PROKR2 is associated with methamphetamine dependence in the Japanese population

Background

Many patients with drug addiction are reported to have comorbid mood disorders. One of the suggested pathophysiological mechanisms for mood disorders is disruption of circadian rhythms. Several animal studies have shown that methamphetamine altered the expression of circadian clock molecules in the brain. Therefore, it is possible that mood disorders and drug addiction have common susceptibility genes. Recently, we reported that the prokineticin 2 receptor gene (PROKR2) was associated with mood disorders including major depressive disorder and bipolar disorder in the Japanese population. In the present study, therefore, we conducted an association analysis of tagging SNPs in PROKR2 with Japanese methamphetamine dependence patients.

Methods

Using five tagging SNPs in PROKR2, we conducted a genetic association analysis of case–control samples (199 methamphetamine dependence patients and 337 healthy controls). The age and sex of the control subjects did not differ from those of the methamphetamine dependence patients.

Results

We detected a significant association between PROKR2 and methamphetamine dependence patients in allele/genotype-wise and haplotype-wise analysis.

Conclusion

Our results suggest that PROKR2 may play a role in the pathophysiology of methamphetamine dependence in the Japanese population. However, because we did not perform a mutation scan of PROKR2, a replication study using a larger sample may be required for conclusive results.     

Association of schizophrenia with the rs821633 polymorphism in the DISC1 gene among Han Chinese

Background

Previous studies report that various single nucleotide polymorphisms (SNP) in the Disrupted-in Schizophrenia 1 (DISC1) gene are closely associated with schizophrenia, but there are no studies that assess the relationship of age of onset of schizophrenia with these SNPs.

Objective

Investigate the relationship between the rs821633 SNP in the DISC1 gene and the occurrence and age of onset of schizophrenia in Han Chinese.

Methods

We used the TaqMan genotyping technology to examine the rs821633 SNP in the DISC1 gene among 315 individuals who developed schizophrenia prior to 19 years of age (‘early-onset’), 407 individuals who developed schizophrenia when 19 years of age or older (‘late-onset’), and 482 healthy controls. We used survival analyses to investigate the relationship between the rs821633(C) risk allele and the age of onset of schizophrenia.

Results

Compared to the prevalence in healthy controls, the prevalence of the C/C genotype of rs821633 and of the C allele in rs821633 were significantly greater in individuals with early-onset schizophrenia (X²=7.17, df=1, p=0.007; X²=7.20, df=2, p=0.032) and significantly greater in individuals with late-onset schizophrenia (X²=5.36, df=1, p=0.022; X²=6.58, df=2, p=0.041). However, there were no significant differences in the prevalence of the C/C genotype or the C allele between individuals with early-onset and late-onset schizophrenia. Kaplan-Meier survival analyses found no significant association between the rs821633(C) risk allele and age of onset in schizophrenia.

Conclusion

We confirm the association of polymorphism in the rs821633 SNP in the DISC1 gene with schizophrenia among Han Chinese, but we found no association between the rs821633(C) risk allele and the age of onset in individuals with schizophrenia.     

Rapid decrease in depressive symptoms with an N-methyl-d-aspartate antagonist in ECT-resistant major depression

Background

Ketamine rapidly improves depressive symptoms in patients with treatment-resistant major depressive disorder (MDD) who do not respond to multiple standard antidepressants. However, it remains unknown whether ketamine is equally effective in patients with MDD who previously also did not respond to electroconvulsive therapy (ECT).

Methods

This study compared 17 patients with treatment-resistant MDD who previously did not respond to ECT and 23 patients with treatment-resistant MDD who had not previously received ECT. All subjects received a single open-label infusion of ketamine (0.5 mg/kg). Patients were evaluated using the Montgomery-Asberg Depression Rating Scale (MADRS) at baseline (60 min before the infusion), as well as at 40, 80, 120, and 230 min after infusion.

