Functional variants of the genes involved in neurodevelopment and susceptibility to schizophrenia in an Armenian population

Aberrant neurodevelopment contributes to the etiology of schizophrenia. This study aimed to investigate the potential association of netrin G1 (NTNG1) rs628117 and brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) genetic polymorphisms with susceptibility to schizophrenia. One hundred three Armenian patients with schizophrenia and 105 healthy control subjects were genotyped by polymerase chain reaction with sequence-specific primers. Whereas the NTNG1 rs628117 genotypes were equally distributed in the groups, the carriers of the less common BDNF 66Met allele were overrepresented among patients with schizophrenia when compared with healthy controls (55% vs 35%, odds ratio = 2.28, 95% confidence interval 1.14-1.98, p(corrected) = 0.006). Furthermore, the 66Met/Met genotype correlated with earlier disease onset (p = 0.024). In conclusion, our single-cohort study nominates the BDNF 66Met allele as a risk factor for schizophrenia in an Armenian population. This must be confirmed in other Armenian cohorts.     

海洛因依赖与儿茶酚胺氧位甲基转移酶基因的关联研究

目的：探讨海洛因依赖和儿茶酚胺氧位甲基转移酶（catechol-O-methyltransferase,COMT)基因的关系。方法：应用聚合酶链反应技术检测313例海洛因依赖者和214名正常对照COMT基因108val/met和900Ins C/Del C两个多态性。结果：海洛因依赖者和对照组之间上述两个多态性的基因型和等位基因频率的差异均无显著性（P＞0．05）。结论：COMT基因108val/met和900Ins C/Del C两个多态性均与海洛因依赖无关联。     

Association analysis of GABA receptor subunit genes on 5q33 with heroin dependence in a Chinese male population.

GABAA receptor subunit genes clustered on 5q33 play a role in the development of alcoholism and methamphetamine use disorder without psychosis. The present study explored the possible contribution of the same subunit genes to the development of heroin dependence. Single nucleotide polymorphisms (SNPs) of the GABAA receptor subunits GABRB2, GABRA6, GABRA1, and GABRG2 were examined in 178 male Han Chinese heroin-dependent and 170 male control subjects. A significant difference in allele frequency for the SNP rs211014 in the GABAAgamma2 receptor subunit gene between cases and controls was identified (P = 0.015). A possible mechanism for the involvement of the GABA receptor subunit genes on 5q33 in the development of heroin dependence is discussed.     

Association of the brain-derived neurotrophic factor gene G196A rs6265 polymorphisms and the cognitive function and clinical symptoms of schizophrenia

This study aimed to explore the association between BDNF G196A gene rs6265 polymorphisms and the cognitive function and clinical symptoms of schizophrenia. Methods: BDNF G196A rs6265 genotype and allele frequency were measured using Polymerase Chain Reaction (PCR) methods in 224 drug-free patients with schizophrenia and 220 controls. Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS), and cognitive functioning was assessed using the Wisconsin Card Sorting Test (WCST) and the Trail Making Test (TMT). In the patient group, differences in severity of symptoms across the three genotypes (i.e., G/G, G/A and A/A) of G196A were assessed using one-way analysis of variance. Results G/A genotype had higher frequencies than GG or AA genotype in both patients and controls. There was no significant difference in G/G, G/A, A/A genotype frequency between patients and controls (P > 0.05). The allele G had higher frequencies than allele A in both patients and controls. There was no significant difference in G or A allele frequency between patients and controls (P > 0.05). There was significant difference in A/A genotype frequency between positive group patients and negative group patients. There was no significant difference in cognitive performance between patients with G/G, G/A and A/A genotype (all P > 0.05). Conclusion BDNF G196A gene rs6265 polymorphism is not associated with the cognitive function but with the clinical symptoms of schizophrenia.     

Transmission distortion of BDNF variants to bipolar disorder type I patients from a South American population isolate.

