The prevalence of obesity continues to rise, along with its metabolic consequences including diabetes, dyslipidemia, hypertension, fatty liver disease, heart disease, and a host of other morbidities. A clear understanding of the genetic architecture of adiposity and its correlated metabolic traits can identify important targets for intervention, either behavioral or pharmaceutical. Significant progress was achieved in the last 4 years of our project in identifying hundreds of common variants associated with adiposity, regional fat distribution, and ectopic fat across 3 major ethnicities;identifying interactions wit physical activity, smoking, gender, and age;identifying pleiotropic loci accounting for the correlated architecture with metabolic traits;and bioinformatic identification of important pathways, tissue specificities, and predicted cellular / organismal functions. In this renewal application, we propose to continue to expand our understanding of the genetic underpinnings of adiposity traits, specifically, body mass index (BMI), measures of centralized obesity (waist- to-hip ratio adjusted for BMI (WHRaBMI) and CT assessed abdominal fat volumes by focusing on rare variation measured by whole exome and whole genome sequencing, carrying out detailed bioinformatic annotation of our findings including predicted functional significance, regulatory function, and pathways using publicly available knowledge databases, and leveraging our collaboration with ENCODE investigators. Finally, we propose to carry out functional mapping and evaluation of our discoveries in humans in a Drosophila model of adiposity and diet-induced diabetes. We will interrogate GWAS-identified genomic regions, by assessing the effect of knock-downs and knock-outs of functional elements (genes, regulatory loci) in those regions on Drosophila adiposity and metabolic phenotypes. This functional mapping will identify genes in the regions of association that influence adiposity traits, providing gene targets for investigation in the human sequence resource. Our basis of operation is within the CHARGE consortium with its outstanding resources and investigators, and with our established collaboration with other consortia, in particular, GIANT. These powerful approaches for discovery, annotation, and screening for functional significance will allow us to expand our knowledge and understanding of the genetic architecture of obesity with the potential to identify pathways / targets amenable to pharmaceutical or behavioral intervention.
The prevalence of obesity continues to rise, along with its metabolic consequences including diabetes, dyslipidemia, hypertension, fatty liver disease, heart disease, and a host of other morbidities. A clear understanding of the genetic architecture of adiposity and its correlated metabolic traits can identify important targets for intervention, either behavioral or pharmaceutical. In this project, we will extend our genetic search from common variants and haplotypes to less frequent / rare variants assessed by chip array or sequencing. The unique information from family studies will be useful in identifying linked regions harboring rare trait variants, search for segregating major genes for obesity, and modeling parent-of-origin effects. All findings will be deeply annotated using a wide variety of knowledge databases, notably those from ENCODE. Finally, we will use an experimental system - Drosophila melanogaster - to carry out functional mapping in associated genomic regions, and to extend our knowledge of the effect of adiposity genes as a function of sex and developmental stage. We anticipate these combined approaches will allow us to continue to expand our knowledge of the genetic architecture of adiposity traits in humans.
|KilpelÃ¤inen, Tuomas O; Carli, Jayne F Martin; Skowronski, Alicja A et al. (2016) Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels. Nat Commun 7:10494|
|(2016) New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk. Nat Commun 7:10495|
|Olfson, E; Saccone, N L; Johnson, E O et al. (2016) Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans. Mol Psychiatry 21:601-7|
|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|
|Wang, Shuai; Zhao, Jing Hua; An, Ping et al. (2016) General Framework for Meta-Analysis of Haplotype Association Tests. Genet Epidemiol 40:244-52|
|CHARGE Consortium Hematology Working Group (2016) Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits. Nat Genet 48:867-76|
|(2016) Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function. Nat Commun 7:10023|
|Zanoni, Paolo; Khetarpal, Sumeet A; Larach, Daniel B et al. (2016) Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Science 351:1166-71|
|Gomez, Felicia; Wang, Lihua; Abel, Haley et al. (2015) Admixture mapping of coronary artery calcification in African Americans from the NHLBI family heart study. BMC Genet 16:42|
|Nettleton, Jennifer A; Follis, Jack L; Ngwa, Julius S et al. (2015) Gene Ã— dietary pattern interactions in obesity: analysis of up to 68 317 adults of European ancestry. Hum Mol Genet 24:4728-38|
Showing the most recent 10 out of 45 publications