Novel biochemical markers of psychosocial stress in women.

BACKGROUND: Prolonged psychosocial stress is a condition assessed through self-reports. Here we aimed to identify biochemical markers for screening and early intervention in women. METHODS: Plasma concentrations of interleukin (IL) 1-alpha, IL1-beta, IL-2, IL-4, IL-6, IL-8, IL-10, interferon-gamma (INF-gamma), tumor necrosis factor-alpha (TNF-alpha), monocyte chemotactic protein-1 (MCP-1), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), thyroid stimulating hormone (TSH), total tri-iodothyronine (TT3), total thyroxine (TT4), prolactin, and testosterone were measured in: 195 women on long-term sick-leave for a stress-related affective disorder, 45 women at risk for professional burnout, and 84 healthy women. RESULTS: We found significantly increased levels of MCP-1, VEGF and EGF in women exposed to prolonged psychosocial stress. Statistical analysis indicates that they independently associate with a significant risk for being classified as ill. CONCLUSIONS: MCP-1, EGF, and VEGF are potential markers for screening and early intervention in women under prolonged psychosocial stress.

Emotionally controlled decision-making and a gene variant related to serotonin synthesis in women with borderline personality disorder.

The Iowa Gambling Task (IGT) was used to examine (i) social decision-making in women with borderline personality disorder (BPD), and (ii) the relationship between impaired decision-making and the tryptophan hydroxylase-1 (TPH-1) gene, involved in serotonin synthesis. Forty-two women with BPD and a history of suicide attempts were genotyped, and the frequency of a TPH-1 haplotype previously uniquely associated with BPD was calculated. The BPD group scored significantly lower than a control group in the IGT. Furthermore, the TPH-1 haplotype displayed a significantly higher frequency in BPD participants with impaired decision making, compared to BPD participants with normal scores. These findings suggest that impaired decision-making as determined by the IGT is a feature of BPD and may be (i) associated with serotonin dysfunction, and (ii) possibly relevant for suicidal behavior.

Haplotype analysis confirms association of the serotonin transporter (5-HTT) gene with schizophrenia but not with major depression.

Serotonin (5-HT) has been implicated in the pathophysiology of several psychiatric disorders including major depressive disorder (MDD) and schizophrenia (SCZ). The serotonin transporter (5-HTT) is a major regulator of 5-HT function. 5-HTT gene polymorphic variants have been associated with both MDD and SCZ. A case-control design was used for candidate gene-disease association in 194 MDD patients, 155 schizophrenic psychosis patients, and 246 healthy controls, all North European Caucasians. Four polymorphisms were analyzed in terms of genotype, allele, and haplotype-based associations. Linkage disequilibrium (LD) analysis was also carried out. Bonferroni correction was used for multiple testing. Haplotype-based analyses showed significant associations between 5-HTT and SCZ but not MDD. No single locus associations were observed. In agreement with published meta-analysis our results indicate that 5-HTT associates with SCZ but not with MDD. It appears that risk for SCZ maps within a specific 5-HTT haplotype block.

The tryptophan hydroxylase (TPH) 2 gene unlike TPH-1 exhibits no association with stress-induced depression.

BACKGROUND: Serotonin (5-HT) has been implicated in the pathophysiology of several psychiatric disorders including major depression (MD). Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of serotonin (5-HT), and might be related to the pathogenesis of MD. Two isoforms are known, TPH-1 and TPH-2. Their association with MD is still debated. METHODS: A case-control design was used for candidate gene-disease association in 194 patients with stress-induced MD, and 246 healthy controls, all North European Caucasians. Five TPH-2 polymorphisms were analyzed in terms of genotype, allele, and haplotype-based associations. RESULTS: Neither single marker nor haplotype-based analyses showed significant associations between TPH-2 and MD. LIMITATIONS: The interpretations are limited by the restricted population size. CONCLUSIONS: There was no association between TPH-2 gene variants and MD in the same population that had shown a strong association with TPH-1. Hence, the results suggest that in this particular group of stress-induced depression patients TPH-1 appears to be more relevant to MD pathogenesis than TPH-2.