Recent reports have implicated polymorphisms in the brain derived neurotrophic factor (BDNF) gene region in the etiology of several psychiatric phenotypes, including bipolar disorder. Significant disease association has been reported for the G allele at SNP rs6265, which encodes for Valine at position 66 of BDNF (Val66Met), an apparently functional variant of this key BDNF. Here we examined a sample of 224 bipolar type I patients and available parents (comprising a total of 212 nuclear families) ascertained in a South American population isolate (Antioquia, Colombia). We tested for transmission distortion to bipolar patients of alleles at the rs6265 polymorphism and at a microsatellite marker 1.3 kb away from this SNP. Significant excess transmission of the rs6265 G allele to cases was observed (chi(2) = 10.77, d.f. = 1, P = 0.001). Two-locus haplotype analysis showed a significant global transmission distortion (chi(2) = 16.059, d.f. = 7, P = 0.025) with an excess transmission of a haplotype comprising the rs6265 G allele and microsatellite allele 227. These results are consistent with previous studies pointing to a role for BDNF in susceptibility to mood disorders.     

Cannabinoid type-1 receptor gene polymorphisms are associated with central obesity in a Southern Brazilian population

The CB1 cannabinoid receptor and its endogenous ligands, the endocannabinoids, are involved in energy balance control, stimulating appetite and increasing body weight in wasting syndromes. Different studies have investigated the relationship between polymorphisms of the cannabinoid receptor 1 (CNR1) gene and obesity with conflicting results. In the present study, we investigated the 1359G/A (rs1049353), 3813A/G (rs12720071) and 4895A/G (rs806368) polymorphisms in the CNR1 gene in a Brazilian population of European descent. To verify the association between these variants and obesity-related traits in this population, 756 individuals were genotyped by PCR-RFLP methods. The 4895G allele was associated with waist to hip ratio (WHR) (P = 0.014; P = 0.042 after Bonferroni correction). An additive effect with the GAA haplotype was associated with WHR (P = 0.028), although this statistical significance disappeared after Bonferroni correction (P = 0.084). No significant association was observed between the genotypes of the 1359G/A and 3813A/G polymorphisms and any of the quantitative variables investigated. Our findings suggest that CNR1 gene polymorphism is associated with central obesity in this Brazilian population of European ancestry.     

Brain‐derived neurotrophic factor Val66Met polymorphism and early life adversity affect hippocampal volume

The interaction between adverse life events during childhood and genetic factors is associated with a higher risk to develop major depressive disorder (MDD). One of the polymorphisms found to be associated with MDD is the Val66MET polymorphism of brain‐derived neurotrophic factor (BDNF). The aim of our two‐center study was to determine how the BDNF Val66Met polymorphism and childhood adversity affect the volumetric measures of the hippocampus in healthy individuals and people with MDD. In this two‐center study, 62 adult patients with MDD and 71 healthy matched controls underwent high‐resolution magnetic resonance imaging. We used manual tracing of the bilateral hippocampal structure with help of the software BRAINS2, assessed childhood adversity using the Childhood Trauma Questionnaire and genotyped Val66Met BDNF SNP (rs6265). MDD patients had smaller hippocampal volumes, both in the left and right hemispheres (F = 5.4, P = 0.022). We also found a significant interaction between BDNF allele and history of childhood adversity (F = 6.1, P = 0.015): Met allele carriers in our samples showed significantly smaller hippocampal volumes when they did have a history of childhood adversity, both in patients and controls. Our results highlight how relevant stress–gene interactions are for hippocampal volume reductions. Subjects exposed to early life adversity developed smaller hippocampal volumes when they carry the Met‐allele of the BDNF polymorphism. © 2013 Wiley Periodicals, Inc.     

