TY - JOUR
T1 - Genetic modulation of GABA levels in the anterior cingulate cortex by GAD1 and COMT
AU - Marenco, Stefano
AU - Savostyanova, Antonina A.
AU - Van Der Veen, Jan Willem
AU - Geramita, Matthew
AU - Stern, Alexa
AU - Barnett, Alan S.
AU - Kolachana, Bhaskar
AU - Radulescu, Eugenia
AU - Zhang, Fengyu
AU - Callicott, Joseph H.
AU - Straub, Richard E.
AU - Shen, Jun
AU - Weinberger, Daniel R.
N1 - Funding Information:
This work was funded entirely by the NIMH IRP. The authors declare that, except for income received by the primary employer (the NIH), no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional services and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.
PY - 2010/7
Y1 - 2010/7
N2 - γ-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 (p0.005) and rs769390 (p0.004)) showed effects on GABA levels as did COMT val158met (p0.04). 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 (N6). 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.
AB - γ-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 (p0.005) and rs769390 (p0.004)) showed effects on GABA levels as did COMT val158met (p0.04). 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 (N6). 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.
KW - Dopamine
KW - Genes
KW - Healthy volunteers
KW - Prefrontal function
KW - Schizophrenia
KW - Single nucleotide polymorphisms
UR - http://www.scopus.com/inward/record.url?scp=77953594619&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77953594619&partnerID=8YFLogxK
U2 - 10.1038/npp.2010.35
DO - 10.1038/npp.2010.35
M3 - Article
C2 - 20357758
AN - SCOPUS:77953594619
SN - 0893-133X
VL - 35
SP - 1708
EP - 1717
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 8
ER -