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Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia.

Publication ,  Journal Article
Egan, MF; Straub, RE; Goldberg, TE; Yakub, I; Callicott, JH; Hariri, AR; Mattay, VS; Bertolino, A; Hyde, TM; Shannon-Weickert, C; Akil, M ...
Published in: Proceedings of the National Academy of Sciences of the United States of America
August 2004

GRM3, a metabotropic glutamate receptor-modulating synaptic glutamate, is a promising schizophrenia candidate gene. In a family-based association study, a common GRM3 haplotype was strongly associated with schizophrenia (P = 0.0001). Within this haplotype, the A allele of single-nucleotide polymorphism (SNP) 4 (hCV11245618) in intron 2 was slightly overtransmitted to probands (P = 0.02). We studied the effects of this SNP on neurobiological traits related to risk for schizophrenia and glutamate neurotransmission. The SNP4 A allele was associated with poorer performance on several cognitive tests of prefrontal and hippocampal function. The physiological basis of this effect was assessed with functional MRI, which showed relatively deleterious activation patterns in both cortical regions in control subjects homozygous for the SNP4 A allele. We next looked at SNP4's effects on two indirect measures of prefrontal glutamate neurotransmission. Prefrontal N-acetylaspartate, an in vivo MRI measure related to synaptic activity and closely correlated with tissue glutamate, was lower in SNP4 AA homozygotes. In postmortem human prefrontal cortex, AA homozygotes had lower mRNA levels of the glial glutamate transporter EAAT2, a protein regulated by GRM3 that critically modulates synaptic glutamate. Effects of SNP4 on prefrontal GRM3 mRNA and protein levels were marginal. Resequencing revealed no missense or splice-site SNPs, suggesting that the intronic SNP4 or related haplotypes may exert subtle regulatory effects on GRM3 transcription. These convergent data point to a specific molecular pathway by which GRM3 genotype alters glutamate neurotransmission, prefrontal and hippocampal physiology and cognition, and thereby increased risk for schizophrenia.

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Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

August 2004

Volume

101

Issue

34

Start / End Page

12604 / 12609

Related Subject Headings

  • Sequence Analysis, DNA
  • Schizophrenia
  • Receptors, Metabotropic Glutamate
  • Prefrontal Cortex
  • Phenotype
  • Neuropsychological Tests
  • Middle Aged
  • Magnetic Resonance Imaging
  • Humans
  • Hippocampus
 

Citation

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ICMJE
MLA
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Egan, M. F., Straub, R. E., Goldberg, T. E., Yakub, I., Callicott, J. H., Hariri, A. R., … Weinberger, D. R. (2004). Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia. Proceedings of the National Academy of Sciences of the United States of America, 101(34), 12604–12609. https://doi.org/10.1073/pnas.0405077101
Egan, Michael F., Richard E. Straub, Terry E. Goldberg, Imtiaz Yakub, Joseph H. Callicott, Ahmad R. Hariri, Venkata S. Mattay, et al. “Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia.Proceedings of the National Academy of Sciences of the United States of America 101, no. 34 (August 2004): 12604–9. https://doi.org/10.1073/pnas.0405077101.
Egan MF, Straub RE, Goldberg TE, Yakub I, Callicott JH, Hariri AR, et al. Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia. Proceedings of the National Academy of Sciences of the United States of America. 2004 Aug;101(34):12604–9.
Egan, Michael F., et al. “Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia.Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 34, Aug. 2004, pp. 12604–09. Epmc, doi:10.1073/pnas.0405077101.
Egan MF, Straub RE, Goldberg TE, Yakub I, Callicott JH, Hariri AR, Mattay VS, Bertolino A, Hyde TM, Shannon-Weickert C, Akil M, Crook J, Vakkalanka RK, Balkissoon R, Gibbs RA, Kleinman JE, Weinberger DR. Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia. Proceedings of the National Academy of Sciences of the United States of America. 2004 Aug;101(34):12604–12609.
Journal cover image

Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

August 2004

Volume

101

Issue

34

Start / End Page

12604 / 12609

Related Subject Headings

  • Sequence Analysis, DNA
  • Schizophrenia
  • Receptors, Metabotropic Glutamate
  • Prefrontal Cortex
  • Phenotype
  • Neuropsychological Tests
  • Middle Aged
  • Magnetic Resonance Imaging
  • Humans
  • Hippocampus