Gray matter deficits and resting-state abnormalities in abstinent heroin-dependent individuals

Previous neuroimaging studies have demonstrated both structural and functional damages in heroin-dependent individuals. However, few studies investigated gray matter deficits and abnormal resting-state networks together in heroin-dependent individuals. In the present study, voxel-based morphometry (VBM) was used to identify brain regions with gray matter density reduction. Resting-state fMRI connectivity analysis was employed to assess potential functional abnormalities during resting-state. All clinical significances were investigated by examining their association with duration of heroin use. Compared with healthy subjects, heroin-dependent individuals showed significant reduction in gray matter density in the right dorsolateral prefrontal cortex (DLPFC) and a decrease in resting-state functional connectivity between the right DLPFC and left inferior parietal lobe (IPL). The gray matter density of the right DLPFC and its resting-state functional connectivity with the left IPL both showed significantly negative correlation with duration of heroin use, which were likely to be related to the functional impairments in decision-making and cognitive control exhibited by heroin-dependent individuals. Our findings demonstrated that long heroin dependence impairs the right DLPFC in heroin-dependent individuals, including structural deficits and resting-state functional impairments.     

Association between FOXP2 polymorphisms and schizophrenia with auditory hallucinations

OBJECTIVE: A mutation in the FOXP2 gene has been the first genetic association with a language disorder. Language disorder is considered as a core symptom of schizophrenia. Therefore, the FOXP2 gene could be considered a good candidate gene for the vulnerability to schizophrenia. METHODS: A set of single nucleotide polymorphisms mainly located in the 5' regulatory region of the FOXP2 gene was analysed in a sample of 186 DSM-IV schizophrenic patients with auditory hallucinations and in 160 healthy controls. RESULTS: Statistically significant differences in the genotype (P=0.007) and allele frequencies (P=0.0027) between schizophrenic patients with auditory hallucinations and controls were found in the single nucleotide polymorphism rs2396753. These P values changed to 0.07 and 0.0273, respectively, after Bonferroni sequential correction. The haplotype rs7803667T/rs10447760C/rs923875A/rs1358278A/rs2396753A (TCAAA) also showed a significant difference confirmed with a permutation test (P=0.009). CONCLUSIONS: These results suggested that the FOXP2 gene may confer vulnerability to schizophrenic patients with auditory hallucinations.     

脑源性神经营养因子相关基因与创伤后应激障碍患者的人格特征关联性

目的:分析脑源性神经营养因子(BDNF)主要传导通路中BDNF、PKB1、GSK-3B、PRKCG基因多态性与创伤后应激障碍(PTSD)康复人群艾森克人格的关联性,探讨其单基因及联合作用对人格的影响。方法:严格按照入组标准筛选创伤后应激障碍患者114例,采用PTSD进行诊断,用艾森克人格问卷(EPQ)测量人格特征。采用聚合酶链反应(PCR)直接测序法检测BDNF、PKB1、GSK-3B以及PRKCG基因的单核苷酸多态性(SNP)。结果:Hardy-Weinberg遗传平衡检验到BDNF、PKBI、GSK-3B、PRKCG 4个基因的6个SNPs,即BDNF rs6265和rs712444,PKBl rs2494746和rs2494738,GSK-3Brs6782799以及PRKCG rs3745406间PTSD患者临床痊愈后所测人格差别无统计学意义。6个SNP基因型分布在总样本中均符合Hardy-weinberg遗传平衡(P0.05),样本具有群体代表性。结论:BDNF rs6265,BDNF rs712444,PKB1rs2494746,PKB1rs2494738,GSK-3Brs6782799,PRKCG rs3745406位点与PTSD患者临床痊愈后所测人格可能无关联。     

Association of AIRE Polymorphisms with Genetic Susceptibility to Rheumatoid Arthritis in a Chinese Population

