This is a Shannon Award providing partial support for the research projects that fall short of the assigned institute's funding range but are in the margin of excellence. The Shannon Award is intended to provide support to test the feasibility of the approach; develop further tests and refine research techniques; perform secondary analysis of available data sets; or conduct discrete projects that can demonstrate the PI's research capabilities or lend additional weight to an already meritorious application. The abstract below is taken from the original document submitted by the principal investigator. This proposal builds upon years 1-3 of our investigation into the genetics of morbid obesity in Utah pedigrees. The first three years of the currently funded grant were to identify, recruit and screen first degree relatives of 75 morbidly obese probands defined as being 100 or more pounds over ideal weight. At the end of year 2, we have screened 54 morbidly obese probands and 364 of their relatives in families with at least two morbidly obese first degree relatives. Through outside supplemental funding, an additional 75 sibships will have been screened (58 screened to date) with at least two morbidly obese siblings. By the start of this proposed continuation grant, we will have screened a total of 150 families with two or more morbidly obese first degree relatives. We have shown that morbid obesity is very familial (50% of all probands have a first degree relative with morbid obesity) and that offspring of morbidly obese parents have about a 2.6 increased risk of becoming morbidly obese themselves. We have also shown that there is sufficient genetic heterogeneity, temporal trends, and/or environmental confounding in the expression of morbid obesity that traditional, model-dependent genetic segregation and linkage analyses will probably not be successful in identifying the genes related to the development of morbid obesity. We have stored white cells from each of these families in preparation for this continuation proposal.
The specific aim of this proposal is to identify and map genes linked or associated with morbid obesity in Utah Caucasian families and in the Northern Ute Indian Tribe. We will expand 50 of the screened Caucasian pedigrees out to the cousins of the proband and their offspring in order to obtain 10 or more morbidly obese subjects per pedigree. Pilot studies on these pedigrees and long experience with pedigree expansion have indicated this is entirely feasible. We will screen an equal number of Ute Indians and their families (approximately 250 families). All registered Ute Indians living on the reservation in Northern Utah will be recruited (approximately 1700 adults). Candidate genes suggested in the literature, followed by a general genome search for linked genes, will proceed for both racial groups using markers spanning the genome at an average of 10 cM. With 10 or more affected persons in each of 50 Caucasian pedigrees, we will have power to detect linkage of a marker to a morbid obesity gene within a single pedigree if certain assumptions are met. This methodology will provide a tremendous advantage by removing inter-pedigree heterogeneity. To detect association with the trait locus, flanking polymorphisms to linked markers will be identified so that the genes may be phenotypically characterized to suggest pathophysiologic mechanisms of action. Investigation of environmental effects on the expression of measured phenotypes by genotype will be done to suggest the most beneficial ways to approach treatment of morbid obesity for a particular genetic defect.
