Abstract
Obesity is a condition of excess body fat that causes or exacerbates several major public health problems. Common obesity is a polygenic disorder arising from the interaction of multiple genetic and environmental factors. Extensive studies have been conducted to decipher the genetic basis of human obesity. These studies, mainly using the linkage and association approaches, have achieved limited success and inconsistent/inconclusive results have accumulated. Although a number of factors may contribute to this situation, the most important reason is that most of the previous genetic studies on obesity lack sufficient statistical power due to small sample sizes and non- robust approaches employed. In this project, I conducted a whole-genome linkage scan for obesity in a large sample of 79 multiplex Caucasian pedigrees comprising 1,816 subjects. The obesity phenotypes studied include body mass index (BMI), fat mass, percentage fat mass (PFM), and lean mass. By performing variance component linkage analyses, I identified several promising genomic regions (including lp36, 2q36, 19q 13, 20p 12-q 13, etc) that may harbor quantitative trait loci (QTLs) contributing to obesity risk. The significance of some of these regions was corroborated by the findings from earlier other studies. In addition, I tested a promising candidate gene, leptin receptor (LEPR), for association with obesity phenotypes in a separate large sample of 405 Caucasian nuclear families comprising 1,873 subjects. LEPR is a strong candidate gene with both positional and functional importance to obesity. The LEPR gene is located at the genomic region lp showing reproducible linkage in the whole-genome linkage scans and LEPR is highly involved in food intake and energy homeostasis. In order to obtain robust association results, I employed the family-based transmission disequilibrium test (TDT), which is immune to population stratification, a potential confounding factor in association studies. The results showed that the LEPR gene polymorphisms contribute to variation in obesity phenotypes in Caucasians. Finally, based on my experience in genetic studies of obesity and on a comprehensive survey of the literature in the field, I addressed major issues that may cause the inconsistent/inconclusive results. The studies presented here delineated further the genetic basis of obesity and highlighted the importance of powerful study design and robust analytical approaches in genetic mapping studies of obesity