title: Genetic modulation of GABA levels in the anterior cingulate cortex by GAD1 and COMT.
abstract: Gamma-aminobutyric acid (GABA)-ergic transmission is critical for normal cortical function and is likely abnormal in a variety of neuropsychiatric disorders. We tested the in vivo effects of variations in two genes implicated in GABA function on GABA concentrations in prefrontal cortex of living subjects: glutamic acid decarboxylase 1 (GAD1), which encodes GAD67, and catechol-o-methyltransferase (COMT), which regulates synaptic dopamine in the cortex. We studied six single nucleotide polymorphisms (SNPs) in GAD1 previously associated with risk for schizophrenia or cognitive dysfunction and the val158met polymorphism in COMT in 116 healthy volunteers using proton magnetic resonance spectroscopy. Two of the GAD1 SNPs (rs1978340 (p=0.005) and rs769390 (p=0.004)) showed effects on GABA levels as did COMT val158met (p=0.04). We then tested three SNPs in GAD1 (rs1978340, rs11542313, and rs769390) for interaction with COMT val158met based on previous clinical results. In this model, rs11542313 and COMT val158met showed significant main effects (p=0.001 and 0.003, respectively) and a trend toward a significant interaction (p=0.05). Interestingly, GAD1 risk alleles for schizophrenia were associated with higher GABA/Cre, and Val-Val homozygotes had high GABA/Cre levels when on a GAD1 risk genotype background (N=6). These results support the importance of genetic variation in GAD1 and COMT in regulating prefrontal cortical GABA function. The directionality of the effects, however, is inconsistent with earlier evidence of decreased GABA activity in schizophrenia.
authors.affiliation: Clinical Brain Disorders Branch, GCAP, IRP, NIMH, Bethesda, MD 20892, USA. marencos@mail.nih.gov
authors.forename: Stefano
authors.initials: S
authors.lastname: Marenco
authors.forename: Antonina A
authors.initials: AA
authors.lastname: Savostyanova
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: van der Veen
authors.forename: Matthew
authors.initials: M
authors.lastname: Geramita
authors.forename: Alexa
authors.initials: A
authors.lastname: Stern
authors.forename: Alan S
authors.initials: AS
authors.lastname: Barnett
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Kolachana
authors.forename: Eugenia
authors.initials: E
authors.lastname: Radulescu
authors.forename: Fengyu
authors.initials: F
authors.lastname: Zhang
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Callicott
authors.forename: Richard E
authors.initials: RE
authors.lastname: Straub
authors.forename: Jun
authors.initials: J
authors.lastname: Shen
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D005260:Female; D005838:Genotype; D005968:Glutamate Decarboxylase / Q000235:genetics*; D006179:Gyrus Cinguli / Q000378:metabolism*; D006801:Humans; D015810:Linkage Disequilibrium / Q000502:physiology; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D008715:Methionine / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011522:Protons; D018709:Statistics, Nonparametric; D014633:Valine / Q000235:genetics; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D011522:Protons; D005680:gamma-Aminobutyric Acid; D008715:Methionine; D002394:Catechol O-Methyltransferase; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D014633:Valine