"Failure to elucidate Type 2 Diabetes (T2D) physiology frustrates efforts to improve therapeutics. Although GWAS has identified 40 T2D genes, mostly expressed in pancreatic beta-cells, this explains no more than 10% of T2D inheritance. Up to 5% of T2D patients have dominantly inherited maturity-onset diabetes of the young (MODY), characterized by beta-cell dysfunction. Elucidating the genetics of familial early-onset T2D, using Whole-Exome Sequencing (WES) can bring breakthroughs in understanding insulin secretion physiology. DNA methylation, particularly in insulin sensitive tissues may also contribute to T2D. Newly-developed genome-wide methylation arrays can be used to identify associations with these epigenetic elements and T2D. In the proposed project, GEPIDIAB, I will take advantage of our MODY family DNA collection and multi-tissue biobank to 1: identify novel genetic causes of familial T2D (WP1) and 2: identify DNA methylation variation associated with T2D (WP2). In WP1, unresolved MODY-X families will be studied using WES to identify novel sequence changes. Then we will elucidate the cellular and metabolic mechanisms leading to beta-cell dysfunction caused by these novel mutations. In WP2, variation in DNA methylation at 450K sites across the genome will be studied in normoglycemic or diabetic bariatric surgery patients. Five separate tissue samples will be studied to identify tissue-specific variation, individual-specific variation and that which varies between cases and controls. We will explore whether there are T2D-specific patterns of methylation that are distinct from those in lean or obese normoglycemic subjects using bisulfite-whole genome sequencing. Overall, we will identify genome-wide methylation patterns that are cell and tissue-specific and disease-specific for five main tissues important in T2D. Together, genetics and epigenetics will complement each other to give a deeper understanding of both insulin deficiency and resistance."