Brain-derived neurotrophic factor Val66Met and psychiatric disorders: meta-analysis of case-control studies confirm association to substance-related disorders, eating disorders, and schizophrenia.

BACKGROUND: There is an increasing recognition that the pathophysiology of mental disorders could be the result of deregulation of synaptic plasticity with alterations of neurotrophins. The valine (Val)66-to-methionine (Met) variant, located in the pro brain-derived neurotrophic factor (BDNF) sequence, has been extensively studied through linkage and association approaches in several psychiatric disorders. METHODS: We performed a meta-analysis restricted to individual case-control studies in different categories of mental disorders and BDNF Val66Met polymorphism. We included data from 39 case-control studies encompassing psychiatric phenotypes: eating disorders, substance-related disorders, mood disorders, and schizophrenia, among others. RESULTS: The association of Val66Met was confined to three diagnoses: substance-related disorders, eating disorders, and schizophrenia. The Val/Met and the Met/Met genotypes increase the risk for eating disorders up to 33%, while these same genotypes confer a 21% protective effect in substance-related disorders. The homozygous carriers Met/Met showed a 19% increased risk of schizophrenia with respect to the heterozygous state. CONCLUSIONS: The study confirms the association of Val66Met to substance-related disorders, eating disorders, and schizophrenia. It remains to be determined if other variants in tight linkage disequilibrium with Val66Met could configure an extended functional haplotype that would explain observed discrepancies in risk estimations across studies.     

Similarities and differences between d-ALA2 MET5 enkephalin amide and morphine in the induction of tolerance to their effects on catalepsy and on dopamine metabolism in the rat brain

Summary Rats were made tolerant to morphine or to DALA, a synthetic analogue of met-enkephalin, by prolonged exposure to these compounds. Tolerance was assessed by evaluating the resistance of the treated rats to present catalepsy after an acute dose of the opiates. Both morphine and DALA induced tolerance and cross-tolerance to the cataleptic effect. Acute administration of morphine and DALA increased the concentration of DOPAC in striatum, limbic area and s.nigra of control rats. This increase was not present when morphine was given acutely to chronically morphine-treated rats, indicating that these animals were tolerant to this effect. Chronically morphine-treated rats given DALA presented partial tolerance to the biochemical effect of the peptide in limbic area and in s.nigra but not in striatum, indicating that only in certain areas was crosstolerance produced by chronic morphine. When DALA was administered at different doses to chronically DALA treated rats, the peptide induced rise in DA catabolite was similar to that produced in control animals, so clearly there was no tolerance to this biochemical effect. In these animals cross tolerance to morphine's effect on DA metabolism was present in s.nigra but not in the other two areas, indicating that s.nigra is particularly sensitive to opiate-induced tolerance on DA metabolism.Supported by CNR-ROME Grant no. CT81.00258.04     

儿茶酚胺氧位甲基转移酶Val/Met基因多态性与精神分裂症的关联性

目的探讨儿茶酚胺氧位甲基转移酶Val/Met基因多态性与精神分裂症的关联。方法对232例符合入组标准的精神分裂症患者和141例同期健康对照者进行病例-对照研究,采用聚合酶链反应-序列特异性引物扩增技术测定基因型。结果COMT基因Val/Met多态性突变率为5%,基因型：G/G、G/A和A/A在患者组和对照组分别为：144,74,14和85,47,9。该多态性在精神分裂症患者组和正常对照组基因型（2=0.119,P=0.942）及基因频率（2=0.115,P=0.735）差异无显著性,患者组和同性别对照组基因型（男性：2=1.341,P=0.511;女性：2=2.379,P=0.304）和基因频率（男性：2=1.271,P=0.260;女性：2=2.323,P=0.128）比较差异无显著性。该多态性基因型及基因频率在不同发病年龄组、临床各亚型组及不同家族史患者组间分布差异也无显著性。结论COMT基因第四外显子区Val/Met多态性与精神分裂症无相关性,与精神分裂症患者性别、临床亚型及家族史亦无关。     

Clinical symptoms in fibromyalgia are associated to catechol-O-methyltransferase (COMT) gene Val158Met polymorphism

Abstract

1.?Fibromyalgia syndrome (FMS) is a common chronic widespread pain syndrome mainly affecting women. The aim of this study was to explore the frequency and clinical significance of catechol-O-methyltransferase (COMT) gene Val158Met polymorphism in a large cohort of Turkish patients with FMS.

2.?The study included 379 FMS patients and 290 controls. Genomic DNA was isolated and genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analyses.