Recently, genetic polymorphisms within the autoimmune regulator (AIRE) have been implicated in the genetic susceptibility to rheumatoid arthritis (RA) in Japanese and Spanish. The aim of this case–control study involving 232 patients with RA and 313 ethnically matched control subjects was to investigate the association of AIRE rs2075876 and rs760426 polymorphisms with genetic predisposition to RA in a Chinese population. The genotypes of AIRE rs2075876 and rs760426 polymorphisms were determined by SNaPshot assay. A significant difference in the allele frequency of AIRE rs2075876 polymorphism between cases and controls was detected (A versus G, OR 1.33, 95 %CI 1.04–1.69, P?=?0.02, P corrected (Bonferroni correction) Pc?=?0.04). Significant evidence was found for the association between the minor allele A of AIRE rs2075876 polymorphism and the risk of RA under the recessive model (AA versus AG?+?GG, P?=?7.15?×?10^?3, Pc?=?1.43?×?10^?2). The frequency of the minor allele G of AIRE rs760426 polymorphism was higher in patients compared with controls (47.8 % versus 42.1 %), and this deviation showed a trend towards significant level (P?=?0.06, Pc?=?0.12). The association between the minor allele G of AIRE rs760426 polymorphism with RA risk under the dominant model and the recessive model revealed that significant evidence was detected under the recessive model (GG versus GA?+?AA, P?=?0.02, Pc?=?0.04). Our results indicated that AIRE rs2075876 and rs760426 polymorphisms were involved in the genetic background of RA in the Chinese population.     

Preservation of gray matter volume in multiple sclerosis patients with the Met allele of the rs6265 (Val66Met) SNP of brain-derived neurotrophic factor

To investigate the association of the rs6265 (Val66Met) single nucleotide polymorphism (SNP) of brain-derived neurotrophic factor (BDNF) with brain morphometry and functional status as measured by quantitative magnetic resonance imaging (MRI) and neurocognitive testing in multiple sclerosis (MS) patients. BDNF is released by neurons and by immune cells in MS brain. The rs6265 SNP variation of BDNF causes substitution of valine (Val) for methionine (Met) and interferes with activity-dependent BDNF secretion. A total of 209 treated MS patients (161 females; 48 males) underwent clinical brain MRI and were genotyped for the BDNF rs6265 Val66Met SNP. A subset of 108 patients had neurocognitive testing for processing speed, memory and executive function. The MRI measurements included T2 and T1-lesion volume (LV); normalized brain volume measures of whole brain (WB) volume, white and gray matter volume (NWMV and NGMV) and the diffusion-weighted imaging measure of WB mean parenchyma diffusivity (MPD). The Met66 allele status was positively associated with NGMV (P = 0.015, standardized beta = 0.15) and negatively associated with T2-LV (P = 0.041, standardized beta = -0.14). There were no significant associations between Met66 allele status and T1-LV, NWMV or MPD. On the Paced Serial Addition Test (PASAT), a trend (P = 0.057) favoring the Met66 allele group was observed. There were no significant associations between Met66 allele status and other neurocognitive measures. The BDNF Met66 allele is associated with lower damage as evidenced by measurement of NGMV and T2-LV in MS patients.     

Association between Val66Met polymorphism of Brain-Derived Neurotrophic Factor (BDNF) gene and a deficiency of colour vision in alcohol-dependent male patients

Brain-derived neurotrophic factor (BDNF) is a protein encoded, in humans, by BDNF gene on chromosome 11. BDNF protects adult neurons and promotes growth and differentiation during ontogenetic development but the nature and magnitude of its effects could be influenced by functional polymorphisms. The BDNF polymorphism Val66Met (rs6265) has been studied in the context of etiology of mental diseases including alcoholism. Alcoholism - a complex disorder known to be linked to several genes - has multiple manifestations, including sensory deficits such as those affecting vision. In the present study we examined a relationship between the Val66Met polymorphism, alcohol dependence and colour vision deficiency (CVD) in 167 alcohol-dependent men and 289 control male subjects. Statistical analysis revealed that almost half (about 48%) of the alcohol dependent men had a CVD. In addition we found that CVD was significantly associated (P=0.005) with the Val66Met polymorphism. The A allele containing 66Met promotes BDNF expression and this may protect humans against CVD induced by long-term excessive alcohol intake. The present findings indicate that alcohol-induced CVD does not depend solely on excessive alcohol consumption but is significantly influenced by genetic predisposition in the form of a specific BDNF polymorphism.     

