title: Epistasis between catechol-O-methyltransferase and type II metabotropic glutamate receptor 3 genes on working memory brain function.
abstract: Dopaminergic and glutamatergic systems are critical components responsible for prefrontal signal-to-noise tuning in working memory. Recent functional MRI (fMRI) studies of genetic variation in these systems in catechol-O-methyltransferase (COMT) and in metabotropic glutamate receptor mgluR3 (GRM3), respectively, suggest that these genes influence prefrontal physiological signal-to-noise in humans. Here, using fMRI, we extend these individual gene findings to examine the combined effects of COMT and GRM3 on dissociable components of the frontoparietal working memory network. We observed an apparent epistatic interaction of these two genes on the engagement of prefrontal cortex during working memory. Specifically, the GRM3 genotype putatively associated with suboptimal glutamatergic signaling was significantly associated with inefficient prefrontal engagement and altered prefrontal-parietal coupling on the background of COMT Val-homozygous genotype. Conversely, COMT Met-homozygous background mediated against the effect of GRM3 genotype. These findings extend putative brain dopaminergic and glutamatergic relationships indexed by COMT and GRM3 to a systems-level interaction in human cortical circuits implicated in working memory dysfunction such as in schizophrenia.
authors.affiliation: Genes, Cognition, and Psychosis Program, Clinical Brain Disorders Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Hao-Yang
authors.initials: HY
authors.lastname: Tan
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chen
authors.forename: Steven
authors.initials: S
authors.lastname: Sust
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Buckholtz
authors.forename: John D
authors.initials: JD
authors.lastname: Meyers
authors.forename: Michael F
authors.initials: MF
authors.lastname: Egan
authors.forename: Venkata S
authors.initials: VS
authors.lastname: Mattay
authors.forename: Andreas
authors.initials: A
authors.lastname: Meyer-Lindenberg
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Callicott
mesh_terms: D000328:Adult; D001519:Behavior; D001921:Brain / Q000378:metabolism*; D001931:Brain Mapping; D002394:Catechol O-Methyltransferase / Q000235:genetics* / Q000378:metabolism*; D004843:Epistasis, Genetic; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008568:Memory / Q000502:physiology*; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics* / Q000378:metabolism*
chemical_list: D018094:Receptors, Metabotropic Glutamate; C102718:metabotropic glutamate receptor 3; D002394:Catechol O-Methyltransferase