Type 2 diabetes (T2D) is characterized by insulin resistance and a relative deficiency of insulin secretion. T2D affects ~300 million people worldwide, >25 million in the US alone. 27% of Americans aged e60y suffer from T2D. T2D incidence and prevalence are increasing rapidly. In the US alone, medical costs of diabetes in 2012 were estimated at $176 billion, ~10% of US health care costs. The increasing number of younger T2D cases amplifies the socioeconomic impact of T2D and increases the urgency with which we must act to identify causes and new treatments. The goal of the Finland-United States Investigation of NIDDM Genetics (FUSION) study is to identify genetic variants that predispose to T2D and that are responsible for variability in T2D-related QTs. Improved understanding of the genetic basis of T2D and related QTs has the potential to reduce the impact of the T2D epidemic by supporting identification of novel drugs and therapies, enabling better targeting of drugs and therapies, and providing more accurate T2D risk prediction. In this proposal, we propose to (1) discover genetic loci and variants that influence T2D risk and variability in T2D-related QTs using association studies based on GWAS and sequence data with increasing emphasis on low-frequency and rare variants;(2) identify muscle and adipose tissue regulatory elements that increase risk of T2D and contribute to variation in related QTs by molecularly characterizing muscle and adipose biopsy samples from 324 individuals from across the glucose tolerance spectrum;and (3) identify the likely causal genes (and other functional units) and disease mechanisms at known T2D and QT loci through genotype-based callback detailed phenotyping in appropriately consented individuals with likely high-impact variants and in non-carrier """"""""controls."""""""" These efforts will contribute to improved understanding of the etiology of T2D, and have the potential to point the way to novel methods of treatment and prevention. Methods developed and lessons learned in the FUSION study will be useful in the study of other complex genetic diseases.
The rising prevalence of type 2 diabetes in the US and worldwide represents one of the major challenges to public health, and improved options for treatment and prevention are required. The present proposal builds on a longstanding and productive collaboration between researchers in the USA and Finland to understand the genetic basis of type 2 diabetes, and to use this information to reveal disease mechanisms. In this proposal, we will continue to identify genetic loci that influence risk to type 2 diabetes and variability in diabetes-related quantitative traits, and increasingly focus on identifying the causl variants, genes and other functional units, and the mechanisms by which they act.
|(2016) The genetic architecture of type 2 diabetes. Nature 536:41-7|
|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|
|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|
|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|
|Beck, Andrew; Luedtke, Alexander; Liu, Keli et al. (2016) A POWERFUL METHOD FOR INCLUDING GENOTYPE UNCERTAINTY IN TESTS OF HARDY-WEINBERG EQUILIBRIUM. Pac Symp Biocomput 22:368-379|
|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|
|Ma, Clement; Boehnke, Michael; Lee, Seunggeun et al. (2015) Evaluating the Calibration and Power of Three Gene-Based Association Tests of Rare Variants for the X Chromosome. Genet Epidemiol 39:499-508|
|(2015) Directional dominance on stature and cognition inÂ diverse human populations. Nature 523:459-62|
|Hwang, Joo-Yeon; Sim, Xueling; Wu, Ying et al. (2015) Genome-wide association meta-analysis identifies novel variants associated with fasting plasma glucose in East Asians. Diabetes 64:291-8|
|Zimmermann, E; Ã„ngquist, L H; Mirza, S S et al. (2015) Is the adiposity-associated FTO gene variant related to all-cause mortality independent of adiposity? Meta-analysis of data from 169,551 Caucasian adults. Obes Rev 16:327-40|
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