The brain-derived neurotrophic-factor (BDNF) val66met polymorphism is associated with geriatric depression: a meta-analysis

Depression has been associated with reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. Genetic association studies of the BDNF Val66Met polymorphism (rs6265) in geriatric depression have produced inconsistent results. A meta-analysis of studies was conducted to compare the frequency of the BDNF Val66Met variant between cases with geriatric depression and age-matched controls. A total of five studies involving 523 cases with geriatric depression and 1,220 psychiatrically healthy controls was included. Met allele carriers had an increased risk for geriatric depression when compared to Val/Val homozygotes (P = 0.004, OR = 1.48, 95% CI = 1.13-1.93). Our findings suggest the BDNF Met allele may confer increased risk for depression as individual age.     

Meta-analysis reveals no association of the Val66Met polymorphism of brain-derived neurotrophic factor with either schizophrenia or bipolar disorder

BACKGROUND: A long-term controversy exists on whether or not major psychotic disorders can be discretely divided into two groups, for example, schizophrenia and bipolar disorder. Many genes and polymorphisms have been studied for a role in both disorders, including the Val66Met (also known as rs 6265 or G196A) variant of brain-derived neurotrophic factor (BDNF). Many case-control association studies have been performed to see if BDNF could serve as a useful clinical diagnostic biomarker for schizophrenia or bipolar disorder, but results have been equivocal. OBJECTIVE: To determine, by meta-analysis, if the Val66Met polymorphism of BDNF influences risk for either schizophrenia, bipolar disorder, or both. METHODS: We searched Pubmed, Medline, and PsycInfo using keywords including Val66Met, Rs6265, G196A, BDNF, schizophrenia, and bipolar disorder. A total of 13 studies for schizophrenia and 11 studies for bipolar disorder were combined by random-effects meta-analysis. MAIN RESULTS: The pooled results from the schizophrenia sample (2955 patients; 4035 controls) and the bipolar disorder sample (3143 patients; 6347 controls) indicated lack of significance with either of the two psychoses, with pooled odds ratios of 1.00 (P=0.944) and 0.95 (P=0.161), respectively. CONCLUSION: Although there are some limitations on the study, our results indicate there is a lack of association between the Val66Met polymorphism and either of the two psychoses. A larger sample size, and evaluation of more single-nucleotide polymorphisms are needed to obtain more robust and conclusive findings regarding the relationship between the BDNF gene and psychosis.     

Computed tomography analysis of the association between the SH2B1 rs7498665 single-nucleotide polymorphism and visceral fat area

Visceral fat accumulation has an important role in increasing morbidity and mortality rate by increasing the risk of developing several metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension. New genetic loci that contribute to the development of obesity have been identified by genome-wide association studies in Caucasian populations. We genotyped 1279 Japanese subjects (556 men and 723 women), who underwent computed tomography (CT) for measuring visceral fat area (VFA) and subcutaneous fat area (SFA), for the following single-nucleotide polymorphisms (SNPs): NEGR1 rs2815752, SEC16B rs10913469, TMEM18 rs6548238, ETV5 rs7647305, GNPDA2 rs10938397, BDNF rs6265 and rs925946, MTCH2 rs10838738, SH2B1 rs7498665, MAF rs1424233, and KCTD15 rs29941 and rs11084753. In the additive model, none of the SNPs were significantly associated with body mass index (BMI). The SH2B1 rs7498665 risk allele was found to be significantly associated with VFA (P=0.00047) but not with BMI or SFA. When the analysis was performed in men and women separately, no significant associations with VFA were observed (P=0.0099 in men and P=0.022 in women). None of the other SNPs were significantly associated with SFA. Our results suggest that there is a VFA-specific genetic factor and that a polymorphism in the SH2B1 gene influences the risk of visceral fat accumulation.     

