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.

Public Health Relevance

PROJECT NARRATIVE 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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
Genetics of Health and Disease Study Section (GHD)
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Mckeon, Catherine T
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Teslovich, Tanya M; Kim, Daniel Seung; Yin, Xianyong et al. (2018) Identification of seven novel loci associated with amino acid levels using single-variant and gene-based tests in 8545 Finnish men from the METSIM study. Hum Mol Genet 27:1664-1674
Kycia, Ina; Wolford, Brooke N; Huyghe, Jeroen R et al. (2018) A Common Type 2 Diabetes Risk Variant Potentiates Activity of an Evolutionarily Conserved Islet Stretch Enhancer and Increases C2CD4A and C2CD4B Expression. Am J Hum Genet 102:620-635
Pan, David Z; Garske, Kristina M; Alvarez, Marcus et al. (2018) Integration of human adipocyte chromosomal interactions with adipose gene expression prioritizes obesity-related genes from GWAS. Nat Commun 9:1512
Latva-Rasku, Aino; Honka, Miikka-Juhani; Stan?áková, Alena et al. (2018) A Partial Loss-of-Function Variant in AKT2 Is Associated With Reduced Insulin-Mediated Glucose Uptake in Multiple Insulin-Sensitive Tissues: A Genotype-Based Callback Positron Emission Tomography Study. Diabetes 67:334-342
Roman, Tamara S; Mohlke, Karen L (2018) Functional genomics and assays of regulatory activity detect mechanisms at loci for lipid traits and coronary artery disease. Curr Opin Genet Dev 50:52-59
Manning, Alisa (see original citation for additional authors) (2017) A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk. Diabetes 66:2019-2032
Civelek, Mete; Wu, Ying; Pan, Calvin et al. (2017) Genetic Regulation of Adipose Gene Expression and Cardio-Metabolic Traits. Am J Hum Genet 100:428-443
Davis, James P; Huyghe, Jeroen R; Locke, Adam E et al. (2017) Common, low-frequency, and rare genetic variants associated with lipoprotein subclasses and triglyceride measures in Finnish men from the METSIM study. PLoS Genet 13:e1007079
Kraja, Aldi T; Cook, James P; Warren, Helen R et al. (2017) New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475?000 Individuals. Circ Cardiovasc Genet 10:
Roman, Tamara S; Cannon, Maren E; Vadlamudi, Swarooparani et al. (2017) A Type 2 Diabetes-Associated Functional Regulatory Variant in a Pancreatic Islet Enhancer at the ADCY5 Locus. Diabetes 66:2521-2530

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