Results

Depressive symptoms were significantly improved in the ECT-resistant group at 230 minutes with a moderate effect size (p < .001, d = 0.50, 95% C.I.: 0.21-0.80). At 230 minutes, the non-ECT exposed group showed significant improvement with a large effect size (p < .001, d = 1.00, 95% C.I.: 0.71-1.29).

Conclusion

Ketamine appears to improve depressive symptoms in patients with MDD who had previously not responded to ECT. These preliminary results encourage further investigation with a larger sample size to determine effectiveness compared to other treatment-resistant patients with MDD.     

A functional polymorphism in estrogen receptor alpha gene is associated with Japanese methamphetamine induced psychosis

Background

A recent study reported an association between rs2234693, which influences enhancer activity levels in estrogen receptor alpha gene (ESR1), and schizophrenia. This study reported that schizophrenic patients with the CC genotype have significantly lower ESR1 mRNA levels in the prefrontal cortex than patients with other genotypes. The symptoms of methamphetamine induced psychosis are similar to those of paranoid type schizophrenia. Therefore, we conducted an association analysis of rs2234693 with Japanese methamphetamine induced psychosis patients.

Method

Using rs2234693, we conducted a genetic association analysis of case-control samples (197 methamphetamine induced psychosis patients and 197 healthy controls). The age and sex of the control subjects did not differ from those of the methamphetamine induced psychosis patients.

Results

We detected a significant association between ESR1 and methamphetamine induced psychosis patients in allele/genotype-wise analysis. For further interpretation of these associations, we performed single marker analysis of subjects divided by sex. Rs2234693 was associated with male methamphetamine induced psychosis.

Discussion

Our results suggest that rs2234693 in ESR1 may play a role in the pathophysiology of Japanese methamphetamine induced psychosis patients.     

DNA variants, plasma levels and variability of Interleukin-6 in myocardial infarction survivors: Results from the AIRGENE study

Introduction

Increased levels of interleukin 6 (IL-6), a marker for systemic inflammation, have been associated with cardiovascular morbidity and mortality.

Materials and Methods

We investigated the influence of IL6 gene polymorphisms on mean level and variability of plasma IL-6 in a population of myocardial infarction survivors recruited in six European cities as part of the AIRGENE study. DNA from each individual was collected and genotyped for eight functional and tagging single nucleotide polymorphisms (SNPs) in the IL6 gene.

Results

We analyzed 946 subjects with 5520 repeated plasma samples for IL-6 levels. For four IL6 SNPs in high linkage disequilibrium, heterozygous and homozygous minor allele genotypes were associated with an increase in mean plasma IL-6 levels. SNP rs1800795 was associated with a 6.3% increase in IL-6 (95% confidence interval [CI] 1.7-11,2%) For these SNPs, we found that genotypes associated with higher IL-6 levels also tended to be associated to higher between-individual variability of IL-6 levels on the log-scale than other genotypes. Variability over time within individuals varied little by genotype.

Conclusions

We found four genetic polymorphisms in the IL6 gene associated with mean level and variability of plasma IL-6 between individuals in myocardial infarction survivors.     

Role of plasminogen in macrophage accumulation during liver repair

Introduction

Although the involvement of plasminogen in liver repair has been reported, its roles are still poorly understood. Here, we investigated the role of plasminogen in accumulations of macrophages and neutrophils after liver injury in mice with gene deficient of plasminogen (Plg^−/−) or its wild type (Plg^+/+).

Materials and Methods

Mice received traumatic liver injury caused by stabbing on the lobe or hepatic ischemia-reperfusion, and the damaged sites were histologically analyzed.

Results

After the traumatic liver injury, both the stab wound and the damaged tissue were decreased until day 7 in the Plg^+/+ mice. In contrast, both the stab wound and the damaged tissue were still remained until day 7 in the Plg^−/− mice. On day 4 after traumatic liver injury, macrophages were abundant at the surrounding area of the damaged site in the Plg^+/+ mice. However, the macrophage accumulation was impaired in the Plg^−/− mice. After hepatic ischemia-reperfusion injury, macrophage accumulation and decrease in the damaged tissue were also observed in the Plg^+/+ mice until day 7. In contrast, these responses were also impaired in the Plg^−/− mice. Furthermore, neutrophil accumulation at the surrounding area of the damaged site was also impaired in the Plg^−/− mice on day 4 after both liver traumatic liver injury and hepatic ischemia-reperfusion injury.

