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 20 years or older and 10.3 million Americans aged 60 years or older 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.
|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|
|Sung, Yun J (see original citation for additional authors) (2018) A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. Am J Hum Genet 102:375-400|
|Dutta, Diptavo; Scott, Laura; Boehnke, Michael et al. (2018) Multi-SKAT: General framework to test for rare-variant association with multiple phenotypes. Genet Epidemiol :|
|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|
|Ray, Debashree; Boehnke, Michael (2018) Methods for meta-analysis of multiple traits using GWAS summary statistics. Genet Epidemiol 42:134-145|
|Mahajan, Anubha (see original citation for additional authors) (2018) Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes. Nat Genet 50:559-571|
|Turcot, Valérie (see original citation for additional authors) (2018) Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nat Genet 50:26-41|
|Liu, Dajiang J (see original citation for additional authors) (2017) Exome-wide association study of plasma lipids in >300,000 individuals. Nat Genet 49:1758-1766|
Showing the most recent 10 out of 121 publications