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. [PMID 15124006] 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. [PMID 23430141] Many association studies have linked the TPH1 gene to suicidality, alcoholism and depression. [PMID 14681922][PMID 9672049][PMID 9326831] 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. [PMID 14563478] It has been shown to be expressed exclusively in the brain, suggesting that it could play a major role in psychiatric disorders. [PMID 15163437]
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. [15124006?dopt=Abstract PMID 15124006] 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). [PMID 19679166] Several other studies have confirmed the association of this SNP and linked SNPS with major depression. [PMID 18180764][PMID 19272410]
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. [PMID 15476687] However, a study of 150 alcohol-dependent patients reported no significant association with alcohol-related suicide behavior. [PMID 21621273] 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. [PMID 20623453]
[PMID 19679166] TPH2 polymorphisms may modify clinical picture in treatment-resistant depression
[PMID 19590397] 5-HTR1A, 5-HTR2A, 5-HTR6, TPH1 and TPH2 polymorphisms and major depression
[PMID 21531467] Serotonin-related gene pathways associated with undifferentiated somatoform disorder
[PMID 17123728] Association study of tryptophan hydroxylase 2 gene polymorphisms in panic disorder.
[PMID 18832011] Association testing of panic disorder candidate genes using CCK-4 challenge in healthy volunteers.
[PMID 19184136] Examination of association of genes in the serotonin system to autism.
[PMID 19359258] Cohort profile: risk patterns and processes for psychopathology emerging during adolescence: the ROOTS project.
[PMID 19742166] Epistasis between IL1A, IL1B, TNF, HTR2A, 5-HTTLPR and TPH2 variations does not impact alcohol dependence disorder features.
[PMID 21172166] Pharmacogenetics of antidepressant response.
[PMID 21621273] Association of polymorphisms in HTR2A, HTR1A and TPH2 genes with suicide attempts in alcohol dependence: a preliminary report.
[PMID 23063133] Genetics of emergent suicidality during antidepressive treatment--data from a naturalistic study on a large sample of inpatients with a major depressive episode.
[PMID 31291234] Role of the Allelic Variation in the 5-Hydroxytryptamine Receptor 1A (HTR1A) and the Tryptophan Hydroxylase 2 (TPH2) Genes in the Development of PTSD.