Conclusions

Our data indicate that plasminogen plays a crucial role in macrophage accumulation together with the neutrophil accumulation after liver injury in both models, which may be essential for triggering the subsequent healing responses including decrease in the damaged tissue.     

Association study of EP1 gene polymorphisms with suicide completers in the Japanese population

Background

Both environmental and genetic factors have been reported to be involved in suicidal behaviors. Considerable evidence indicates that impulsive aggression is one of the important risk factors that contribute to suicide. A recent study has shown that prostaglandin E2 type 1 receptor (EP1) signaling regulates impulsive-aggressive behaviors in mice under both social and environmental stresses. To test the possible involvement of the EP1 gene in suicide, we carried out an association study of EP1 gene polymorphisms with suicide completers in the Japanese population.

Methods

We studied 5 SNPs including one SNP in exon 2 (rs3745459) and four SNPs in the potential promoter region of the EP1 gene (rs3810255, rs3810254, rs3810253 and rs10416814) in 374 healthy control and 287 completed suicide victims using standard Taqman probe genotyping assays.

Results

No significant differences of the genotypic distribution, allelic frequency or haplotype distribution between controls and suicide completers were found. Gender based analysis revealed that genotypic, allelic and haplotypic distributions of rs3810255, rs3810254, rs3810253 and rs10416814 SNPs were significantly different between the female control and female suicide groups, although the differences did not withstand correction for multiple comparisons.

Conclusion

We could not find an association of EP1 gene with suicide in the Japanese population. Because several SNPs in the promoter region of the EP1 gene were nominally significantly associated with suicide in the female, further studies with a larger sample size and different population are needed to confirm this result.     

Initial evidence for the role of CACNA1C on subcortical brain morphology in patients with bipolar disorder

Background

The polymorphism rs1006737 within the CACNA1C gene is associated with increased risk for bipolar disorder (BD) and variations in brain morphology and function of subcortical regions. Here we sought to investigate the influence of CACNA1C polymorphism on key subcortical brain structures implicated in the pathophysiology of BD.

Methods

Structural magnetic resonance imaging scans were acquired from 41 euthymic patients with BD and 40 healthy controls, who were also genotyped for the CACNA1C rs1006737 polymorphism. The effect of diagnosis, genotype and their interaction was examined in predefined volumes of interest in the basal ganglia, hypothalamus and amygdala extracted using SPM5.

Results

Carriers of the CACNA1C rs1006737 risk allele showed increased grey matter density in the right amygdala and right hypothalamus irrespective of diagnosis. An interaction between genotype and diagnosis was observed in the left putamen which was smaller in BD patients carrying the risk allele than in healthy controls.

Conclusions

: The CACNA1C rs1006737 polymorphism influences anatomical variation within subcortical regions involved in emotional processing.     

The impact of endothelin-1 genetic analysis and job strain on ambulatory blood pressure

Objective

An interaction between the endothelin-1 gene (EDN1), blood pressure (BP) and social determinants has been previously found. Using a well-characterized cohort of participants, the impact of associations between genetic factors and job strain on BP was evaluated.

Methods

A cross-sectional analysis of five polymorphisms covering the EDN1, of which 2 were previously reported to be associated with BP, was performed. Study subjects had previously completed a baseline evaluation including 24-h ambulatory BP monitoring and an assessment of job strain. This report presents the findings for 184 subjects who gave DNA samples for genetic analysis. One-way analysis of variance (ANOVA) was performed between each genetic marker and 24-h systolic blood pressure (SBP) and diastolic blood pressure (DBP), as well as two-way ANOVAs to test the interaction effect with job strain.

