PROJECT SUMMARY Ten percent of Americans suffer from diabetes, and in the next twenty years this number is projected to rise alongside disease related medical and societal costs. With the rise in prevalence of diabetes, early and precise diagnosis of diabetes subtypes are crucial for correct treatment and management of the disease. Maturity Onset Diabetes of the Young (MODY) is a rare familial monogenic form of diabetes that is caused by mutations in genes that are involved in the development and function of the pancreatic beta cell, and is often misdiagnosed as other diabetes subtypes. Mutations in the MODY genes not only cause MODY; mutations with less severe functional impairment have been shown to associate with type 2 diabetes (T2D) risk. Rare mutations have been difficult to study in a population-based setting because of how infrequently they present in the population. Historically, MODY has been studied in small family-based settings, likely biasing penetrance estimates and missing the complete phenotypic picture of the disease. The majority of MODY gene research has been done in European ancestry individuals, making it more difficult for non-European ancestry groups to access genetically-informed medicine. With the availability of large-scale and diverse biobanks, such as the Mount Sinai BioMe biobank and the UK Biobank (UKBB), it is now possible to study MODY gene mutations in a multi-ancestry population setting and assess their impact on MODY, T2D and related traits. To address the current knowledge gaps, we propose the following aims: Aim 1- To assess and interrogate known and novel MODY-causing mutations in individuals of diverse ancestry of the BioMe Biobank and UKBB. We will do this by examining the penetrance and expressivity of diabetes in MODY-causing mutations, broadening the clinical spectrum of MODY-causing mutations by applying phenome-wide association studies and identifying previously unknown MODY-causing mutations. We hypothesize that estimates of penetrance of known MODY-causing mutations will be more accurate than family based findings, the clinical spectrum of phenotypic associations for known MODY-causing mutations will be broadened, and we will discover novel MODY-causing mutations. We further aim to use the population-based biobanks to study the interplay between rare and common genetic variation and the association to T2D and related traits. We propose: Aim 2- To examine how individuals' risk of T2D is influenced by polygenic risk of T2D and mutations in MODY genes in BioMe and the UKBB. We will examine the impact of rare functionally damaging MODY gene mutations on T2D among individuals with low and high polygenic risk of T2D and glycemic traits. We hypothesize that carrying a damaging mutation will exacerbate the risk of T2D conferred by a polygenic burden. These steps toward understanding the impact of rare MODY gene mutations will facilitate our long-term objective to better understand the genetics of diabetes, ...