Global study finds new set of genes associated with body fat distribution and obesity

Oct 12 2010

Two major international studies looking at data from a quarter of a million people around the globe have found a new set of genes associated with body fat distribution and obesity. Researchers at 280 institutions worldwide, including Albert Einstein College of Medicine of Yeshiva University, conducted the studies. The research, published in the October 10 online edition of Nature Genetics, sheds light on the biological processes involved in body fat distribution, possibly leading to new ways of treating obesity.

"These studies open the door to better understanding the mechanisms that lead to the most harmful forms of obesity, which can result in heart attack, stroke and diabetes," said Robert Kaplan, Ph.D., professor of epidemiology & population health at Einstein and a co-author of the studies. "The findings provide important leads for researchers who are working to develop new medications to treat or prevent obesity."

In one study, researchers identified 13 new gene regions where variations in DNA sequence can be linked to a person's fat distribution—whether they store fat around the mid-section or below the waist. In the second study, researchers found 18 new genetic variations associated with increased susceptibility to obesity. The first study included data from almost 200,000 people, while the second study included data from nearly 250,000 people. Both studies were led by researchers at Oxford University and the Medical Research Council (MRC) Epidemiology Unit in Cambridge, England.

Using data from the large sample pool helped reveal genes that are exerting very subtle effects on body weight. "A lot of the genes we found were surprises," said Dr. Kaplan. "For every one of the new genes identified, we now can pose several new research questions to find out why it is associated with obesity."

The first study looked at a person's waist-to-hip ratio, which indicates a person's body shape. Someone who stores more fat around the waist (apple-shaped) is at greater risk of developing type 2 diabetes and heart disease, compared with someone who stores fat mainly in the thighs and buttocks (pear-shaped). The researchers note that while there are clear differences in body shape between men, who are more likely to be apple-shaped, and women, who are likelier to be pear-shaped, the mechanisms underlying these differences are not well understood. They found that genetic variations linked to where a person's body fat collects have a markedly stronger impact on women than on men. They also found that the genetic influences on body fat distribution are generally not the same as those involved in the risk of obesity.

The genes identified in the first study explain only about one percent of the variation in waist-to-hip ratios among different people. "But just because the percentage is very small, it doesn't mean that the finding isn't biologically important," Dr. Kaplan said. "We've learned in other areas of medicine that seemingly small influences can have a large impact, such as the correlation of high cholesterol to heart disease, for example. While high cholesterol doesn't account for a huge fraction of heart attack risk, we have been able to reduce the risk of heart attack in many patients by lowering cholesterol."

In the second study, the researchers examined the association between genes and body mass index (BMI), a measure of whether an individual's weight is healthy for a person of his or her height. An adult with a BMI of 25-29.9 is considered overweight, while a person with a BMI of 30 or greater is defined as obese. The study found 18 new genetic regions linked to BMI, bringing the known DNA variations linked to BMI to 32.

The study also revealed that a person of average height who inherited many of the "BMI-increasing" gene variants would weigh 15 to 20 pounds more than another person who inherited few of these variants. However, despite this large difference, the 32 confirmed genetic variations explain only 1.45% of the variation in people's BMIs. This suggests that a person's weight can be influenced by many other factors yet to be discovered, the researchers say.

"Clearly, genetics is not the whole story when it comes to obesity," Dr. Kaplan said. "The prevalence of obesity has skyrocketed in recent years, especially here in the Bronx, and our genes have not changed in that short period of time. Environmental factors, ranging from what we eat to how physically active we are, play a large role. But genetics are important because they may help us in terms of finding new obesity treatments, which so far have proven disappointing."

The studies were carried out by the GIANT (Genetic Investigation of Anthropometric Traits) consortium, an international collaboration of more than 400 scientists who receive funding support from many funding agencies worldwide.

The papers, "Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index" and "Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution," were published in the October 10 online edition of Nature Genetics.