Genetics of Polygenic Obesity

In the UK obesity (defined by a Body Mass Index 30kg/m2) is nearing epidemic proportions, with estimates of 1/3 of the population being affected within only a few years. Obesity predisposes to type 2 diabetes, coronary artery disease, osteoarthritis and some cancers leading to a significant reduction in life expectancy, especially in the young obese. Childhood obesity now affects 20-30% of children in the 5-10 years old age group. Although bad nutrition and sedentary lifestyle play a major role in this recent epidemics, severe and early onset forms of obesity both have a strong genetic basis and result from the cumulative effects of DNA variation in individuals living within an ?obesogenic? environment. In other words, genetically predisposed children are the first and most affected victims of our deleterious way of life. Identifying obesity and associated diabetes genes and risk bimarkers will provide vital information for the prevention and treatment of the condition, resulting in significant improvements in the quality of life and productivity in the UK population.

Twin and family studies have demonstrated the contribution of genetic factors to severe obesity, a life-threatening condition affecting 1-5% of the world population. However, apart from rare monogenic forms of obesity, its genetic basis is not well understood. Family genome scans have revealed multiple obesity linkage peaks, several being clearly replicated, and recently positional candidates for obesity have been reported by us and others.
Our first aim is an in-depth, analysis of genetic variation in linked chromosomal regions overlapping from at least three independent obesity studies and our own data. We will initially genotype 2,800 French subjects using 12,000 SNPs on a customised Illumina Infinium BeadChip, covering 58Mb (overall SNP density 1/4.8Kb). In addition to Hapmap-based tag SNPs, rarer SNPs with MAF 2% will be chosen within genes, and in conserved and regulatory intergenic regions. The next stages include confirmation of the most promising SNP associations in an additional 4,200 case/control subjects, followed by extended genotyping around replicated positively-associated loci in 7,000 case/control subjects and in 1,400 family subjects.
The second aim is the elucidation of the role of genes causing monogenic obesity in polygenic obesity. We have preliminary evidence for association of tagged SNPs in PCSK1, BBS genes, SIM1 and LEPR with common obesity and we aim to take this work further.
The third aim is the evaluation of the functional effects of validated obesity-associated SNPs, their contribution to the disease risk in the North European general population ( 15,000 subjects) and in type-2 diabetes subjects ( 15000 subjects). We aim to examine how T2D develops in the context of obesity, because we have recently done for adiponectin and ENPP1/PC-1. We will take advantage of the extensive metabolic phenotyping of our very obese cohorts (especially children) and their families to investigate the contribution of obesity genes found in aim 1 and 2 to ?diabesity? and the associated metabolic abnormalities.
The likelihood of success for the proposed project is high due to its high numbers of subjects, including familial severe obesity, the extensive metabolic phenotyping, the targeted high SNP density analysis allowed by the initial selection of best linked regions, access to the latest generation of SNP microarrays, and the expertise of the applicants in complex trait genetics and obesity physiology. It should provide new insights into the molecular determinants of severe obesity and should contribute to the understanding and improved reduction of the associated T2D risk.