Results

Trends for relationships were observed between SBP and two polymorphisms: rs10478694 and rs5369. An interaction between job strain and those heterozygous for two polymorphisms showed higher SBP (P=.029 and .008) and a tendency for higher DBP. All findings were more significant when analyses were confined to the 139 Caucasian subjects.

Conclusion

This is the first study to report an interaction between the EDN1 gene, job strain and BP, supporting previous evidence of a role of this gene in the interaction between environmental stress and ambulatory BP. Given the limited sample size, the results should be considered preliminary, and further studies are required.     

Purification, biochemical properties and antithrombotic effect of a novel Streptomyces enzyme on carrageenan-induced mice tail thrombosis model

Introduction

The prevalence of cardiovascular diseases, one of the major causes of worldwide mortality, is being increasingly reported. Safer, more effective, and less expensive thrombolytic drugs can possibly overcome the underlying problems associate with current thrombolytic drugs.

Methods

A thrombolytic enzyme was purified and characterized from a Streptomyces strain. Carrageenan induced tail-thrombosis mice model was used to evaluate in vivo antithrombotic effect of the enzyme.

Results

First 15 N-terminal amino acids of the purified enzyme were IAGGQAIYAGGGRRS, which are significantly different from the reported fibrinolytic enzymes. The enzyme exhibited 14.3 ± 2.3-fold stronger thrombolytic activity than that of plasmin. In carrageenan induced tail-thrombosis model, the enzyme caused reduction in frequency of thrombus. Tail-thrombus of the enzyme treated group was significantly shorter than the physiological saline treated group and the thrombus decrement was correlated with the enzyme dose.

Conclusions

The enzyme purified from the Streptomyces strain can be a potential candidate for the treatment of thrombosis.     

Association study of PDE4B with panic disorder in the Japanese population

Background

Panic disorder (PD) is a severe and chronic psychiatric disorder with genetic components underlying in its etiology. The Phosphodiesterase 4B (PDE4B) gene has been reported to be associated with several psychiatric disorders. Several studies indicated that PDE4B may be involved in the regulation of anxiety and depression. Therefore, we investigate the association of PDE4B with PD in the Japanese population.

Methods

We genotyped 14 single nucleotide polymorphisms (SNPs) of PDE4B in 231 PD cases (85 males and 146 females) and 407 controls (162 males and 245 females). Differences in the genotype, allele and haplotype frequencies between the two groups were compared.

Results

We found a significant association between PDE4B and PD in the haplotype analysis (haplotype C-T-T-A, permutation P = 0.031, OR = 1.81, 95% CI = 1.30-2.51). Sex-specific analyses demonstrated that PDE4B was associated with PD in females in the allele/genotype and haplotype analyses (rs10454453, allele P = 0.042, genotype P = 0.0034; haplotype C-T-T-A, permutation P = 0.028).

Conclusion

Our results suggest that PDE4B may play a role in the pathophysiology of PD in the Japanese population. Replication studies using larger samples will be needed for more reliable conclusions.     

The inhibition of the integrin VLA-4 in MV3 melanoma cell binding by non-anticoagulant heparin derivatives

Introduction

The integrin VLA-4-mediated binding is important for the metastatic dissemination of melanoma cells. Recently we found that heparin possesses a binding capacity to VLA-4. This could contribute to the heparin function to attenuate metastasis in a selectin-dependent manner. Aiming to a purposive, anti-adhesive heparin application, structural requirements of heparin for VLA-4 recognition have to be elucidated.

Materials and methods

A series of non-anticoagulant heparin derivatives were investigated concerning their inhibitory capacities for VLA-4 mediated binding of human melanoma MV3 cells to VCAM-1 under physiological flow conditions in vitro. A surface acoustic wave biosensor was applied to detect kinetic constants of selected derivatives binding to both, VLA-4 or P- and L-selectin.

