This is an application for a competitive renewal of R01DK44073 to complete Phase III of a genetic study aimed at mapping and eventually identifying genes for human obesity. During Phases I-II, we accrued over 300 families segregating extreme obesity and normal weight. We completed 60 papers, including two genome scans. We detected linkage to several genomic regions and examined candidate genes and sequences within selected regions. We also completed mutation screening of candidate genes, genetic association studies, and linkage disequilibrium analyses. During Phase III we propose to conduct fine linkage and linkage disequilibrium mapping in a region of chromosome 12 that provided the strongest and most consistent support for linkage across obesity phenotypes and analytic methods in our most recent genome scan. The results meet the most conservative criteria for genome wide significance.
Specific Aim 1 : We will conduct fine linkage mapping studies for the peak linkage signal found in our second-generation genome scan on chromosome 12. We will use 305 families segregating extreme obesity and normal weight. We will conduct combined linkage and linkage disequilibrium studies of the same data. Our goal is to reduce the confidence interval by about 25-30% to approximately 8 Mb.
Specific Aim 2. Beginning in year 2 of the project, we will conduct linkage disequilibrium mapping studies using 500 proband-parent triads (collected in a separate project, R01DK56210, but with similar ascertainment criteria) for an 8 Mb interval of chromosome 12.
Specific Aim 3. We will identify up to 5 candidate genes or expressed sequences in close physical proximity to identified marker and screen polymorphisms for associations with obesity phenotypes. Obesity is an increasingly prevalent condition having serious consequences for health and quality of life. The identification of genes for common forms of obesity should lead to more individualized therapies and more effective prevention strategies. ? ?
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