Type 2 diabetes (T2D) is a major cause of morbidity and mortality in the USA and worldwide. While disease prevalence varies with age, gender, and population, in 2007 an estimated 23.5 million Americans (10.7%) age 20 years or older and 12.2 million Americans (23.1%) age 60 years or older suffered from diabetes. Substantial evidence exists supporting a genetic component in the etiology of T2D and T2D-related quantitative traits (QTs). Our overall goal is to identify genetic variants that predispose to T2D and that are responsible for variability in T2D-related QTs. In the current proposal we seek to build on our recent successes, particularly identification of loci associated with T2D and selected QTs, by moving from locus to gene to determine the specific causal genes responsible for these association signals. Although some loci identified by genome-wide association (GWA) studies strongly suggest a nearby gene of likely diabetes relevance, numerous robustly replicated association signals do not contain obvious links to underlying genes or known T2D pathways. Furthermore, while currently funded deep resequencing and GWA studies of lower frequency variants will suggest many candidate causal T2D variants, functional studies are required to determine which variants have a biological effect. Specifically, we will test risk variants identified from deep T2D resequencing using follow-up association studies in >28,000 samples, determine the metabolic and functional consequences of T2D- and QT-associated rare potentially causal variants, and identify the most likely candidate causal genes and biological mechanisms at T2D- and QT-associated loci using gene knockdown and over expression studies. The proposed project combines outstanding resources of well- characterized samples with expertise in functional, genome, and statistical analysis. Successful identification of genes and variants underlying risk of T2D and related QTs has the potential to reduce the impact of the current T2D epidemic by supporting identification of novel treatments, enabling better targeting of preventive and therapeutic approaches, and providing more accurate T2D risk prediction.
Type 2 diabetes is a leading cause of morbidity and mortality in both men and women worldwide. Type 2 diabetes and plasma concentrations of glucose have a strong inherited basis, and recent studies have revealed previously unsuspected genes associated with these traits. The proposed work will validate novel genes that influence diabetes, determine how DNA variants influence gene function, and may provide targets for new therapies.
|Simon, Jeremy M; Davis, James P; Lee, Saangyoung E et al. (2016) Alterations to chromatin in intestinal macrophages link IL-10 deficiency to inappropriate inflammatory responses. Eur J Immunol 46:1912-25|
|Walford, Geoffrey A; Gustafsson, Stefan; Rybin, Denis et al. (2016) Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci. Diabetes 65:3200-11|
|(2016) New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk. Nat Commun 7:10495|
|Johnson, Amy R; Qin, Yuanyuan; Cozzo, Alyssa J et al. (2016) Metabolic reprogramming through fatty acid transport protein 1 (FATP1) regulates macrophage inflammatory potential and adipose inflammation. Mol Metab 5:506-26|
|(2016) The genetic architecture of type 2 diabetes. Nature 536:41-7|
|Schick, Ursula M; Jain, Deepti; Hodonsky, Chani J et al. (2016) Genome-wide Association Study of Platelet Count Identifies Ancestry-Specific Loci in Hispanic/Latino Americans. Am J Hum Genet 98:229-42|
|Scott, Laura J; Erdos, Michael R; Huyghe, Jeroen R et al. (2016) The genetic regulatory signature of type 2 diabetes in human skeletal muscle. Nat Commun 7:11764|
|Horikoshi, Momoko; Pasquali, Lorenzo; Wiltshire, Steven et al. (2016) Transancestral fine-mapping of four type 2 diabetes susceptibility loci highlights potential causal regulatory mechanisms. Hum Mol Genet 25:2070-2081|
|RodrÃguez, Alejandra; Gonzalez, Luis; Ko, Arthur et al. (2016) Molecular Characterization of the Lipid Genome-Wide Association Study Signal on Chromosome 18q11.2 Implicates HNF4A-Mediated Regulation of the TMEM241 Gene. Arterioscler Thromb Vasc Biol 36:1350-5|
|Wessel, Jennifer; Chu, Audrey Y; Willems, Sara M et al. (2015) Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. Nat Commun 6:5897|
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