Genetic variation in cholinergic muscarinic-2 receptor gene modulates M2 receptor binding in vivo and accounts for reduced binding in bipolar disorder

Abstract

Genetic variation in the cholinergic-muscarinic2 (M2)receptor gene (CHRM2) has been associated with the risk for developing depression. We previously reported that M2-receptor distribution volume (VT) was reduced in depressed subjects with bipolar disorder (BD) relative to depressed subjects with major depressive disorder (MDD) and healthy controls (1). In the current study we investigated the effects of six single nucleotide polymorphisms (SNP) 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 VT observed in BD. The M2-receptor VT was measured using PET and [18F]FP-TZTP in unmedicated, depressed subjects with BD (n=16) or MDD (n=24) and healthy controls (n=25), and the effect of genotype on VT 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 VT in the pregenual and subgenual anterior cingulate cortices in the direction AA<AT<TT. In contrast, in BD subjects with the TT-genotype VT 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 VT (by 27 to 37% across regions) than healthy controls 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 M2-receptor VT 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.