Contribution of rare DNA variants to the risk of metabolic disorders and to the level of associated metabolic traits

Aims: In this proposal, based on our data in a French population, we aim to confirm in the UK Biobank association signals between specific DNA variants and genetic regions, and the risk of various metabolic disorders.
Scientific rationale: Diabetes affects 420 million patients worldwide and that number will increase to 700 million by 2030. Diabetes is the sixth leading cause of mortality. Type 2 diabetes (T2D) represents more than 90% of all diabetes cases. Diabetes is a complex genetic disorder, with 72% of heritability. The worldwide prevalence of obesity nearly tripled between 1975 and now. Such as T2D, obesity is highly heritable (~70% heritability). Two billion people are currently overweight, and their co-morbidities represent a major medical burden and challenge of the health care system. Obesity and T2D are leading causes of kidney diseases, which happens in many patients with T2D and/or obesity. Many of these patients will progress to end-stage renal disease requiring dialysis. Large international studies including those using the UK Biobank have identified one thousand DNA regions associated with T2D risk, obesity, kidney diseases, or associated with lipid traits. However, they still only explain ~20% of disease heritability. In 2012, we demonstrated the contribution to T2D risk of rare deleterious mutations affecting the melatonin receptor (melatonin being a key controller of the day/night clock). Since then, many studies have highlighted the contribution to common disease of rare mutations impairing important protein of metabolism. We have recently sequenced the genome of 10,000 French individuals with T2D, obesity, kidney diseases and normal controls and identified many mutations of potential interest. We would like to use the UK Biobank to verify and expand our data.
Project duration: 5 years
Public health impact: This project should lead to the identification of new genes and mechanisms involved in the development of metabolic disorders as the first stage towards the establishment of the 21st century 4P Precision Medicine that should be Predictive, Preventive, Personalized and Participatory.