Genetic and Physiological Studies in Obesity Associated Neuroendocrine Dysfunction. (360G-Wellcome-099038_Z_12_Z)

Disorders of weight regulation such as obesity and anorexia nervosa are frequently associated with neuroendocrine abnormalities. Genetic studies in patients with severe obesity have highlighted the role of the hypothalamic leptin-melanocortin pathway in energy homeostasis, reproduction, growth and thyroid hormone synthesis. We have identified 230 severely obese patients with central hypothyroidism and/or hypogonadism that cannot be explained by mutations in known genes. The aim of my proposal is to identify novel low frequency/rare genetic variants in these patients using whole exome sequencing (exon capture using the Agilent SureSelect system; sequencing using Illumina GII platform), to compare this data to data from 2000 patients with severe obesity alone and 4000 controls sequenced as part of the UK10K project. This work will be conducted in collaboration with Dr Ines Barroso at the Wellcome Trust Sanger Institute, where I will receive training in the analysis and interpretation of this data. I will investigate co-segregation of genetic variants in families, examine the impact of mutations on the functional properties of the proteins involved and conduct endocrine and metabolic studies. My long term aim is to make a significant contribution to the understanding of the mechanisms underlying the neuroendocrine consequences of obesity.