Results

Experimental metastasis of MV3 cells in mice confirmed the relevance of VLA-4 for metastatic dissemination. LMWHs (enoxaparin, tinzaparin) efficiently blocked VLA-4 cell binding, dominantly via the integrin`s α-chain. Desulfation at 2-O-position, N-acetylation or a size smaller than tetradecasaccharide disfavoured VLA-4 inhibition. Glycol-splitting of heparin and thus higher chain flexibility is a tolerable parameter. A derivative with 50% 6-O-desulfation appeared promising and exceeded tinzaparin in VLA-4 inhibition, both compounds displayed binding affinities to VLA-4 in the low micromolar range.

Conclusions

These findings provide structure-activity relationships for heparin VLA-4 binding, which partly differ from P- and L-selectin requirements. The data confirm that anti-coagulative and anti-adhesive function of heparin can be distinguished favouring applications of non-anticoagulant heparins in antimetastatic approaches without the risk of bleeding complications. The 50% 6-O-desulfated heparin-derivative appears promising to further evaluate the interference with selectin and VLA-4 binding functions in vivo.     

Tangier disease phenotype diversity in dizygous twin sisters

Introduction

Tangier disease (TD) is a rare autosomal recessive disorder characterized by a deficiency or absence of high-density lipoprotein (HDL) caused by mutations in the adenotriphosphate-binding cassette transporter-1 gene (ABCA1). Mutations of ABCA1 lead to a defect in cellular cholesterol removal and to deposition of cholesterol esters throughout the body.

Observation

We report here on the case of a 53-year-old woman with a severe phenotype of TD. The patient had a dizygous twin sister who had only asymptomatic corneal opacities and thrombopenia.

Conclusion

This family demonstrates the wide intrafamilial phenotype diversity of TD.     

Influence of GGCX genotype on warfarin dose requirements in Chinese patients

Introduction

It has been widely accepted that genetic factors were the major sources of the variation in warfarin dose. This study is intended to investigate whether the 3261G>A variation in GGCX gene influences stable warfarin dose in Chinese patient population.

Materials and Methods

A total of 217 patients with stable warfarin dose were enrolled. Genomic DNA was extracted from each subject and the genotype of GGCX 3261G>A was determined by using of denaturing high-performance liquid chromatography (DHPLC). Least significant difference tests (LSDs) were used to compare dose with genotypes. Analysis of variance (ANVOA) was used to calculate the proportion of warfarin dose that could be explained by variation in genotype.

Results

In the total of 217 subjects, 84 patients (38.7%) were GG homozygote, whereas 117 (53.9%) were GA heterozygote and 16 (7.4%) were AA homozygote. Patients with the GGCX 3261AA genotype had a significantly higher average daily maintenance dose (3.39 ± 1.40 mg) than those with the GG genotype (2.69 ± 1.07 mg; P = 0.027), and GGCX 3261G>A explains 2.3% of the univariate warfarin dose variance.

Conclusion

GGCX 3261G>A may affect warfarin dose requirements, and showed a small but significant effect on warfarin dose in a Chinese patient population.     

Association of p22phox gene C242T polymorphism with coronary artery disease: A meta-analysis

Introduction

The C242T polymorphism of p22phox gene (rs4673) has been linked to the reduced coronary artery disease (CAD) risk, but results in the published literatures are controversial. A meta-analysis was performed to assess the effect of this polymorphism on the CAD risk.

Methods

A comprehensive search was conducted to identify all studies on the association of p22phox gene C242T polymorphism with CAD risk. The fixed or random effect pooled measure was selected based on the homogeneity test among studies. Heterogeneity among studies was evaluated using Q test and the I² of Higgins and Thompson. Meta-regression was used to explore the sources of between-study heterogeneity. Publication bias was estimated using modified Egger's linear regression test proposed by Harbord etal.

Results

We identified 15 published articles including 6273 CAD cases and 5045 controls. In this studied overall and non-Asian populations, we didn't found any significant association of p22phox gene C242T polymorphism with CAD in any of codominant, dominant, and recessive models. Only in Asian population, both fixed effect model (FEM) and random effect model (REM) indicated the significant protective effect both in codominant (FEM: OR = 0.771, 95%CI: 0.681-0.873; REM: OR = 0.751, 95%CI: 0.607-0.930) and dominant (FEM: OR = 0.714, 95%CI: 0.621-0.822; REM: OR = 0.694, 95%CI: 0.538-0.895) models with strong evidence for between-study heterogeneity (I² = 52.6% for codominant and I² = 56.5% for dominant), but not in recessive model. No evidence of publication bias was detected.

