Association between SNPs in the promoter region of the tryptophan hydroxylase 2 gene (TPH2) and the hypothalamic-pituitary-adrenocortical (HPA) axis dysregulation in patients with major depression

Recent models of affective disorders propose an involvement of malfunctions of the serotonergic system, as well as a dysregulation of the activity of the HPA axis. Previous studies from our and other groups have shown that the neuronal TPH2, the rate limiting enzyme in the synthesis of the neurotransmitter serotonin (5-HT), is predominantly expressed in several regions of the human brain and that TPH2 polymorphisms are associated with major depression. Moreover, we could recently demonstrate that a functional SNP in the TPH2 promoter region (rs11178997) alters the transcriptional activity of the gene. Therefore we investigated the impact of this polymorphism and two additional promoter SNPs (rs11178998, rs4570625) in the TPH2 gene on HPA axis dysregulation, determined by the Dex/CRH test in 206 patients with major depression. Carriers of the A-Allele of rs11178997 showed a decreased cortisol and ACTH stimulation during the first Dex/CRH test after admission than the other genotypes (ANOVA (AUC): p<0.01). Interestingly the A-allele of rs11178997 leads also to a decreased transcriptional activity. Similar results were obtained for carriers of the A-allele of rs11178998. SNP rs4570625 showed no relation to the HPA-axis activity. Our data suggest that polymorphisms in the promoter region of the TPH2 gene might be crucial factors for the HPA system hyperactivity in major depression. This project is supported by the German Federal Research Ministry within the promotional emp