Genetic variation in cholinergic muscarinic-2 receptor gene modulates M 2 receptor binding in vivo and accounts for reduced binding in bipolar disorder

D. M. Cannon, J. K. Klaver, S. K. Gandhi, G. Solorio, S. A. Peck, K. Erickson, J. S. N Akula, W. C. Eckelman, M. L. Furey, B. J. Sahakian, F. J. McMahon, W. C. Drevets

Research output: Contribution to journalArticle

Abstract

Genetic variation in the cholinergic muscarinic-2 (M2) receptor gene (CHRM2) has been associated with the risk for developing depression. We previously reported that M2-receptor distribution volume (V T) was reduced in depressed subjects with bipolar disorder (BD) relative to depressed subjects with major depressive disorder (MDD) and healthy controls (HCs). In this study, we investigated the effects of six single-nucleotide polymorphisms (SNPs) for CHRM2 on M2-receptor binding to test the hypotheses that genetic variation in CHRM2 influences M2-receptor binding and that a CHRM2 polymorphism underlies the deficits in M2-receptor V T observed in BD. The M2-receptor V T was measured using positron emission tomography and 18 FFP-TZTP in unmedicated, depressed subjects with BD (n16) or MDD (n24) and HCs (n25), and the effect of genotype on V T was assessed. In the controls, one SNP (with identifier rs324650, in which the ancestral allele adenine (A) is replaced with one or two copies of thymine (T), showed a significant allelic effect on V T in the pregenual and subgenual anterior cingulate cortices in the direction AAATTT. In contrast, in BD subjects with the TT genotype, V T was significantly lower than in BD subjects with the AT genotype in these regions. The BD subjects homozygous for the T-allele also showed markedly lower V T (by 27 to 37% across regions) than HCs of the same genotype. Post hoc analyses suggested that T homozygosity was associated with a more severe illness course, as manifested by lower socioeconomic function, poorer spatial recognition memory and a greater likelihood of having attempted suicide. These data represent novel preliminary evidence that reduced M 2-receptor V T in BD is associated with genetic variation within CHRM2. The differential impact of the M2-receptor polymorphism at rs324650 in the BD and HC samples suggests interactive effects with an unidentified vulnerability factor for BD.

Original languageEnglish (US)
Pages (from-to)407-418
Number of pages12
JournalMolecular psychiatry
Volume16
Issue number4
DOIs
StatePublished - Apr 1 2011

Keywords

  • CHRM
  • G-protein coupled receptor
  • PET
  • [F]FP-TZTP
  • depression
  • muscarinic M binding

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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    Cannon, D. M., Klaver, J. K., Gandhi, S. K., Solorio, G., Peck, S. A., Erickson, K., N Akula, J. S., Eckelman, W. C., Furey, M. L., Sahakian, B. J., McMahon, F. J., & Drevets, W. C. (2011). Genetic variation in cholinergic muscarinic-2 receptor gene modulates M 2 receptor binding in vivo and accounts for reduced binding in bipolar disorder. Molecular psychiatry, 16(4), 407-418. https://doi.org/10.1038/mp.2010.24