ABSTRACT
BACKGROUND: Microtubule-associated protein tau (MAPT) has been associated with several neurodegenerative disorders including forms of parkinsonism and Parkinson disease (PD). We evaluated the association of the MAPT region with PD in a large cohort of familial PD cases recruited by the GenePD Study. In addition, postmortem brain samples from patients with PD and neurologically normal controls were used to evaluate whether the expression of the 3-repeat and 4-repeat isoforms of MAPT, and neighboring genes Saitohin (STH) and KIAA1267, are altered in PD cerebellum. METHODS: Twenty-one single-nucleotide polymorphisms (SNPs) in the region of MAPT on chromosome 17q21 were genotyped in the GenePD Study. Single SNPs and haplotypes, including the H1 haplotype, were evaluated for association to PD. Relative quantification of gene expression was performed using real-time RT-PCR. RESULTS: After adjusting for multiple comparisons, SNP rs1800547 was significantly associated with PD affection. While the H1 haplotype was associated with a significantly increased risk for PD, a novel H1 subhaplotype was identified that predicted a greater increased risk for PD. The expression of 4-repeat MAPT, STH, and KIAA1267 was significantly increased in PD brains relative to controls. No difference in expression was observed for 3-repeat MAPT. CONCLUSIONS: This study supports a role for MAPT in the pathogenesis of familial and idiopathic Parkinson disease (PD). Interestingly, the results of the gene expression studies suggest that other genes in the vicinity of MAPT, specifically STH and KIAA1267, may also have a role in PD and suggest complex effects for the genes in this region on PD risk.
Subject(s)
Gene Expression/genetics , Genetic Predisposition to Disease/genetics , Genetic Variation/genetics , Parkinson Disease/genetics , tau Proteins/genetics , Aged , Brain/metabolism , Brain/pathology , Chromosomes, Human, Pair 17/genetics , Cohort Studies , DNA Mutational Analysis , DNA Repeat Expansion/genetics , Female , Genetic Testing , Genotype , Haplotypes/genetics , Humans , Male , Middle Aged , Parkinson Disease/metabolism , Parkinson Disease/pathology , Polymorphism, Single Nucleotide/geneticsABSTRACT
OBJECTIVE: The NHLBI Family Heart Study (FHS) genome-wide linkage scan identified a region of chromosome 7q with a logarithm of odds score of 4.9 for body mass index (BMI). DESIGN: We report the results of fine mapping the linkage peak using 1020 single nucleotide polymorphisms (SNPs) to test for association to obesity in families exhibiting linkage to chromosome 7. Association observed in linked families (284 obese cases/381 controls) was examined in an independent set of unrelated FHS participants (172 obese cases/308 controls) to validate the observed association. Two dichotomous obesity phenotypes were studied based on clinical BMI cutoffs and the sex-specific distribution of both BMI and leptin levels. RESULTS: Using a P-value of 0.01 as criteria for association in the linked families, a P-value of 0.05 as criteria for association in the unrelated sample, and requiring consistency in the direction of the effect of the minor allele between the two samples, we identified two coding SNPs in the NYD-SP18 gene with minor alleles increasing the risk of obesity. Adjustment for exercise, smoking and FTO genotype did not influence the result in linked families, but improved the result in the unrelated sample. Carrying a minor allele of the nonsynonymous SNP rs6971091 conferred an odds ratio of at least 2 for obesity defined by both BMI and leptin levels. CONCLUSION: The effect of the NYD-SP18 SNP on obesity was larger than the effect of FTO in FHS families. Publicly available results from genome-wide association studies support the association between NYD-SP18 and BMI. The NYD-SP18 gene is described as testes development related, but little is known about the gene's function or the mechanism by which it may influence risk for obesity.
Subject(s)
Genetic Linkage , Obesity/genetics , Polymorphism, Single Nucleotide/genetics , Body Mass Index , Chromosome Mapping , Chromosomes, Human, Pair 7/genetics , Epidemiologic Methods , Female , Gene Expression/genetics , Genotype , Humans , Leptin/metabolism , Male , Middle AgedABSTRACT
The traditional approach to the study of biology employs small-scale experimentation that results in the description of a molecular sequence of known function or relevance. In the era of the genome the reverse is true, as large-scale cloning and gene sequencing come first, followed by the use of computational methods to systematically determine gene function and regulation. The overarching goal of this new approach is to translate the knowledge learned from a systematic, global analysis of genomic data into a complete understanding of biology. For investigators who study shock, the specific goal is to increase understanding of the adaptive response to injury at the level of the entire genome. This review describes our initial experience using DNA microarrays to profile stress-induced changes in gene expression. We conclude that efforts to apply genomics to the study of injury are best coordinated by multi-disciplinary groups, because of the extensive expertise required.
