Type 2 diabetes (T2D) is a major cause of morbidity and mortality in the USA and worldwide. While disease prevalence varies with age, sex, and population, it is estimated that in 2005, 20.6 million Americans aged e20 years and 10.3 million Americans aged e60 years suffered from T2D. Similar rates of T2D have been observed in Finland. The incidence and prevalence of T2D are increasing in the USA and worldwide. In the USA alone, it is estimated that medical expenditures due to diabetes totaled $132 billion in 2002, ~10% of all USA 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 its causes and new treatments. There is substantial evidence of a genetic component in the etiology of T2D and T2D-related quantitative traits (QTs). 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 current T2D epidemic by supporting identification of novel drugs and therapies, enabling better targeting of preventive and therapeutic approaches, and providing more accurate T2D risk prediction. In this proposal, we seek to build on our successes of the last five years, particularly the initial findings of our genome-wide association studies of T2D and related QTs. Specifically, we will (1) increase substantially our available sample of well-phenotyped study subjects, (2) obtain tissue samples (fat, muscle, skin) and carry out functional assays on an extensively studied subset of our study subjects using these tissues and the wider array of tissues made possible by the directed differentiation of induced pluripotent stem cell (iPS) lines into precursor cell lineages towards but not limited to the generation of islet-like and hepatocyte-like tissues, (3) continue and expand on our current genome-wide analyses to identify additional T2D and T2D- related-QT loci by using our existing Finnish samples, samples newly-obtained during this project period, and continued joint and/or meta-analysis with collaborators, and (4) fine map and identify predisposing variants in the T2D and QT loci we have discovered or will discover, assess the allelic spectrum of relevant variants, and assess the predictive power of identified variants. 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 this study will be useful in the study of other complex genetic diseases.
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 and related traits 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.
|Zillikens, M Carola; Demissie, Serkalem; Hsu, Yi-Hsiang et al. (2017) Large meta-analysis of genome-wide association studies identifies five loci for lean body mass. Nat Commun 8:80|
|Varshney, Arushi; Scott, Laura J; Welch, Ryan P et al. (2017) Genetic regulatory signatures underlying islet gene expression and type 2 diabetes. Proc Natl Acad Sci U S A 114:2301-2306|
|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|
|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|
|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|
|Estes, Jason P; Rice, John D; Li, Shi et al. (2017) Meta-analysis of gene-environment interaction exploiting gene-environment independence across multiple case-control studies. Stat Med 36:3895-3909|
|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:|
|Scott, Robert A; Scott, Laura J; Mägi, Reedik et al. (2017) An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans. Diabetes 66:2888-2902|
|Cannon, Maren E; Duan, Qing; Wu, Ying et al. (2017) Trans-ancestry Fine Mapping and Molecular Assays Identify Regulatory Variants at the ANGPTL8 HDL-C GWAS Locus. G3 (Bethesda) 7:3217-3227|
|Beck, Andrew; Luedtke, Alexander; Liu, Keli et al. (2017) A POWERFUL METHOD FOR INCLUDING GENOTYPE UNCERTAINTY IN TESTS OF HARDY-WEINBERG EQUILIBRIUM. Pac Symp Biocomput 22:368-379|
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