Rs1386494

rs1386494 is a SNP in the tryptophan hydroxylase 2 (TPH2) gene on chromosome 12. It is located about 20,000 bp from the 5' end of the gene. This SNP has been found to be associated with various mental health disorders.

TPH1 and TPH2 are two isoforms of the rate-limiting enzyme for the biosynthesis of 5-HT (serotonin), a neurotransmitter involved in many neurological processes. Both isoforms have been studied extensively as genetic markers of mental health. Many association studies have linked the TPH1 gene to suicidality, alcoholism and depression. However, the second TPH isoform was not discovered until more recently, when it was observed that TPH1 knockout mice were still able to produce normal levels of 5-HT. It has been shown to be expressed exclusively in the brain, suggesting that it could play a major role in psychiatric disorders.

The association between the SNP rs1386494 and major depression (MD) was first reported in a study of a cohort of 300 Caucasian patients with MD. rs1386494 was found to be the most significantly associated of all 10 SNPs studied, with a p-value of 0.0012. Another study of the association between the TPH2 gene and depression was conducted in a Finnish population of 119 patients who showed treatment risistance. The researchers showed that A/A depression patients had significantly more severe depression, as measured by the Montgomery and Åsberg Depression Rating Scale (MADRS), (p < 0.001) but showed a greater decline in MADRS score as a result of electroconvulsive therapy (ECT) treatment (p = 0.03). Several other studies have confirmed the association of this SNP and linked SNPS with major depression.

Similarly, rs1386494 has been linked to suicide attempts. In a case study of 263 individuals who committed suicide and matched control patients, SNP, haplotype and LD studies support association between the TPH2 SNP and completed suicide. However, a study of 150 alcohol-dependent patients reported no significant association with alcohol-related suicide behavior. Both studies were conducted in Caucasian populations.

More recently, studies have linked rs1386494 with schizophrenia in Asian populations. In a case-control study of 289 Malaysians, the G allele was found to be enriched in schizophrenic patients. Due to the low occurrence of suicidality in the study population, the authors rule out the role of suicidal behavior in this association, supporting a more direct neurological role of this SNP.

In a study of TPH2 SNPs in panic disorder, rs1386494 was found to have a gender-specific effect, where the association was seen only the female subgroup.