The long-term goal of this study is to identify genes for common forms of obesity. To this end, the investigators previously have completed studies of the epidemiology, heritability and mode of inheritance of obesity. They have developed a cohort of families having both extreme obesity and thinness, and they have used this sample to examine candidate genes and regions, and, more recently, in a genome scan searching for linkage to obesity phenotypes. In a first stage scan they identified several genomic regions of interest, particularly a 15 cM interval of 20ql3 which may contain one or more obesity related genes. They have separate support to expand their linkage sample and conduct another genome scan, which should refine existing linkages and identify additional candidate regions for the fine mapping studies proposed in this application. However, it is doubtful that linkage methods alone will permit a resolution finer than two to five cM, an interval too large for positional cloning. The investigators note that there is a need for a cohort of triads which can be used to fine map genes for obesity, including those identified through their own linkage studies as well as through reported linkage and association studies conducted by others. In the current application, the investigators propose to develop another cohort of families consisting of extremely obese individuals and their parents for family based linkage disequilibrium studies. Specifically, the investigators propose to do the following: 1) develop a sample of 600 triads (160 from currently supported studies and 440 newly collected triads) having extremely obese female probands (BMI >= 40 kg/m2) and two parents assessed for obesity phenotypes (one or more parents will be of normal weight with maximum lifetime BMI<27); 2) genotype triads for markers and candidate genes in regions of interest; 3) conduct family based transmission disequilibrium studies to fine map obesity related genes to within as few as 50 kb (0.05 cM). Although no support is requested for further aims, later studies will examine genes and expressed sequences in the identified regions using single strand conformational analysis and sequencing. Candidate sequences then will be tested for effects on obesity phenotypes through functional assays. The investigators note that obesity is an increasingly prevalent condition having serious consequences for health and quality of life. They further note that the identification of genes for common forms of obesity should lead to more individualized therapies and more effective prevention strategies.
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