TPH2rs4290270 was genotyped in 165 suicide attempters and 188 suicide non-attempters diagnosed with major depressive disorder, bipolar disorder and schizophrenia.
Three TPH2 polymorphisms, -703G/T (rs4570625), -473T/A (rs11178997), and 1463G/A (rs120074175), were selected based on previous findings of associations with MD.
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.
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 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.
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.
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.
Those who did not drink alcohol before suicide were more likely to have a diagnosis of major depressive disorder in their medical record and more often had the TT genotype of the tryptophan hydroxylase 2 gene.
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.
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.
The mechanisms underlying these changes are uncertain, but increased TPH2 expression and serotonin turnover could result from genetic influences, adverse early life experiences, or acute stressful life events, all of which can alter serotonergic neurotransmission and have been implicated in determining vulnerability to major depression.