A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia

An excess dopaminergic activity may be implicated in the etiology of schizophrenia. Our objective was to identify nucleotide variants in the 5' region of the dopamine D2 receptor gene (DRD2) and to clarify their effects on schizophrenia. We identified two polymorphisms, the A-241G and -141C Ins/Del, by examination of 259 bp in the 5'-flanking region and 249 bp of exon 1 of DRD2. Reporter constructs containing the -141C Del allele cloned into a luciferase reporter plasmid drove 21% (Y-79 cells) and 43% (293 cells) expression compared with the -141C Ins allele. In a case-control study, the -141C Del allele frequency was significantly lower in 260 schizophrenic patients than in 312 controls (OR = 0.60, 95%CI 0.44-0.81, P < 0.001). No significant association was found between the A-241G polymorphism and in vitro luciferase activity, or in allele frequency between the patients versus controls. These findings show that the -141C Ins/Del may be a functional polymorphism in the 5'-promoter region of DRD2 and may affect the susceptibility to schizophrenia.      

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism in schizophrenia is associated with age at onset and symptoms

The substantia nigra pars reticulata (SNR) plays important roles in movement and, in an age- and sex-dependent manner, in seizure control. GABAergic synaptic transmission is critical in both normal development and seizures. In many neuronal types it is excitatory early in development and later switches to the mature hyperpolarizing type. We assessed the time course of the switch of GABAA receptor-mediated postsynaptic currents (PSCs) in anterior SNR neurons of male and female developing rats using the gramicidin perforated patch clamp technique. The switch occurred in males around postnatal day (PN) 17 and in females around PN10. This sex dimorphism may play a role in several other recognized sex differences in the development of SNR and in its regulatory role in seizures.     

Interleukin-1B polymorphism is associated with age at onset of Alzheimer's disease

Interleukin-1alpha (IL-1alpha) and IL-1beta are two pro-inflammatory cytokines involved in the pathogenesis of Alzheimer's disease (AD). The genes coding for IL-1alpha (IL-1A) and for IL-1beta (IL-1B) are clustered in chromosome 2q14-2q14.2. In a previous work, we investigated the role of IL-1A promoter polymorphism (-889 position) in AD pathogenesis: IL-1A -889 TT genotype was associated with sporadic early onset AD. We now report the study on polymorphism of exon 5 IL-1B in position +3953, the nearest polymorphism to -889 IL-1A. We found that the genotype distribution of IL-1B +3953 varied significantly between patients with early and late onset of AD (P<0.0001). Patients carrying IL-1B +3953 CT or TT genotypes had 4 or 5 years anticipation of AD onset (P=0.0034; odds ratio for early onset, 3.01) and 7 years anticipation if they also carried the IL-1A -889 TT genotype (P<0.0001; odds ratio for early onset, 7.4). These data further support a role for inflammation-related genes in AD or indicate linkage disequilibrium with an unknown chromosome 2 locus.     

A functional polymorphism in the parkin gene promoter affects the age of onset of Parkinson's disease

Mutations in the parkin gene are the major cause of autosomal recessive early-onset forms of Parkinson's disease (PD). As reduced parkin expression might also affect the clinical course of idiopathic PD we investigated the effect of a low expressing allele in the parkin promoter region on the age at disease onset (AAO). Patients with PD (n=175) fulfilling standard diagnostic criteria were recruited by experienced neurologists at two movement disorders clinics in Sydney and Brisbane, Australia. DNA was extracted from whole blood and the -258 T/G polymorphism genotyped using PCR/RFLP. AAO effects were analysed using univariate ANOVA, binomial logistic regression modelling and Kaplan-Meier survival analysis. Subjects with the GG genotype (n=10, mean AAO=46.2+/-11.5 (S.D.) years) had a significantly lower mean AAO compared to the common TT genotype (n=104, mean AAO=56.1+/-12.7, p=0.02). There was no difference in mean AAO between the TT and TG individuals (n=61, mean AAO=55.3+/-11.6). Stratifying the sample by median AAO (55 years) revealed that the GG genotype was over-represented in the early-onset group (n=9, OR=18.6, 95% CI=1.41-245.3, p=0.03). We speculate that reduced expression of normal parkin protein may result in an early manifestation of PD symptoms.     

