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

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.