Association of TPH-1 and TPH-2 gene polymorphisms with suicidal behavior: a systematic review and meta-analysis

Abstract

BackgroundIt is widely acknowledged that suicidal behavior (SB) has a genetic influence. As a consequence, molecular genetic studies have been mostly conducted on serotonergic genes. One of the most promising candidate genes of this system is tryptophan hydroxylase (TPH). Although there have been several positive studies associating TPH genes and SB, the evidence is not entirely consistent. Therefore, we performed a meta-analysis to gain a better understanding into this issue.MethodsThe meta-analysis was conducted with 37 articles of genetic association studies of TPH-1 (A218C and A779C) and TPH2 (G-703 T, A-473 T and G19918A) genes. To analyze the association of these variants with SB we used the following models: allelic, additive, dominant and recessive. In addition, we performed a sub-group analysis by Caucasian and Asian populations using the same four models.ResultsTPH-1 gene variants showed a positive significant association with SB, but only in the fixed effects models. With regard to TPH-2 gene variants we could not find an association with SB.ConclusionsThe study provides evidence that A218C/A779C TPH-1 variants may be a risk factor to manifest SB at the clinical level, which is in agreement with previously reported meta-analyses. With regard to G-703 T/A-473 T/G19918A TPH-2 variants, our up-to-date meta-analysis could not detect any significant association between those genetic variants and SB. However, these results should be interpreted with caution since further studies need to be undertaken using larger sample sizes in different ethnic populations to confirm our findings.

Genetic moderation of cocaine subjective effects by variation in the TPH1, TPH2, and SLC6A4 serotonin genes

“…Moreover, it is interesting that the participants with the AA/AC, AA/AT, L′S′/S′S′ genotype pattern group experienced more positive and less negative effects of cocaine, greater physiological response, and more daily cocaine use. These findings support prior literature that demonstrates that lower serotonin production associated with TPH1 A and TPH2 A is related to suicidality, alcoholism, and impulsive behavior (González-Castro et al , 2014, Nielsen et al , 1994, Nielsen et al , 1998, Slof-Op’t Landt et al , 2013, Staner et al , 2002). This indicates a potential genetic marker of vulnerability to cocaine addiction.…”

“…The tightly linked variants (rs1799913 and rs1800532) in TPH1 (originally designated TPH prior to the discovery of TPH2 ) have been associated with behaviors including suicidality (González-Castro et al , 2014, Nielsen et al , 1994), alcoholism (Nielsen et al , 1998), impulsive behavior (Staner et al , 2002), and with cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) levels (Jönsson et al , 1997, Nielsen et al , 1994). Specifically, male TPH1 A allele carriers have been shown to have lower levels of serotonin production as measured by CSF 5-HIAA levels (Jönsson et al , 1997) and decreased risk for suicide attempt (González-Castro et al , 2014, Nielsen et al , 1994).…”

“…Specifically, male TPH1 A allele carriers have been shown to have lower levels of serotonin production as measured by CSF 5-HIAA levels (Jönsson et al , 1997) and decreased risk for suicide attempt (González-Castro et al , 2014, Nielsen et al , 1994). TPH2 rs4290270 has been shown to have differential allelic expression in the cortex, hypothalamus, thalamus, hippocampus, amygdala, and cerebellum (Lim et al , 2007).…”

Aspekte der Genetik, Epigenetik und Gen-Umwelt-Interaktion bei suizidalem Verhalten

“…Metaanalysen zum häufig untersuchten A218C-Polymorphismus im Intron 7 des TPH1-Gens konnten die Häufung des A-Allels bei Patienten mit suizidalem Verhalten zeigen (4,47). Weitere Metaanalysen unterstützen den Einfluss von TPH1-Polymorphismen auf suizidales Verhalten (1,4,13,23,31,39,47). TPH2, eine zweite Variante des serotonergen Schrittmacherenzyms, scheint im Vergleich zu TPH1 eine wichtigere Rolle im Gehirn einzunehmen, da TPH1-knockout-Mäuse nur ein mäßig erniedrigtes Serotonin im Hippocampus und im frontalen Kortex aufwiesen (62).…”

Sequence Analysis of Drug Target Genes with Suicidal Behavior in Bipolar Disorder Patients

“…Hypothesis-driven studies have identified a number of potential candidate genes. These include the brain-derived neurotrophic factor ( BDNF ) [8], neurotrophic tyrosine receptor kinase 2 ( NTRK2 ) [9], serotonin 2A receptor ( HTR2A ) [10], and tryptophan hydroxylase ( TPH2 ) [11]. However, as the effect sizes of markers in these genes have been small, it is likely that suicidal behavior is influenced by many still unidentified genetic factors.…”