Studies of the human brain have revealed two isoforms of the gene coding for tryptophan hydroxylase 1 and 2, termed TPH1 and TPH2. One of them, the TPH2 gene, is of interest because this tryptophan hydroxylase 2 isoform regulates the biosynthetic pathway of 5-HT in the serotoninergic neurons of raphe nuclei and has been implicated kinase inhibitor Idelalisib in the pathogenesis of major depressive disorder and the mechanism of antidepressant action [14].Investigations of the functional effects of genetic variations in the TPH2 gene have demonstrated that a haplotype of 3 SNPs within the gene promoter (?703G>T, ?473T>A, and 90A>G) influenced transcription in human cell lines. Similarly, the TPH2 c.1077G>A polymorphism within the coding region (Pro312Pro; SNP 7305115) increased expression levels of the gene in the human pons, containing the dorsal and median raphe nuclei [15].

This SNP has previously demonstrated an association with major depression and suicide [16].Monoamine oxidase (MAO) is an important enzyme associated with the metabolism of biogenic amines and neurotransmitters, including norepinephrine (NE), DA, and 5-HT. Two forms of the enzyme, MAOA and MAOB, are found in the human brain [17]. Of the two, MAOA exhibits a higher affinity for 5-HT and NE, whereas DA is preferentially metabolized by both forms of the enzyme. The MAOA gene (MAO-A) has been mapped to the short arm of the X chromosome; thus, functional polymorphisms of this locus are expected to manifest in a sex-specific fashion. The human MAO-A contains a variable-number tandem repeat (VNTR) polymorphism in its promoter region that may alter the transcriptional efficiency of MAOA expression [18].

Most of the other known MAO-A polymorphisms either affect intronic sequences or introduce a silent change in the open-reading frame (i.e., the EcoRV polymorphism and Fnu4HI polymorphism, SNPs: 1137070 and 6323, resp.). These variants are unlikely to affect MAO function, although they may be in disequilibrium with GSK-3 other, as yet unidentified, functional variants. The primary role of MAOA in regulating monoamine turnover, and hence ultimately influencing levels of NE, DA, and 5-HT, indicates that its gene is a highly plausible candidate for affecting individual differences in the manifestation of psychological traits and psychiatric disorders [19, 20]. For example, several studies indicate that the MAO-A gene may be involved in the pathogenesis of depression and major depressive disorder [21, 22].However, genetic factors can modulate the risk for depression by influencing monoaminergic activity in a sexually dimorphic manner. Because the MAO-A gene is X-linked, males are hemizygous at this locus, whereas females are homozygous or heterozygous.