Interleukin-10 -1082 promoter polymorphism is associated with schizophrenia in a Han Chinese sib-pair study

The interleukin-10 (IL-10) gene has been identified as a susceptibility gene for schizophrenia in Caucasians. A previous case-control study conducted by our group revealed a weak association between polymorphism, -592C/A, of the IL-10 gene promoter and schizophrenia. Our present study was aimed at confirming the association of the IL-10 promoter with schizophrenia using 197 Han Chinese sib-pair families. A family-based association test (FBAT) and haplotype analysis was undertaken using the FBAT v1.5.5. The global TDT was significant for a different polymorphism, -1082G/A (chi2=13.16, P=0.000285) and that the allele -1082G was preferentially transmitted to schizophrenia-affected children. Furthermore, haplotype TDT analysis showed that haplotype "GCC" was significantly associated with the disease (chi2=8.1, P=0.00443). Our results also indicate that the IL-10 gene may play a significant role in the etiology of schizophrenia among Han Chinese.     

<Emphasis Type="Italic">Apolipoprotein E</Emphasis> polymorphism is associated with age of onset in schizophrenia

The aims of the study were to investigate the relationship between Apolipoprotein E (APOE) polymorphism, risk of schizophrenia, treatment response to conventional anti-psychotics, and age of onset in schizophrenia. The sample comprised 94 Finnish patients with a DSM-IV diagnosis of schizophrenia. Forty-three of the patients were good responders to conventional anti-psychotics and 51 were classified as non-responders. The control group consisted of 98 healthy blood donors. The APOE allele frequencies (2, 3, and 4) were 4.8, 72.3, and 22.9% in patients and 7.1, 75.0, and 17.9 in controls. None of the differences between groups were statistically significant. No association between treatment response and APOE genotype was found. Patients with APOE 4/4 genotype had a markedly lower age of onset compared with rest of the sample (p=0.0015), which remained significant when controlling for gender (p=0.02). There was an increasing linear trend between the number of 3 alleles (0, 1, or 2) and age of onset in schizophrenia (p=0.08). An inverse trend was found between the number of 4 alleles and age of onset (p=0.07). No relationship between APOE polymorphism and risk for schizophrenia was found. APOE 4/4 genotype may be associated with early onset schizophrenia. APOE 3 allele may function protectively in later onset in this disease.     

多巴胺受体D2型基因启动区多态性与精神分裂症关联研究

目的探讨湖北武汉地区汉族人群中多巴胺受体D2型基因(dopamine receptor D2, DRD2)启动区-141位点胞嘧啶插入/缺失多态性与精神分裂症的关联关系.方法应用聚合酶链反应-限制性片段长度多态性方法,对120例精神分裂症患者、100名健康对照者进行基因分型.对精神分裂症患者的 DRD2 -141位点胞嘧啶插入/缺失多态性进行了相关分析.结果 DRD2型基因启动区-141位点的等位基因、基因型频率在精神分裂症组与对照组之间的分布差异有统计学意义(P<0.05).在精神分裂症组中,-141C缺失的等位基因频率为0.11,对照组为0.18(比值比为0.55,95%可信区间为0.30～0.96,P <0.05).结论 -141位点胞嘧啶插入/缺失多态性非独立性地对精神分裂症与 DRD2基因的相关性产生修饰作用.-141位点胞嘧啶缺失可能是湖北武汉汉族精神分裂症患者的保护因素之一.     

