Type 2 diabetes (T2D) is a major cause of morbidity and mortality in the USA and worldwide. While T2D prevalence varies with age, sex, and population, it is estimated that in 2005, >20 million Americans suffered from T2D. The incidence and prevalence of T2D are increasing in the USA and worldwide. It is estimated that in the USA alone, medical expenditures due to diabetes totaled $132 billion in 2002, ~10% of all USA health care costs. There is substantial evidence of a genetic component in the etiology of T2D. The last three years have seen remarkable progress in our understanding of this genetic component, particularly in European-origin populations, with ~20 T2D loci now robustly confirmed. Despite these successes, much remains to be done as we seek to identify the causative variants at these loci, assess their relevance in non- European populations, and identify additional T2D variants in all ancestry groups. In this application, we seek to clarify further the complex genetic basis of T2D by participating in a cooperative study based on RFA-DK- 09-004: Multiethnic Study of Type 2 Diabetes Genes. We bring to this effort (a) a highly productive, well integrated team of researchers with a wealth of experience in all aspects of diabetes genetics research and particular expertise in statistical genetics, (b) demonstrated leadership in large-scale genetic studies including recent genome-wide association studies of T2D and related traits, (c) access to large, well- characterized samples of T2D cases and controls and cohorts representing European, Hispanic, and East Asian populations, and (d) strong collaborative relationships with multiple other T2D research groups. In this proposal, we seek to build on our recent successes to further our understanding of T2D genetics by gathering together DNA samples and phenotype data across the available cohorts, playing a key role in the analysis of sequence trace data, and carrying out fine mapping, re-sequencing, and follow up to identify T2D causative variants. Our efforts for this RFA will improve our understanding of T2D etiology, and have the potential to point the way to novel methods of prevention and treatment. Methods developed and lessons learned in this study will be useful in studies of other common diseases. RELEVANCE: Type 2 diabetes is a major cause of morbidity and mortality in the USA and worldwide, and its frequency and impact are increasing rapidly. Improved understanding of the genetic basis of type 2 diabetes has the potential to reduce the impact of the diabetes epidemic by supporting identification of novel drugs and therapies, enabling better targeting of preventive and therapeutic approaches, and providing more accurate risk prediction.