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

摘要

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 (VT) 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 VT observed in BD. The M2-receptor VT was measured using positron emission tomography and [18F]FP-TZTP in unmedicated, depressed subjects with BD (n=16) or MDD (n=24) and HCs (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