Conclusions

The results suggested a significant heterogeneity across ethnicities about the relationship between the T allele of p22phox gene C242T polymorphism and reduced CAD risk, with a significant protective effect only in Asian population that needs to be confirmed by further studies.     

The clock gene Per2 is required for normal platelet formation and function

Introduction

Apoptotic cell death is a highly regulated genetic program, which has been observed in mature megakaryocytes fragmenting into platelets. The clock gene Per2, a key component of core clock oscillator, was involved in affecting both cell cycle control and apoptosis. Thus, loss of Per2 function may be considered potential influence of platelet formation and function.

Methods

Per2-null mice and C57BL/6 mice were used in the study. Bleeding time, platelet count, megakaryocyte count, megakaryocyte ploidy, megakaryocyte apoptosis, rate of proplatelet formation, clot retraction, platelet aggregation and secretion were performed to evaluate thrombopoiesis and hemostasis. Quantitative RT-PCR was employed to analyze genes expression in liver, bone marrow and enriched megakaryocytes.

Results

The Per2-null mice had nearly 50% platelet counts in peripheral blood. Per2-null platelets were compromised in their ability to aggregate and secretion, consistent with a marked reduction in the number of dense and a-granules. Megakaryocytes from Per2-null mice showed no significant variation in number but increased in ploidy. Ultrastructural examination of Per2-null megakaryocytes revealed many vacuoles in demarcation membranes and reduction in platelet granules. Megakaryocytes from Per2-null bone marrow decreased the rate of proplatelet formation and impaired apoptosis. Per2-null mice showed increased both in Tpo in livers and its receptors C-mpl in bone marrow, and the megakaryocytes from these mice decreased P53 expression, consequently increased Bcl-xl and Bcl-2 level.

Conclusions

The clock gene Per2 modulating the apoptosis of megakaryocytes was required for platelet formation and function.     

A case-control study provides evidence of association for a common SNP rs974819 in PDGFD to coronary heart disease and suggests a sex-dependent effect

Introduction

Peden et al. have revealed a significant association between four new risk loci and coronary heart disease (CHD) in Europeans and South Asians. The goal of this study is to evaluate the contribution of these genetic loci to CHD risk in Han Chinese.

Methods

We recruited 161 CHD patients and 112 controls proved by angiography originated from Ningbo in the Eastern China, and performed a case-control association study of the four significant SNPs.

Results

Among the four tested SNPs, we found a significant association of rs974819 in PDGFD gene with CHD (allele p = 0.04; OR = 1.45, 95% CI = 1.02 - 2.08) and the allele A/G of rs974819 shows significant difference in females (allele p = 0.04; OR = 1.83, 95% CI = 1.01 - 3.31). A further meta-analysis showed that rs974819 of PDGFD gene was significantly associated with an increasing risk of CHD (OR = 1.08, 95% CI = 1.05 - 1.11) in both Europeans and South Asians including Han Chinese.

Conclusions

Our findings suggests that rs974819 of PDGFD is also a CHD risk factor in Han Chinese. In addition, it presents a sex-dependent genetic effect.     

Glucocorticoid receptor gene haplotype predicts increased risk of hospital admission for depressive disorders in the Helsinki birth cohort study

Background

Although glucocorticoid receptors (GR) are involved in mediating hypothalamic-pituitary-adrenal-axis functioning, which is altered in acute depression, data on associations between GR gene (NR3C1) polymorphisms and depression are scarce. We examined if single nucleotide polymorphisms (SNPs) and their haplotypes spanning the entire NR3C1 are associated with depressive disorders and with self-reported depressive symptoms in adulthood.

