UNC Health Talk

Largest ever genome-wide study on body fat and BMI strengthen genetic links to obesity

There are many reasons why two people with the same diets and exercise regimens can gain different amounts of weight and why fat becomes stored in different parts of their bodies. Now, an international collaboration of scientists, including several from the UNC School of Medicine and the UNC Gillings School of Global Public Health, has helped researchers home in on genetic reasons. Their findings were published in companion papers – genome-wide association studies – in the journal Nature.

Using the largest-ever set of genetic samples for the study of body fat distribution and body mass, the Genetic Investigation of Anthropometric Traits consortium of researchers – or GIANT – analyzed more than 300,000 genetic samples and found 89 new genetic locations across the genome that play roles in obesity, including body mass index and where fat is stored in the body. Previously, researchers including UNC’s Karen Mohlke, PhD, and Kari North, PhD, used a smaller sample size to find 48 loci in the genome.

Finding these locations is a necessary step toward pinpointing individual genes that play major roles in traits related to obesity. If researchers find that specific genetic variants or proteins have a significant effect on body shape and size, then these genes or proteins could become targets for therapeutic interventions.

“Obesity is a worldwide public health burden with no safe and long-term treatments available,” said North, professor of epidemiology at the UNC Gillings School of Global Public Health and senior co-author of one of the Nature papers. “Our development of new therapies is limited by our lack of knowledge of the underlying pathophysiology of obesity. One novel and exciting way to identify new biology is through the study of human genetics.”

By using new computational methods, the researchers identified the 89 new genetic locations that play roles in observable traits, including waist-to-hip circumference ratio and body mass index (BMI) – a measure of a person’s size based on weight and height.

“Obesity is a worldwide public health burden with no safe and long-term treatments available.”

Led by Mohlke, professor of genetics in the UNC School of Medicine, researchers found 33 new genetic locations associated with waist-to-hip ratio. Most people with waistlines larger than hip circumference have more visceral fat surrounding internal abdominal organs. People with this body type are more likely to have metabolic conditions, such as type-2 diabetes, and cardiovascular problems than are people with body fat deposited more in the hip area or distributed equally throughout the body.

These waist-to-hip genetic locations are associated with genes important for the creation of adipose tissue. The researchers determined that 19 of the “waist-to-hip” genetic locations had a stronger effect in women; one had a stronger effect in men.

“We now can point to new biological pathways in the brain that regulate body weight, and these pathways could be targets for more effective therapies.”

Identifying these genetic locations allows scientists to search for specific variants of genes that might play roles in obesity and body fat distribution. “We want to find out how genetic variants affect biology,” said Mohlke, who is also a member of the UNC Lineberger Comprehensive Cancer Center. “Could they affect the gene’s expression or function? Maybe a variant decreases or increases the gene’s function. That’s part of why we do these large GWAS studies – to generate potential avenues of research.”

Led by North, researchers found 56 new genetic locations important for high BMI, and many act in the brain.

“We now can point to new biological pathways in the brain that regulate body weight, likely through mechanisms such as appetite, and these pathways could be targets for more effective therapies,” North said. “Interestingly, the genetic locations associated with BMI are different from the biological locations that emerged from the parallel study on waist-hip ratio.”

Mohlke said it’s possible that some of these “obesity” genes could be part of novel biology that hasn’t been researched yet. Some of the genes could already be implicated in other aspects of human health. Researching their functions related to body fat and obesity could provide a better picture of the roles these genes play in a variety of diseases.

“That’s what part of my lab is now focused on,” Mohlke said. “We’ve found these associations; now let’s find the underlying genes to figure out how all of this works.”

Co-first authors include former UNC graduate student Damien Croteau-Chonka, PhD, now a research fellow at Harvard, and Anne Justice PhD, epidemiology postdoctoral fellow in North’s lab. Other UNC authors include Linda Adair, PhD, professor of nutrition, and current UNC School of Medicine graduate students Martin Buchkovich and Tamara Roman, both in Mohlke’s lab.

The National Institutes of Health was one of the funders of this international collaboration.