Genome-wide association (GWA) methods have now been successfully used to detect disease-related susceptibility genes numerous genetically complex disorders. In these studies, a critical element for success is that the sample size be large enough so that there is adequate power to detect genes with small effect sizes at a genome-wide significance level. As an example, type 2 diabetes, susceptibility genes with odds ratios of ~1.3 were detected with cohorts of ~15,000 cases and a comparable number of controls. For AD, preliminary GWA studies utilized samples of 1,000 cases or less have been performed. These studies have the power to detect modest effect loci but not the small effect genes typically found in the analysis of other complex disorders. The primary goals of this application are to: 1) Assemble enough AD cases and comparable elderly normal controls to detect small effect loci;2) Perform GWA studies using a high- density genotyping platform to detect small effect loci that contribute to AD susceptibility;3) Analyze a large familial AD collection using the same genotyping platform so that family-based methods can be applied to AD gene discovery;4) Provide a DNA, phenotype, and genotype resource of well- characterized AD cases, mild cognitive impaired (MCI) subjects, and controls for the genetics community to analyze. The cases, MCI subjects, and controls will be the approximately 16,500 subjects currently being studied by the 29 NIA-funded Alzheimer's Disease Centers (ADC's). Extensive phenotype data as a Uniform Data Set (UDS) for these subjects is in a centralized database (National Alzheimer Coordinating Center or NACC). DNA from these subjects will be deposited in the National Cell Repository for Alzheimer's Disease (NCRAD), an existing repository. A second cohort will be multiplex families with extensive phenotype data and DNA currently available from the NIMH Genetics Initiative repository. This study will make use of the infrastructure of the existing Alzheimer's Disease Genetics Consortium (ADGC) to coordinate that data from multiple GWA studies for subsequent meta and combined analysis of multiple AD GWA studies, and to provide investigators with AD GWA data for subsequent analysis.
Alzheimer's disease affects over 5 million people in the US costing the Federal Government over $100 billion dollars/year. Because our population is aging, in 2050, if the disease remains untreatable, there will be 16 million people in the US with AD costing $1 trillion dollars/year. Presently there are no methods of preventing AD or halting progression. Thus, more fundamental knowledge on disease mechanism is needed.
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