Methods

We successfully genotyped 10 SNPs spanning the NR3C1, and performed SNP and haplotype analyses in 1075 women and 928 men participating in the Helsinki birth cohort study. Diagnoses of depressive disorders were extracted from the Finnish Hospital Discharge Register covering a 35-year period from early to late adulthood. In addition, depressive symptoms were self-reported with standardized questionnaire in late adulthood.

Results

In comparison to the most common haplotype, one haplotype in the regulatory region of the NR3C1 was associated with increased risk of hospital admission (OR: 3.35; 95% confidence interval 1.5 to 7.3) for depressive disorders after adjusting for sex, birth year, and education. The association was statistically significant after Bonferroni correction for multiple testing. There were no other significant associations.

Conclusions

Haplotypic variation in the regulatory region of the NR3C1 may increase vulnerability to depressive disorders requiring hospital admission, but is not associated with self-reported symptoms.     

Serotonin receptor HTR1A and HTR2C variants and personality traits in suicide attempters and controls

Introduction

Serotonin has been extensively studied in relation to both personality features and suicidal behaviours.

Objective

In this study, we considered the association between the serotonin receptor 1A (HTR1A) and 2C (HTR2C) SNPs and personality traits, as measured by the Temperament and Character Inventory (TCI), in a sample of suicide patients and healthy volunteers.

Methods

The SNPs considered were, for HTR1A rs1423691, rs878567 and rs6295, and for HTR2C rs547536, rs2192372, rs6318, rs2428707, rs4272555 and rs1801412. The sample was composed of three groups: two German samples, consisting of a healthy control group of 289 subjects (42.6% males, mean age: 45.2 ± 14.9) and a psychiatric patient group of 111 suicide attempters (38.7% males, mean age: 39.2 ± 13.6), and an Italian sample, composed of 64 mood disorder patients (35.9% males, mean age: 43.0 ± 14.8). In the German samples all the SNPs were investigated, while in the Italian sample only the HTR1A rs6295 and the HTR2C rs6318 SNPs were considered.

Results

Controlling for sex, age and educational level, single markers and haplotypes were not or only marginally associated with personality dimensions.

Conclusions

Our study does not support the role of HTR1A and HTR2C gene variants on personality traits in both healthy volunteers and mood disorder patients.     

Hopelessness, a potential endophenotpye for suicidal behavior, is influenced by TPH2 gene variants

Objectives

Hopelessness is one of the strongest risk factors for suicidal behavior but relevant genetic studies are poorly available. Tryptophan hydroxylase (TPH) is widely considered to be a good candidate for genetic association studies on depression and suicide, however, investigations on these complex, multifactorial phenotypes have resulted in conflicting data. We hypothesized that hopelessness could be a mediating phenotype between TPH2 gene, depression and suicidal behavior.

Methods

Depressive phenotype and suicidal risk were investigated of 760 individuals from general population by Zung Self Rating Depression Scale (ZDS), Beck's Hopelessness Scale (BHS) and a detailed background questionnaire. All participants' DNA samples were genotyped for 7 tag SNPs in TPH2 gene. Generalized linear models were performed for single marker association studies and p-values were corrected by Bonferroni criteria. In haplotype analyses score tests were used and permutated p-values were computed.

Results

Four SNPs of TPH2 gene showed association with hopelessness but only rs6582078 had a significant effect on the BHS scores after Bonferroni's correction; GG individuals had significantly higher BHS scores, while GT and TT had intermediate and lower BHS scores respectively (p = 0.0047). Compared with other genotypes, homozygous GG individuals also had almost three times greater estimated suicidal risk, as did carriers of the AA genotype of rs6582078 (OR = 2.87; p = 0.005) and also of rs1352250 (OR = 2.86; p = 0.006). A risk and a protective haplotype of TPH2 gene were also identified in association with hopelessness. ZDS scores have not shown any association with TPH2 gene.

Conclusions

We found that hopelessness, with its allied increased suicidal risk was strongly associated with TPH2 gene variants in multiple tests. These findings suggest that TPH2 gene confers risk for suicidal behavior while hopelessness can be a potential endophenotype for suicidal vulnerability.