title: Epistatic interaction between COMT and DTNBP1 modulates prefrontal function in mice and in humans.
abstract: Cognitive functions are highly heritable and the impact of complex genetic interactions, though undoubtedly important, has received little investigation. Here we show in an animal model and in a human neuroimaging experiment a consistent non-linear interaction between two genes--catechol-O-methyl transferase (COMT) and dysbindin (dys; dystrobrevin-binding protein 1 (DTNBP1))--implicated through different mechanisms in cortical dopamine signaling and prefrontal cognitive function. In mice, we found that a single genetic mutation reducing expression of either COMT or DTNBP1 alone produced working memory advantages, while, in dramatic contrast, genetic reduction of both in the same mouse produced working memory deficits. We found evidence of the same non-linear genetic interaction in prefrontal cortical function in humans. In healthy volunteers (N=176) studied with functional magnetic resonance imaging during a working memory paradigm, individuals homozygous for the COMT rs4680 Met allele that reduces COMT enzyme activity showed a relatively more efficient prefrontal engagement. In contrast, we found that the same genotype was less efficient on the background of a dys haplotype associated with decreased DTNBP1 expression. These results illustrate that epistasis can be functionally multi-directional and non-linear and that a putatively beneficial allele in one epistastic context is a relatively deleterious one in another. These data also have important implications for single-locus association analyses of complex traits.
authors.affiliation: 1] Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy [2] Department of Scienze del Farmaco, Universita' degli Studi di Padova, Padova, Italy [3] Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, National Institute of Mental Health, Bethesda, MD, USA.
authors.forename: F
authors.initials: F
authors.lastname: Papaleo
authors.affiliation: Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, National Institute of Mental Health, Bethesda, MD, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Burdick
authors.affiliation: Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, National Institute of Mental Health, Bethesda, MD, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Callicott
authors.affiliation: 1] Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, National Institute of Mental Health, Bethesda, MD, USA [2] Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA [3] Departments of Psychiatry, Neurology, Neuroscience and the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Weinberger
mesh_terms: D000483:Alleles; D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002394:Catechol O-Methyltransferase / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D004843:Epistasis, Genetic; D059907:Functional Neuroimaging; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D006720:Homozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008570:Memory, Short-Term / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D017397:Prefrontal Cortex / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; C432416:DTNBP1 protein, human; C498992:Dtnbp1 protein, mouse; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D002394:Catechol O-Methyltransferase