DNA Variations and Body Fat Distribution

Research published yesterday in Nature Genetics identifies genetic variants associated with obesity. The discovery could help with the development of targeted interventions that will be able to reduce the risks of obesity-related chronic illnesses.

Previously, genome-wide association studies have identified 49 loci that predispose individuals to a higher waist-to-hip ratio (WHR)—lower values of which are associated with lower incidence of these diseases. The present study focused specifically on coding variations, which have the potential to change the function of genes and their proteins.

“A better understanding of the genetic underpinnings of body fat distribution may lead to better treatments for this highly prevalent disease and the cascade of downstream diseases obesity also impacts,” says co–first author Anne Justice, former postdoctoral research at the University of North Carolina.

The team found 24 variations that predispose an individual to have a higher WHR. Further analysis revealed pathways 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 affect body fat accumulation across species.

“For the first time we were able to look at, on a large scale, how low-frequency and rare variants influence body fat distribution,” says senior author Cecilia Lindgren of the University of Oxford. “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 body ­fat distribution, which could lead to a better understanding of the causal influence of body fat distribution on downstream diseases like type 2 diabetes and cardiovascular disease.

“By knowing the genes that determine where excess fat will be stored—is it preferentially at the hips or more often at the waist—we are a step closer in understanding the biology that explains why some people, when they gain weight, are at risk of diabetes or cardiovascular disease, and why others are not,” says coauthor Ruth Loos of Mount Sinai.