The -295T-to-C promoter polymorphism of the IL-16 gene is associated with Crohn's disease

Recently, a T-to-C polymorphism at position -295 in the promoter region of the human interleukin-16 (IL-16) gene was reported. The expression of IL-16 is increased in inflammatory bowel disease, in particular in Crohn's disease. However, data concerning the IL-16 promoter polymorphism in inflammatory bowel disease are lacking. Thus, the current study aimed at the assessment of this polymorphism in Crohn's disease and ulcerative colitis. One hundred three patients with Crohn's disease, 100 patients with ulcerative colitis, and 120 healthy unrelated controls were genotyped for the promoter polymorphism. Furthermore, patients with Crohn's disease were stratified according to disease localization and the respective clinical phenotype (fistulizing, fibrostenotic, or inflammatory). The frequencies of the T allele (P < 0.01) and the TT genotype (P < 0.01) were significantly increased in patients with Crohn's disease compared to the controls, regardless of the disease phenotype or the site of intestinal involvement. An association with ulcerative colitis was not observed. Herein a new association between a promoter polymorphism of the IL-16 gene and Crohn's disease was observed and correlates with the previously described increased mucosal expression of IL-16 in inflammatory bowel disease.     

Association of six polymorphisms of the NOTCH4 gene with schizophrenia in the Japanese population.

The NOTCH4 gene is located at 6p21.3 and involved in the development and patterning of the central nervous systems. Recently, Wei and Hemmings [2000] observed that the gene was associated with schizophrenia. Subsequent to the report, several studies investigated the gene in schizophrenia, with controversial and inconclusive results. In the present study, we investigated six polymorphisms (SNPs 1-5 and a CTG repeat) of the gene in Japanese subjects with schizophrenia (n = 284) and the same number of controls. The polymorphisms include SNP5, which has been observed to be associated with schizophrenia in a Chinese population and two new SNPs 3-4 adjacent to SNP5, in addition to the SNPs 1-2 and the CTG repeat, which were suggested for the association with the disease in the previous study. As a result, no significant difference in genotypic distributions or allelic frequencies of the six polymorphisms of the gene was observed between the patients and the controls. Also, no significant difference was found in frequencies of haplotypes of the six polymorphisms between the patients and the controls. However, the distribution of SNP2 was significantly deviated from Hardy-Weinberg equilibrium in the patients (P = 0.000986), not in the controls, which could be a chance or due to an association of SNP2 with the disease. In conclusion, the present study provided no clear evidence for an association between the NOTCH4 gene and schizophrenia in the Japanese population.     

Estrogen receptor alpha gene polymorphism in schizophrenia: frequency, age at onset, symptomatology and prognosis

Schizophrenic disorders are equally distributed for both sexes; however, later onset, milder psychopathology and better outcome are associated with the female gender. This sex difference is thought to be partly due to the estrogen system. Recent studies have determined that estrogen receptor alpha subtype (ER alpha) genetic polymorphisms may affect the expression of ER alpha, and are associated with Alzheimer's disease. For this study, we investigated the association of ER alpha polymorphisms for 125 schizophrenic patients and 142 control subjects. No significant differences for genotype distribution or allele frequency were revealed comparing controls and schizophrenic patients. The ER alpha genotypes were not associated with onset age, psychiatric symptoms or outcome for schizophrenic cases. With new research highlighting the prominent role of sex hormones in neurological and psychological dysfunction, further study is needed to explore the genetic effect of the sex hormone receptor gene on susceptibility mental disorders and associations with different phenotypes.     

(CCTTT)n repeat polymorphism in the NOS2 gene promoter is associated with atopy.

BACKGROUND: Several studies have shown that nitric oxide (NO) plays a role in the regulation of the T(H)1/T(H)2 balance, indicating the potential for NO to contribute to the development of atopy and several other allergic diseases, including bronchial asthma. NO synthase 2 (NOS2) is critically involved in the synthesis of NO during several inflammatory states, and the gene encoding NOS2 is located at chromosome 17q11.2-q12, where 2 genome scans have identified a candidate locus for atopy and asthma. OBJECTIVE: The 14-repeat allele of the (CCTTT)(n) repeat polymorphism in the NOS2 promoter region is a powerful enhancer of promoter activity in reporter constructs in vitro. We tested whether this potentially functional allele in the NOS2 gene influences the development of atopy and asthma. METHODS: We studied a total of 497 unrelated Japanese subjects (141 nonatopic healthy controls, 102 atopic healthy controls, 56 nonatopic asthmatic subjects, and 198 atopic asthmatic subjects). The odds ratio (OR) was calculated for atopy and asthma in carriers of the 14-repeat allele through use of logistic regression models. Atopy was defined as a positive specific IgE level to at least 1 of 10 common inhaled allergens. RESULTS: The 14-repeat allele was inversely associated with atopy (OR = 0.42, P < .01). The association remained significant when the model was controlled for asthmatic status (OR = 0.36, P < .01). This allele, however, was associated neither with the development of asthma nor with total serum IgE levels. CONCLUSION: Our findings suggest that the (CCTTT)(n) repeat polymorphism in the promoter of the NOS2 gene that affects promoter activity is a risk factor for the development of atopy, and this genetic effect seems independent of asthma.     

