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

• Published in: Journal of affective disorders 2019-03, Vol.246, p.376-386
• Main Authors: Chao, Jian-Kang, Yang, Ming-Chang, Chen, Chia-Sheng, Wang, I-Chou, Kao, Wei-Tsung, Shi, Ming-Der
• Format: Article
• Language: English
• Subjects: Adult; Aged; Alleles; Asian Continental Ancestry Group; Catechol O-Methyltransferase - genetics; China; Depressive Disorder, Major - diagnosis; Depressive Disorder, Major - genetics; Female; Genetic Predisposition to Disease; Genetic Variation; Genotype; Haplotypes; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Severity of Illness Index; Young Adult
• ISSN: 0165-0327; 1573-2517
• DOI: 10.1016/j.jad.2018.12.088

•Haplotype TG of COMT rs4633-rs4680 is associated with MDD risk.•Homozygous TG is correlated with upregulated total-COMT mRNA in MDD and controls.•Haplotype TG female controls had relatively higher MB-COMT protein and activity.•The non-TG female control group had higher S-COMT protein, but lower COMT activity.•COMT activity was much lower in MDD subjects compared to controls. 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. 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. 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. Restricted numbers of homozygous TG carriers were recruited and analyzed for COMT mRNA, protein and activity. Only peripheral blood samples were used. 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.