A polymorphism in the CCL2 chemokine gene is associated with asthma risk: a case-control and a family study in Tunisia

Asthma is a complex genetic disorder characterized by chronic airway inflammation. We hypothesized that genetic polymorphisms in chemokines and their receptors alter leukocyte mobilization and may thus influence the risk and severity of childhood asthma. Distributions of the chemokine CCL2-2578G, CCL2-927C, CCR2-V64I, CX3CR1-V249I and CX3CR1-T280M receptor polymorphisms were examined in a case-control study of 121 children with asthma and 226 age-matched healthy controls and then replicated in a family study of 99 simplex families (297 individuals). The case-control study revealed that the CCL2-2578G allele was less frequent in children with than in those without asthma (P=0.0012). No association with asthma was found for the CCL2-927, CCR2 or CX3CR1 polymorphisms. The finding in the family study that the CCL2-2578G allele was transmitted less often by heterozygous parents to their children with asthma (P=0.0016) confirms the association of CCL2-2578G with asthma risk. Biochemical studies indicated that plasma CCL2 concentrations were higher in both patients (P=0.0214) and controls (P=0.001) carrying the G allele than in subjects with other polymorphisms. Both case-control and family-based studies suggest a protective effect of allele CCL2-2578G in Tunisian asthmatic children.     

Combining spatial and temporal information to explore resting-state networks changes in abstinent heroin-dependent individuals

Majority of previous heroin fMRI studies focused on abnormal brain function in heroin-dependent individuals. However, few fMRI studies focused on the resting-state abnormalities in heroin-dependent individuals and assessed the relationship between the resting-state functional connectivity changes and duration of heroin use. In the present study, discrete cosine transform (DCT) was employed to explore spatial distribution of low frequency BOLD oscillations in heroin-dependent individuals and healthy subjects during resting-state; meanwhile resting-state functional connectivity analysis was used to investigate the temporal signatures of overlapping brain regions obtained in DCT analysis among these two groups. Main finding of the present study is that the default mode network (DMN) and rostral anterior cingulate cortex (rACC) network of heroin-dependent individuals were changed compared with healthy subjects. More importantly, these changes negatively correlated with duration of heroin use. These resting-state functional abnormalites in heroin-dependent individuals provided evidence for abnormal functional organization in heroin-dependent individuals, such as functional impairments in decision-making and inhibitory control.     

Genetic association between PIK3CA gene and oral squamous cell carcinoma: a case control study conducted in Chongqing,China

PIK3CA has been shown to be involved in many malignant tumors. This study was designed to determine the expression level of PIK3CA in oral squamous cell carcinoma (OSCC) and the association of gene polymorphisms of PIK3CA with OSCC in Chinese population. The expression of PIK3CA was detected by real-time PCR in tumor and pericarcinomatous tissues of 10 OSCC patients. Nine single-nucleotide polymorphisms (SNPs) of PIK3CA (rs1607237, rs17849079, rs2677764, rs2699887, rs4855094, rs4975596, rs6443624, rs7651265 and rs7736074) in blood of 113 OSCC patients and 184 normal controls were genotyped using matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) assay. The gene expression of PIK3CA was significantly higher in tumor tissues of OSCC patients than that in pericarcinomatous tissues (P = 0.012). An increased frequency of the C allele of PIK3CA rs1607237 was observed in OSCC patients as compared with controls; However, the significance was lost after Bonferroni correction (P = 0.048, p_c = 0.576). In further stratification analysis, although the frequencies of PIK3CA rs4975596 A allele in male patients and rs1607237 C allele in female patients were increased (P = 0.032, P = 0.020, respectively), the significance was also missing when Bonferroni correction was performed (P _c = 0.384, (P _c = 0.24, respectively). The prevalence of other SNPs of PIK3CA did not differ between OSCC patients and controls. The expression of PIK3CA was increased in OSCC tumors; however, none of the nine tested SNPs of PIK3CA was associated with susceptibility to OSCC in the studied population.