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.
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.
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.
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.
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.
This SNP and additional SNPs were discovered through a systematic characterization of the genetic architecture of the TPH2 gene for further genetic and functional investigations of its relationship to major depression and other psychopathology.
TPH2rs4290270 was genotyped in 165 suicide attempters and 188 suicide non-attempters diagnosed with major depressive disorder, bipolar disorder and schizophrenia.
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.