014633:Valine / Q000235:genetics
chemical_list: D050486:Serotonin Plasma Membrane Transport Proteins; D008715:Methionine; D002394:Catechol O-Methyltransferase; D014633:Valine; D010100:Oxygen