3.?The genotype frequencies of Val158Met polymorphism showed a small difference between FMS patients and healthy controls (p?=?0.047), however, the Met/Met genotype was significantly higher in FMS patients than healthy controls (p?=?0.016). No difference was observed for allele frequencies between two groups. Stratification analysis according to clinical features for this disease reveals that weight, FMS Impact Questionnaire score, algometry and Raynaud’s syndrome, were detected to have statistically significant associations with Val158Met polymorphism (p?=?0.037, p?=?0.042, p?=?0.039 and p?=?0.033, respectively). Pain sensitivity, measured by algometry, was statistically higher in patients with Met/Met genotype than the patients with Val/Val and Val/Met genotypes (p?=?0.017).

4.?The results of this study suggested that COMT gene Val158Met polymorphism is positively associated with FMS and play a relevant role in the clinical symptoms of the disease.     

A community needs assessment among Asian American elders

Despite a significant increase in the size of the Asian American elderly population, little is known about their social service needs and the level of service being provided them. This study used a survey methodology to examine all Asian American senior programs (N = 20) in a major American metropolitan region. The response rate was 90% with respondent agencies serving as the unit of analysis. Findings suggest that Asian elderly clients were primarily women and 'old-old', and that many of them were on SSI. Services provided were primarily tangible and facilitative, rather than clinical. Services needed but not provided were emergency psychiatric care, home attendants, home-delivered meals, legal services, medical services, and protective services. Findings of this study provide useful information for further research and program planning for Asian American elders in urban settings.     

Shp2 deletion in hepatocytes suppresses hepatocarcinogenesis driven by oncogenic β-Catenin,PIK3CA and MET

1. Download high-res image (129KB)
2. Download full-size image

     

Molecular heterosis in metamphetamine abusers

Objective. The aim of our study was to assess whether the catechol-O-methyltransferase (COMT) genetic background of patients dependent on metamphetamine is related to their non-abstinence in a 1-year follow-up. Methods. We examined COMT gene Val158Met polymorphism and 1-year abstinence in a group of 31 (women N=8) Czech Caucasian metamphetamine abusers (average age, 23.8±4.0years). Results. Non-abstinence was significantly (P=0.046, Fisher's exact test) associated with the heterozygous Val/Met genotype. Conclusion. The case where subjects heterozygous for a specific genetic polymorphism show a significantly greater or lesser effect for a phenotypic trait than subjects homozygous for either allele is described as molecular heterosis in the literature. We discuss several explanations and recommendations for further research.     

Genetics of serum BDNF: Meta-analysis of the Val66Met and genome-wide association study

Abstract

Objectives. Lower levels of serum brain derived neurotrophic factor (BDNF) is one of the best known biomarkers of depression. To identify genetic variants associated with serum BDNF, we tested the Val66Met (rs6265) functional variant and conducted a genome-wide association scan (GWAS). Methods. In a community-based sample (N = 2054; aged 19–101, M = 51, SD = 15) from Sardinia, Italy, we measured serum BDNF concentration and conducted a GWAS. Results. We estimated the heritability of serum BDNF to be 0.48 from sib-pairs. There was no association between serum BDNF and Val66Met in the SardiNIA sample and in a meta-analysis of published studies (k = 13 studies, total n = 4727, P = 0.92). Although no genome-wide significant associations were identified, some evidence of association was found in the BDNF gene (rs11030102, P = 0.001) and at two loci (rs7170215, P = 4.8 × 10^–5 and rs11073742 P = 1.2 × 10^–5) near and within NTRK3 gene, a neurotrophic tyrosine kinase receptor. Conclusions. Our study and meta-analysis of the literature indicate that the BDNF Val66Met variant is not associated with serum BDNF, but other variants in the BDNF and NTRK3 genes might regulate the level of serum BDNF.     

Reduced hippocampal volumes in healthy carriers of brain-derived neurotrophic factor Val66Met polymorphism: Meta-analysis

Abstract

Objectives. Converging evidence suggests that the brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism affects brain structure. Yet the majority of studies have shown no effect of this polymorphism on hippocampal volumes, perhaps due to small effect size. Methods. We performed a meta-analysis of studies investigating the association between Val66Met BDNF polymorphism and hippocampal volumes in healthy subjects by combining standardized differences between means (SDM) from individual studies using random effect models. Results. Data from 399 healthy subjects (255 Val-BDNF homozygotes and 144 carriers of at least one Met-BDNF allele) in seven studies were meta-analysed. Both the left and right hippocampi were significantly larger in Val-BDNF homozygotes than in carriers of at least one Met-BDNF allele (SDM = 0.41, 95% Confidence Interval = 0.20; 0.62, z = 3.86, P = 0.0001; SDM = 0.41; 95% Confidence Interval = 0.20; 0.61, z = 3.81, P = 0.0001, respectively), with no evidence of publication bias. Conclusions. Healthy carriers of BDNF gene Val66Met polymorphism show bilateral hippocampal volume reduction. The effect size was small, but the same direction of effect was seen in all meta-analyzed studies. The association with the BDNF gene Val66Met polymorphism makes hippocampal volume a potential candidate for an endophenotype of disorders presenting with reduced hippocampal volumes.