Discovery of gene deletions and duplications associated with severe obesity

肥胖率的上升是由环境因素推动的，包括高热量食物的消费和体力活动水平的减少。然而，家庭、双胞胎和收养研究一直表明，生活在特定环境中的人之间体重差异的40%-70%可以由遗传因素解释。在过去的20年里，候选基因的测序导致了严重肥胖的单基因形式的识别，这些形式影响了参与中枢瘦素-黑素皮质素途径的蛋白质的功能。这些发现为分层治疗铺平了道路，如重组瘦素治疗先天性瘦素缺乏症。然而，人类肥胖的遗传性中有很大一部分尚未得到解释。该项目的目的是探索拷贝数变异(CNV)在严重肥胖症发生中的作用。该项目建立在此前Farooqi团队证明染色体16p11.2缺失与高渗透性严重早发性肥胖症和严重胰岛素抵抗相关的工作基础上。随着Sh2b1基因敲除小鼠出现肥胖和胰岛素抵抗，有人认为SH2B1基因的破坏是导致缺失携带者肥胖的原因。这在进一步的人类遗传学研究中得到了证实，该研究发现了SH2B1的多个错义突变，该突变通过参与能量平衡的分子来破坏信号传递。总而言之，这些发现为既有缺失又有编码突变的患者参加MC4受体激动剂Setmelanoide的临床试验铺平了道路。在这个项目中，我的目标是通过询问英国剑桥Farooqi实验室提供的严重肥胖人群(肥胖遗传学研究队列中的约7000人)中的缺失和复制来发现新的肥胖基因。找到导致肥胖的基因可以为患者提供诊断，洞察肥胖发生的潜在机制，并确定减肥治疗的目标。

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.