精神分裂症白质损害与发病年龄的弥散张量成像研究

目的:应用弥散张量成像(DTI)比较精神分裂症患者脑白质与正常人群间的差异,并探究各向异性比值(FA)的改变与发病年龄之间的相关性。方法:纳入27例精神分裂症患者和29名性别、年龄及受教育程度相匹配的健康对照。两组研究对象均接受头颅磁共振检测。患者组按照发病年龄分为早发组(发病年龄18岁)和成年发病组(发病年龄≥18岁)。采用基于体素的分析方法,分别比较患者组和对照组、早发组和成年发病组之间FA值的差异,并在控制性别、病程和药物剂量影响的前提下,分析FA值与患者发病年龄的相关性。结果:与健康对照比较,患者组在右侧上纵束、右侧放射冠上部的FA值降低;患者组中早发组和成年发病组间FA值的差异无显著性。患者组FA值与发病年龄呈正相关的脑区包括右侧放射冠前部(r=0.70,P0.01)、右侧胼胝体膝部(r=0.65,P0.01);未发现呈负相关的脑区。结论:本研究提示精神分裂症患者右侧脑区上纵束及放射冠部位存在白质损害,发病年龄愈早,右侧放射冠及胼胝体膝部白质纤维的受损愈重。这对精神分裂症病理生理改变及脑结构异常的进一步研究具有提示作用。     

Correlation of tau gene polymorphism with age at onset of Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disease and its prevalence increases with age. The microtubule-associated protein tau (MAPT) is thought to be implicated in the pathogenesis of PD. Association of the MAPT H1 haplotype with PD in Caucasians has been extensively studied, however, the results were inconsistent. In this study, we investigated whether MAPT gene variants contribute to the pathogenesis process including the age at onset in Japanese PD. Promoter region of MAPT gene was analyzed to find polymorphisms in Japanese population. Two single nucleotide polymorphisms (SNPs), C-639T and Del-568TIns, in promoter region were found. C-639T was novel. Unlike Caucasians, the −226C and −45A alleles consisting of the H1 haplotype were monomorphic in Japanese population. Association analysis was performed using 240 PD and 191 controls in these SNPs. No significant association was observed between these SNPs and PD. Haplotype analysis also showed no significant association (P = 0.72). However, the age at onset showed significant correlation with the genotypes of Del-568TIns in PD samples when analyzed by Kendall rank correlation test (Kendall tau = −0.098, P = 0.0243). These results suggested that MAPT gene variants may modify the pathogenesis process of PD.     

Association study of a promoter polymorphism of UFD1L gene with schizophrenia

Schizophrenia or schizoaffective disorders are often found in patients affected by DiGeorge/velo-cardio-facial syndrome (DGS/VCFS) as a result of hemizygosity of chromosome 22q11.2. We evaluated the UFD1L gene, mapping within the DGS/VCFS region, as a potential candidate for schizophrenia susceptibility. UFD1L encodes for the ubiquitin fusion degradation 1 protein, which is expressed in the medial telencephalon during mouse development. Using case control, simplex families (trios), and functional studies, we provided evidence for association between schizophrenia and a single nucleotide functional polymorphism, -277A/G, located within the noncoding region upstream the first exon of the UFD1L gene. The results are supportive of UFD1L involvement in the neurodevelopmental origin of schizophrenia and contribute in delineating etiological and pathogenetic mechanism of the schizophrenia subtype related to 22q11.2 deletion syndrome.     

