SNP- and Haplotype Analysis of the Tryptophan Hydroxylase 2 Gene in Alcohol-Dependent Patients and Alcohol-Related Suicide

Abstract

Several lines of evidence indicate that disturbances of the central serotonergic system are involved in the pathophysiology of alcohol dependence and suicidal behavior. Recent studies have indicated that a newly identified second isoform of the tryptophan hydroxylase gene (TPH2) is preferentially involved in the rate limiting synthesis of neuronal serotonin. Genetic variations in the TPH2 gene have been associated with an increased risk for major depression and suicidal behavior. We performed single SNP (single nucleotide polymorphism), linkage disequilibrium and haplotype studies on 353 alcohol-dependent patients of whom 102 individuals had a history of at least one suicide attempt and 305 healthy controls with 20 SNPs covering the entire gene region of TPH2. Neither single SNP-, nor haplotype analysis could detect significant associations with alcohol dependence and/or suicidal behavior among alcohol-dependent patients. One major haplotype block of strong linkage disequilibrium between introns 5 and 8 of the TPH2 gene has been found in alcoholics and controls, which is in concordance with recent reports. In conclusion, our results suggest that single SNPs, respectively, haplotypes of the TPH2 gene are unlikely to play a major role in the pathophysiology of alcohol dependence or the alcoholism-related phenotype suicidal behavior. Further analysis are needed to confirm these results.

Functional promoter polymorphism of the neuronal isoform of tryptophan hydroxylase (Tph2) in suicide

“…Frequency of -703T allele of G-703T polymorphism in our control sample, being 20.4 %, fits well in the range of 18%-23%, reported for other Caucasian populations (Zhou et al, 2005;Reuter et al, 2007a;Zill et al, 2007). It should be noted that significantly higher frequencies of -703T allele were found in non-Caucasian populations such as African American (39%) (Zhou et al, 2005), American Indian (48%) (Zhou et al, 2005), Korean (57%) (Yoon et al, 2009) and Japanese (45%) (Mouri et al, 2009).…”

“…Nevertheless, our results, as well as findings on other populations (Zhou et al, 2005;Zill et al, 2007;Mouri et al, 2009), even ethnically very distant ones, clearly speak against the major role of functional variant G-703T of the Tph2 gene in the susceptibility to suicide.…”

“…Even when only violent suicide victims (N=282) were taken into consideration, no association was found (data not shown). The very recent study on suicide victims of Japanese origin (Mouri et al, 2009), as well as the two previous studies on suicide attempters (Zhou et al, 2005;Zill et al, 2007) also found no evidence for the effect of G-703T polymorphism on suicidal behavior. Yoon et al (2009), on the other hand, reported excess of GG homozygotes among suicidal depressed patients as compared to healthy controls.…”

Risk-Taking Behavior in a Gambling Task Associated with Variations in the Tryptophan Hydroxylase 2 Gene: Relevance to Psychiatric Disorders

“…Furthermore, we could not demonstrate any association between haplotype variants of the TPH2 gene and BSI depression, BSI anxiety, BFI neuroticism, or IVE impulsiveness scores. This is in agreement with recent studies which failed to find any association between the TPH2 gene and depression/suicidal behavior (Mann et al, 2008;Must et al, 2007;Zill et al, 2007b;De Luca et al, 2006;Lopez et al, 2007b), but in contrast to earlier findings reporting such an involvement (Zill et al, 2004a, b;Zhou et al, 2005;Van Den Bogaert et al, 2006;Haghighi et al, 2008;Lopez et al, 2007a;Ke et al, 2006). Therefore, the interpretation we favor is that the variations in the TPH2 gene might be linked to an endophenotype influencing risktaking behavior that could be an additive or in some cases a vulnerability factor, for psychiatric disorders, for example, affective disorders or disturbed mood in impulse control or substance misuse disorders.…”

A Functional Tph2 C1473G Polymorphism Causes an Anxiety Phenotype via Compensatory Changes in the Serotonergic System

“…Although earlier studies reported significant associations between several TPH2 SNPs and both depression and suicidal behavior (Haghighi et al, 2008;Ke et al, 2006;Lopez de Lara et al, 2007;Van Den Bogaert et al, 2006;Zhou et al, 2005;Zill et al, 2004a, b) more recent studies failed to confirm these findings (De Luca et al, 2006;Mann et al, 2008;Zill et al, 2007). Among functionally characterized TPH2 polymorphisms only a few (including G1463A) result in a clear reduction in enzymatic activity, whereas other polymorphisms have only a minor effect on TPH2 activity (McKinney et al, 2009).…”