RESUMO
Malfunctioning of cyclin-dependent kinase 5 (CDK5) through aberrant proteolytic cleavage of its neuronal activators p35 and p39 is involved in neurodegeneration in Alzheimer's disease (AD) and other neurodegenerative brain diseases. By extensive genetic analysis of the genes encoding CDK5 (CDK5), p35 (CDK5R1) and p39 (CDK5R2), we excluded causal mutations in 70 familial early-onset AD patients. We performed an association study with five informative SNPs in CDK5 in two independent samples of early-onset AD patients and matched control individuals from The Netherlands and northern Sweden. Association was observed with g.149800G>C in intron 5 of CDK5, and a two times increased risk was observed in both patient samples for carriers of the C-allele. Our data are indicative for a role of the CDK5 molecular complex in the genetic etiology of early-onset AD, and suggest that a yet unknown functional variant in CDK5 or in a nearby gene might lead to increased susceptibility for early-onset AD.
Assuntos
Doença de Alzheimer/enzimologia , Doença de Alzheimer/genética , Quinases Ciclina-Dependentes/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Idoso , Quinase 5 Dependente de Ciclina , Análise Mutacional de DNA , Éxons/genética , Feminino , Frequência do Gene/genética , Testes Genéticos , Variação Genética/genética , Genótipo , Haplótipos , Humanos , Íntrons/genética , Masculino , Pessoa de Meia-Idade , Países Baixos , SuéciaRESUMO
Increasing amounts of data suggest that affective disorders might be related to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, one of the stress-response systems. Arginine vasopressin (AVP) influences several symptoms, relevant to affective disorders, notable memory processes, pain sensitivity, synchronization of biological rhythms and the timing and quality of REM sleep. We examined whether genetic variations in the AVP receptor 1b gene (AVPR1b) could be associated with increased susceptibility to affective disorders using a gene-based association analysis of single-nucleotide polymorphisms (SNPs). Five SNPs were identified in AVPR1b and genotyped in two well-diagnosed samples of patients with recurrent major depression and matched controls. In the Swedish sample, we observed significant allele (P=0.02) and genotype (P=0.01) association with SNP AVPR1b-s3, and in the Belgian sample, a borderline significant association with SNP AVPR1b-s5 (P=0.04). In both patient-control samples, the haplotype defined by alleles A-T-C-A-G for the AVPR1b-s SNPs s1-s2-s3-s4-s5 was significantly over-represented in controls compared to patients. Our data support a protective effect of this major haplotype for recurrent major depression.
Assuntos
Transtorno Depressivo/genética , Transtorno Depressivo/prevenção & controle , Polimorfismo de Nucleotídeo Único/genética , Receptores de Vasopressinas/genética , Idoso , Sequência de Bases , Bélgica , Feminino , Haplótipos , Humanos , Sistema Hipotálamo-Hipofisário/fisiologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Masculino , Sistema Hipófise-Suprarrenal/fisiologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Valores de Referência , SuéciaRESUMO
BACKGROUND: Conflicting results have been reported in previous association studies of the serotonin transporter promoter repeat length polymorphism (5-HTTLPR), seasonal affective disorder (SAD) and seasonality (seasonal variations in mood and behaviour). The aim of this study was to test for association in new case-control and population-based materials, and to perform a combined analysis of all published studies of 5-HTTLPR and SAD. METHOD: One hundred and forty-seven new SAD cases and 115 controls were genotyped for 5-HTTLPR and in total 464 patients and 414 controls were included in the pooled analysis. In addition, 226 individuals selected for unusually high or low seasonality scores from a population based material and 46 patients with non-seasonal depression were analysed. Different genetic models were tested and seasonality was analysed both as a qualitative (high v. low) and as a quantitative trait in the different sample sets. RESULTS: No association between 5-HTTLPR and SAD was found in the new case-control material, in the combined analysis of all samples, or when only including 316 patients with controls (N = 298) selected for low seasonality. A difference was detected between the population based high and low seasonality groups, when assuming a recessive effect of the short allele (20% and 10% short allele homozygotes, respectively, OR (95% CI): 2.24 (1.03-4.91)). Quantitative analysis of seasonality revealed no association with 5-HTTLPR in any sample set. CONCLUSIONS: These results do not suggest a major role of the short variant of 5-HTTLPR in susceptibility to SAD, but provide modest evidence for an effect on seasonality.