Tryptophan hydroxylase-1 gene variants associated with schizophrenia.

BACKGROUND: Serotonin (5-HT) has been implicated in the pathophysiology of schizophrenia. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of serotonin (5-HT), and as such it might be related to the pathogenesis of schizophrenia. Two isoforms are known, TPH-1 and TPH-2. TPH-1 association with schizophrenia is debated. METHODS: A case-control design was employed for gene-disease association in 155 schizophrenic psychosis patients and 253 healthy controls, all North European Caucasians. Six single nucleotide polymorphisms (SNPs) with a haplotype block structure spanning over 23 kb of the total TPH-1 29 kb were analyzed. Linkage disequilibrium and haplotype analyses were performed. Bonferroni correction was used for multiple testing. RESULTS: Single marker association analyses showed two SNPs significantly associated with schizophrenia. Several haplotypes were associated with the disease. A "sliding window" analysis attributed the strongest disease association to a haplotype configuration localized between the promoter region and intron 3. CONCLUSIONS: Our data indicate that TPH-1 associates with schizophrenia. It appears that specific combinations of promoter variants vis-à-vis gene transcript variants contribute to genetic predisposition to the disease.

Tryptophan hydroxylase-1 gene variants associate with a group of suicidal borderline women.

Alterations in the serotonin (5-HT) system have been related to impulsive aggression and suicidal behavior, common features of the borderline personality disorder (BPD). Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in 5-HT biosynthesis. Two isoforms are known, TPH-1 and TPH-2. TPH-1 has been correlated to various psychiatric and behavioral disorders by gene polymorphism association studies. We aimed to determine whether specific TPH-1 haplotypes associate with BPD. A case-control design was employed. The control group included 98 women without psychiatric history. In all, 95 patients were included, all Caucasian women with a BPD diagnosis who had attempted suicide at least twice during their lifetime. Exclusion criteria were: (i) substance dependence; (ii) dementia or other irreversible organic brain syndromes; (iii) psychotic disorders or major depressive illness with melancholic features; (iv) life-threatening eating disorders. Six single-nucleotide polymorphisms (SNPs) were found at significant linkage disequilibrium across 23 kb of the TPH-1 gene in both patients and controls, suggesting a haplotype block structure. While no individual SNP showed association, several haplotypes associated with the BPD group. In particular, one six-SNP haplotype was absent from the control group while representing about one-quarter of all haplotypes in the BPD group (corrected P<<10(-5)). A 'sliding window' analysis attributed the strongest disease association to haplotype configurations located between the gene promoter and intron 3. We conclude that TPH-1 associates with BPD in suicidal women. Our data support the expectation that haplotype analysis is superior to single locus analysis in gene-disease, case-control association studies.

Haplotype analysis reveals tryptophan hydroxylase (TPH) 1 gene variants associated with major depression.

BACKGROUND: Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of serotonin (5-HT) and might be related to the pathogenesis of major depression (MD). Two isoforms are known, TPH-1 and TPH-2. Tryptophan hydroxylase-1 association with MD is still debated. METHODS: A single nucleotide polymorphism (SNP) screening strategy was used to define TPH-1 haplotypes spanning over 23 kilobase (kb) of the 29 kb gene length. Genotyping was performed in 228 MD patients and 253 healthy control subjects. RESULTS: Six SNPs were found at linkage disequilibrium in both patients and control subjects, suggesting a haplotype block structure. Single marker association analyses showed only one SNP significantly associated with MD. Several haplotypes were associated with MD. When all six locus haplotypes were divided into two groups, above or below a 5% threshold, the compound haplotype group below a 5% frequency resulted as associated with the disease (31.6% vs. 18.0% in control subjects, p < 10(-5)). A "sliding window" analysis attributed the strongest disease association to a haplotype configuration localized between introns 7 and 8 (p < 10(-5)). CONCLUSIONS: Haplotype analysis indicates that TPH-1 associates with MD. The most common TPH-1 variants appear to carry no risk, while some of the less frequent variants might contribute to genetic predisposition to MD.