Discovery of gene deletions and duplications associated with severe obesity

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The rising prevalence of obesity is driven by environmental factors including the consumption of high-calorie foods and reduced levels of physical activity. However, family, twin, and adoption studies have consistently demonstrated that 40%–70% of the variation in body weight between people living in a given environment can be explained by genetic factors. Over the last 20 years, sequencing of candidate genes has led to the identification of monogenic forms of severe obesity which impact on the function of proteins involved in the central leptin-melanocortin pathway. These findings have paved the way for stratified therapy as seen with the treatment of congenital leptin deficiency by recombinant leptin. However, a substantial proportion of the heritability of human obesity has yet to be explained. The aim of this project is to explore the contribution of copy number variants (CNVs) to the development of severe obesity. This project builds on previous work where the Farooqi team demonstrated that deletion of chromosome 16p11.2 was associated with highly penetrant severe early-onset obesity and severe insulin resistance. As Sh2b1 knockout mice develop obesity and insulin resistance, it was suggested that disruption of the SH2B1 gene was responsible for the obesity of deletion carriers. This was verified in further human genetic studies which identified multiple missense mutations in SH2B1 which impaired signaling by molecules involved in energy balance. Together these findings have paved the way for patients with both deletions and coding mutations to be enrolled in clinical trials of MC4 Receptor agonist Setmelanotide. In this project, my aim is to discover new obesity genes by interrogating deletions and duplications in large cohorts (cohort of the Genetics of Obesity Study with ~7000 people) with severe obesity available in the Farooqi lab in Cambridge, UK. Finding the genes whose disruption causes obesity can provide a diagnosis for patients, insights into the mechanisms underlying the development of obesity and can identify targets for weight loss therapy.