Insights into metabolic health and disease from human genetic variants with major functional impact

The metabolism of macronutrients is controlled by the interplay of key organs, including liver, muscle and adipose tissue, orchestrated by hormonal and other signals. Disturbances in this network are associated with metabolic disease. We will build on our experience of using human genetics to illuminate mechanisms of insulin resistance to enhance understanding of the molecular control of human metabolism and its dysfunction in a range of diseases. We will use three independent but related approaches, each of which will exploit the power of rare non-synonymous human genetic variants with major functional impact. - We will study rare mutations significantly associated with metabolic phenotypes in large epidemiological studies. - We will identify and study rare, functionally significant mutations in genes that are known from studies in cells and animals to be important for metabolic control but where little information is currently available in humans. - We will study humans with rare extreme metabolic phenotypes; continuing to discover new genetic disorders and adding to knowledge of genotype/phenotype correlation. Each approach will involve the deep phenotyping of cells and humans. Any required extension of work into transgenic murine models will be the subject of a bid for additional, independent funding.