A gender-specific COMT haplotype contributes to risk modulation rather than disease severity of major depressive disorder in a Chinese population

Background: COMT rs4680 Val158 allele is associated with high MB-COMT protein expression and elevated activity compared to the Met158 allele in post-mortem brains. A meta-analysis study suggested the link between COMT SNPs and MDD risk; in addition, MB membrane-bound (MB-COMT) specific genetic variation was reported that influences predisposition to depression amongst females. Methods: Four tagSNPs, including rs4680, were genotyped. 268 MDD subjects and 223 controls were enrolled. MDD severity was rated by HDRS. Total-COMT and MB-COMT mRNA were detected by quantitative PCR. COMT protein and activity were assayed by western blot and methyltransferase assay, respectively. Results: Haplotype TG of rs4633-rs4680, rs4646312 C, and rs4633 T allele might be linked to MDD vulnerability. Haplotype TG may interact with gender and affect MDD risk, since female haplotype TG carriers were estimated for a 9.17-fold higher risk than counterparts. COMT SNPs were not associated with HDRS scores. Haplotype TG female controls had higher MB-COMT protein, whereas non-TG female controls had higher soluble cytoplasmic (S-COMT) protein than other groups. COMT activity was much higher in controls than in MDD subjects. Limitations: Restricted numbers of homozygous TG carriers were recruited and analyzed for COMT mRNA, protein and activity. Only peripheral blood samples were used. Conclusions: A female-specific haplotype (haplotype TG)-MDD vulnerability association was found. TG female controls had higher MB-COMT protein and S-COMT. Altogether, high COMT protein and activity in female TG controls may be predisposing factors for enhanced MDD risk, though not correlated to MDD severity as rated by HDRS.