SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression

Abstract

Tryptophan hydroxylase (TPH), being the rate-limiting enzyme in the biosynthesis of serotonin plays a major role as candidate gene in several psychiatric disorders. Recently, a second TPH isoform (TPH2) was identified in mice, which was exclusively present in the brain. In a previous post-mortem study of our own group, we could demonstrate that TPH2 is also expressed in the human brain, but not in peripheral tissues. This is the first report of an association study between polymorphisms in the TPH2 gene and major depression (MD). We performed singlenucleotide polymorphism (SNP), haplotype and linkage disequlibrium studies on 300 depressed patients and 265 healthy controls with 10 SNPs in the TPH2 gene. Significant association was detected between one SNP (P ¼ 0.0012, global P ¼ 0.0051) and MD. Haplotype analysis produced additional support for association (Po0.0001, global P ¼ 0.0001). Our findings provide evidence for an involvement of genetic variants of the TPH2 gene in the pathogenesis of MD and might be a hint on the repeatedly discussed duality of the serotonergic system. These results may open up new research strategies for the analysis of the observed disturbances in the serotonergic system in patients suffering from several other psychiatric disorders.

Genetic architecture of the human tryptophan hydroxylase 2 Gene: existence of neural isoforms and relevance for major depression

“…These results provide evidence for association of TPH2 with major depression and/or suicide, since the majority of our cases had major depression and had committed suicide, and therefore support previous reports of associations of a TPH2 variant (rs1386494) with both depression 19 and suicide 20 …”

“…Although numerous haplotype block definitions are possible, we adopted the more conservative four-gamete test, 33 yielding a total of nine blocks ranging from 88 to 15 335 bp in length. The associations with major depression reported previously 19,20 and in the present study, fall entirely within the second block. Within these haplotype blocks, spanning 44 SNPs, we identified 15 tag-SNPs (Table 3).…”

“…The first is locus rs1386493 that is 2636 bp downstream from rs1386494, the locus reported previously to be associated with depression and suicide. 19,20 The second is the novel variant g.22879A > G discovered in our present study. The strongest evidence for association was observed with the major depression clinical model (rs1386493-P = 0.001 and g.22879A > G-P = 0.05), that remained statistically significant after adjustment for multiple models and markers tested (global empirical P = 0.01).…”

“…Recent studies report associations of TPH2 with major depression and with suicide, involving single nucleotide polymorphisms (SNPs) in intron 5 and exon 11. 12,13,19,20 Thus, while we explored the coding portion of the TPH2 gene and sections of each intron, we focused our analyses on the SNPs that lie in these two regions in an effort to replicate the previously reported positive findings in our dataset. In addition, we report on the first systematic examination of the TPH2 gene variants covering both the coding and non-coding regions and transcript variants in human brain.…”

A regulatory variant of the human tryptophan hydroxylase-2 gene biases amygdala reactivity

“…2 In contrast, both TPH1 and TPH2 are expressed in the human brain 3 and genetic variation in both isoforms have been associated with alterations in mood and 5-HT function. 4,5 Furthermore, a relatively rare single nucleotide polymorphism in human TPH2 (hTPH2) associated with depression has been shown to alter TPH enzymatic efficiency in vitro. 6 However, the functional consequence of genetic variation in hTPH2 on the neural circuitry of mood and emotional behaviors is unknown.…”