TPH2rs4290270 was genotyped in 165 suicide attempters and 188 suicide non-attempters diagnosed with major depressive disorder, bipolar disorder and schizophrenia.
A rare mutation in tryptophan hydroxylase 2 (Tph2), the rate limiting enzyme for 5-HT synthesis, was identified in several patients with major depression, and knock-in mice expressing the analogous mutation (R439H Tph2 KI) show 80% reduction in 5-HT synthesis and tissue levels.
Although the majority of first-line antidepressants increase brain serotonin and rare polymorphisms in tryptophan hydroxlase-2 (Tph2), the rate-limiting enzyme in the brain serotonin synthesis pathway, have been identified in cohorts of subjects with major depressive disorder, the circuit level alterations that results from serotonergic hypofunction remain poorly understood.
Although the majority of first-line antidepressants increase brain serotonin and rare polymorphisms in tryptophan hydroxlase-2 (Tph2), the rate-limiting enzyme in the brain serotonin synthesis pathway, have been identified in cohorts of subjects with major depressive disorder, the circuit level alterations that results from serotonergic hypofunction remain poorly understood.
Although the sample size is small, results from this study suggest that the TPH2C2755A polymorphism may represent a population-specific risk factor for peripartum major depression and anxiety disorder, perhaps by interacting with hormones.
Furthermore, an increased frequency of G allele of TPH2 SNP may be associated with elevated suicidal behavior itself rather than with the diagnosis of major depression and may increase risk of suicidality, independent of diagnosis.
Gene-disease association studies have reported a relationship between TPH2 and major depressive disorder (MDD) in different populations, however subsequent studies have produced contradictory results.
In this study, we aimed to investigate the association of tryptophan hydroxylase 2 gene with MDD and its treatment response in the Chinese Han population.
In total, 14 single nucleotide polymorphisms (SNPs) in coding regions of 10 serotonergic genes (HTR1A, HTR1B, HTR1D, HTR2A, HTR3A, HTR3C, HTR3D, HTR3E, HTR5A and TPH2) were genotyped in 308 Chinese Han patients with major depressive disorder.
One hundred and thirteen patients with MDD and eighty-six healthy controls underwent T1-weighted structural magnetic resonance imaging and genotyping for TPH2rs4570625.
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.
Our findings show that TPH2 genetic variants may play a role in MDD susceptibility and in acute therapeutic response to selective serotonin reuptake inhibitors.
Polymorphisms in the gene encoding the serotonin synthesis enzyme Tph2 have been identified in mental illnesses, including bipolar disorder, major depression, autism, schizophrenia, and ADHD.
Single locus analysis in pooled and ethnically stratified subjects revealed no association between each of the three variants of the TPH2 gene with susceptibility to MDD.