The -403 G-->A promoter polymorphism in the RANTES gene is associated with atopy and asthma

Asthma is a complex inflammatory condition often associated with bronchial hyperreactivity and atopy. Genetic and environmental factors are implicated and several candidate genes have been implicated. Of these, the chemokine RANTES is responsible for the recruitment of inflammatory cells such as eosinophils and T-lymphocytes. We have recently identified a polymorphism within the RANTES promoter (-403 G-->A) and have examined its role, using a PCR-RFLP assay, in the development of atopy and asthma in 201 Caucasian subjects. Atopic status was determined using skin prick testing and serum IgE levels. Severity of airway dysfunction was assessed using spirometric measurement (FEV1) and methacholine challenge (PC20). The -403 A allele was associated with an increased susceptibility to both atopy and asthma. Thus, the proportion of subjects carrying this allele was higher in each of atopic non-asthmatics, non-atopic asthmatics and atopic asthmatics compared with non-atopic, non-asthmatic controls. In particular, this allele was associated with skin test positivity but not IgE level. Homozygosity for the -403 A allele conferred a 6.5-fold increased risk of moderate/severe airway obstruction (FEV1 < or = 80% predicted), a marker for established asthma. Our data, whilst preliminary, indicate that the association of RANTES genotype with both atopy and asthma reflect independent effects, suggesting different mechanisms for the role of this chemokine in atopy and development of airway obstruction.     

Disruption of the neurexin 1 gene is associated with schizophrenia

Deletions within the neurexin 1 gene (NRXN1; 2p16.3) are associated with autism and have also been reported in two families with schizophrenia. We examined NRXN1, and the closely related NRXN2 and NRXN3 genes, for copy number variants (CNVs) in 2977 schizophrenia patients and 33 746 controls from seven European populations (Iceland, Finland, Norway, Germany, The Netherlands, Italy and UK) using microarray data. We found 66 deletions and 5 duplications in NRXN1, including a de novo deletion: 12 deletions and 2 duplications occurred in schizophrenia cases (0.47%) compared to 49 and 3 (0.15%) in controls. There was no common breakpoint and the CNVs varied from 18 to 420 kb. No CNVs were found in NRXN2 or NRXN3. We performed a Cochran-Mantel-Haenszel exact test to estimate association between all CNVs and schizophrenia (P = 0.13; OR = 1.73; 95% CI 0.81-3.50). Because the penetrance of NRXN1 CNVs may vary according to the level of functional impact on the gene, we next restricted the association analysis to CNVs that disrupt exons (0.24% of cases and 0.015% of controls). These were significantly associated with a high odds ratio (P = 0.0027; OR 8.97, 95% CI 1.8-51.9). We conclude that NRXN1 deletions affecting exons confer risk of schizophrenia.     

Tumor necrosis factor-alpha -308A/G polymorphism is associated with age at onset of Alzheimer's disease

Pro-inflammatory cytokines and acute-phase proteins play an important role in Alzheimer's disease (AD) neurodegeneration, and common polymorphisms of genes controlling their production have been shown to be associated with AD. Tumor necrosis factor (TNF)-alpha is an inflammatory cytokine involved in the local immune response occurring in the central nervous system of AD patients. Genetic variation could contribute to the risk of developing AD or influence the age at the onset of the disease. We genotyped 222 patients (152 women, 70 men; age range 60-87) and 240 non-demented age-matched healthy controls for TNF-alpha -308 G/A single nucleotide polymorphism (SNP). No significant differences were observed in genotyped frequencies between patients and controls, whereas carriers of -308A showed a significantly lower mean age at onset than non-carriers of this allele. This difference was more evident taking into account ApolipoproteinE (ApoE) status since the lowest age at onset was observed in patients carrying the -308ATNF+/APOE4+ genotypes. In conclusion, our data support previous suggestions that, at least in Caucasians, the TNF gene is a disease modifier gene in patients in which AD is rising, bringing to light the importance of genetic variation at the pro-inflammatory components in the progression of AD.