The COMT gene maps to

The COMT gene maps to chromosome 22q11.2 (Grossman et al., 1992) and has two protein isoforms. The differences between S-COMT and longer MB-COMT are in the N-termini, which use alternative translation initiation sites and promoters. These two isoforms display different affinity and capacity for COMT substrate (Jeffery and Roth, 1984, Tenhunen et al., 1994); Several studies have suggested that the COMT gene may have a vital role in neuropsychiatric diseases including mood disorders, schizophrenia, obsessive-compulsive disorder, and substance abuse (Lachman et al., 1996, Taylor, 2018, Wang et al., 2016). Nevertheless, the associations may be specific to COMT rs4680 allele, sex, ethnicity, and diagnostic system, and association tests are needed to properly define the sub-groups of study cohorts. COMT 108/158 polymorphism (rs4680) of S-COMT/MB-COMT causes a valine-to-methionine (Val/Met) substitution and significantly alters COMT activation (Lachman et al., 1996). The Val and Met allele was associated with high and low (3 ∼ 4-fold lower) COMT activity, respectively (Chen et al., 2004, Lotta et al., 1995). The Val158 allele was associated with 40% higher MB-COMT activity in postmortem brains compared to Met158 allele at a physiological temperature of 37 °C (Chen et al., 2004). The s4680 is also assumed as a single polymorphism characterized by its influence on two isoforms of COMT protein expression and enzyme activity, but not on mRNA expression as detected by Taqman assay (Hs_00241349m1)(Chen et al., 2004). Differences in protein integrity may account for the difference in enzyme activity between chemical library of rs4680. In familial studies, the high COMT activity allele (Val) was preferentially transmitted from parents to their affected offspring (Kunugi et al., 1997, Li et al., 1996). COMT rs4680 polymorphism influences physiological response in the prefrontal cortex based on the Wisconsin card sorting test (WCST), where the Val allele may be associated with impaired prefrontal cognition and physiology because it increases prefrontal dopamine depletion in patients with schizophrenia (Egan et al., 2001). Moreover, rs4680 polymorphism was reported to be associated with prefrontal cortex (PFC) activation during both emotional processing and working memory (WM) (Opmeer et al., 2013); differences in drug responses in psychiatric disorders (Craddock et al., 2006); and regional white matter hyperintensity (WMH) affecting cognitive function in a healthy population according to imaging genetic studies (Liu et al., 2014, Surguladze et al., 2012). Most SNP-MDD association studies focused on rs4680 have yielded conflicting results(Hatzimanolis et al., 2013, Taylor, 2018, Wang et al., 2016), with limited studies examining the relationship between other polymorphisms or haplotypes (Funke et al., 2005, Pap et al., 2012). Chen and colleagues further analyzed two reported schizophrenia risk-associated SNPs, rs737865 (located in intron 1) and rs165599 (in the 3′ flanking region) which all exhibited negative findings for gene regulation of mRNA expression levels, protein immunoreactivity, or enzyme activity. However, these two SNPs somehow have a cis-acting role affecting the allelic distribution of rs4680 and were identified have a small impact when forming a haplotype with rs4680 (Chen et al., 2004). A 4-marker haplotype GTGG of rs6269, rs4633, rs4818 and rs4680 was more frequently detected in MDD (3.3%, P = 0.0025); in contrast, haplotype CCA of rs4633-rs4818-rs4680 was more frequent in responders than non-responders and controls, indicating that this haplotype may be linked to MDD susceptibility or treatment response phenotypes (Kocabas et al., 2010). Moreover, these 4 SNPs (rs6269, rs4633, rs4818 and rs4680) were demonstrated to combine into three common functional haplotypes (high: GCGG, intermediate: ATCA, and low: ACCG) that are inversely associated with pain sensitivity and the risk of developing temporomandibular joint disorder (Diatchenko et al., 2005). A further study found that these haplotypes cause variation in COMT protein expression and enzyme activity by affecting the stability of COMT mRNA secondary structure (Nackley et al., 2006).