A new breakthrough from the Genetic Investigation of Anthropometric Traits consortium, which includes many public health researchers from the University of North Carolina at Chapel Hill, identifies multiple genetic variants associated with how the body regulates and distributes body-fat tissue. The new findings broaden the understanding of how genes can predispose certain individuals to obesity.
The GIANT Consortium is a major international collaboration of more than 275 scientists that seeks to identify genetic sites that affect human body size and shape, including height and measures of obesity.
Kari E. North, professor of epidemiology at the University of North Carolina at Chapel Hill Gillings School of Global Public Health, is joint lead author of the new study, “Protein-Coding Variants Implicate Novel Genes Related to Lipid Homeostasis 1 Contributing to Body Fat Distribution,” published February 18 in Nature Genetics.
Other co-authors from the UNC Gillings School include assistant professor Kristin Young, assistant professor Misa Graff, and postdoctoral fellow Heather Highland, all in the UNC Gillings School’s department of epidemiology.
Identifying the genetic variants associated with obesity is central to developing targeted interventions that can reduce the risk of chronic illnesses, such as hypertension, type 2 diabetes, and heart disease, to which obesity contributes in significant ways. Genome-wide association studies previously identified 49 loci, or positions along a chromosome where the related genetic variants are located, that predispose individuals to a higher waist-to-hip ratio, which is a way to assess body-fat distribution. Lower values of WHR are associated with lower incidence of these diseases.
In this study, with a specific focus on coding variation, the team found 24 coding loci – 15 common and nine rare – along the chromosomes of individuals that predispose to higher WHR. Further analysis revealed pathways and gene sets that influenced not only metabolism but also the regulation of body fat tissue, bone growth and adiponectin, a hormone that controls glucose levels and breaks down fat.
The team also performed functional studies across other organisms and identified two genes that were associated with a significant increase in triglyceride levels and body fat across species.
“For the first time, we were able to examine, on a large scale, how low-frequency and rare variants influence body fat distribution,” said Kari E. North. “These variants are rarer in the population, but the effects they have on individuals are much larger, possibly making them more clinically relevant.”
Another major finding from this study is the importance of lipid metabolism to bodyfat distribution, which could lead to a better understanding of how obesity causes downstream diseases such as Type 2 diabetes and cardiovascular disease.
“A better understanding of the genetic underpinnings of body fat distribution may lead to better treatments for obesity and the cascade of downstream diseases obesity also impacts, for example type 2 diabetes and heart disease” North said.
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Other lead authors include Anne E. Justice, former UNC Gillings School postdoctoral fellow, now assistant professor of biomedical and translational informatics in the Geisinger Health System; Cecilia M. Lindgren, professor of genomic endocrinology and metabolism in the University of Oxford (U.K.) Nuffield Department of Medicine; and Ruth J.F. Loos, Charles Bronfman Professor in Personalized Medicine at Mt. Sinai’s Icahn School of Medicine.
About the University of North Carolina at Chapel Hill
The University of North Carolina at Chapel Hill, the nation’s first public university, is a global higher education leader known for innovative teaching, research and public service. A member of the prestigious Association of American Universities, Carolina regularly ranks as the best value for academic quality in U.S. public higher education. Now in its third century, the University offers 74 bachelor’s, 104 master’s, 65 doctorate and seven professional degree programs through 14 schools including the College of Arts & Sciences. Every day, faculty, staff and students shape their teaching, research and public service to meet North Carolina’s most pressing needs in every region and all 100 counties. Carolina’s nearly 330,000 alumni live in all 50 states, the District of Columbia, US Territories and 161 countries. Over 178,000 live in North Carolina.
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