Why do some people stay slim while others develop obesity? Scientists have come closer to uncovering the genetic roots of obesity with new research that links 140 regions on the human genome to the disease.

Hundreds of researchers have undertaken the largest genomic study for obesity to date and together found at least 140 locations on the human genome that seem to relate to the disease, thereby tripling the previously known number of contributing genetic factors. Their findings, catalogued in two studies published Wednesday in the journal Nature, represent a growing body of knowledge about the role genes play in a disease that afflicts over a third of American adults – though other factors are still largely responsible for most cases.  

“This is a very important step to again broaden the horizon that obesity is a very complex issue,” David Lau, a physician and biochemist at University of Calgary, said. “When we're dealing with helping individuals lose weight, for instance, it would certainly be good to know their genotype.”

The researchers studied the body mass index and waist-to-hip ratio, two common measurements for obesity, of over 300,000 people to hone in on areas of the genome that seemed to strongly match up with either metric. The scientists who collaborated on this work were part of an international group called the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. The tedious work of parsing through the human genome has largely fallen to big groups such as this one with the ability to crunch huge data sets.

In the first study, the team studying body mass index found 97 regions that were likely to influence obesity, which is three times the number scientists had known of before the analysis. Elizabeth Speliotes, a study coauthor and specialist in bioinformatics at University of Michigan, thinks there are still thousands more such regions to be identified. She says their findings underscore the complexity of obesity as a disease that typically does not result from any single factor, genetic or otherwise.

“We wanted to understand obesity because obesity predisposes people to a lot of diseases,” Speliotes says. “Nobody really understands what causes obesity and how that leads to any of this metabolic disease, so we wanted to kind of get to the bottom of it.” As part of their analysis, her team identified regions that were related not only to obesity but also to health issues such as coronary artery disease and diabetes. Speliotes says examining these results in particular may provide clues to treating these illnesses at the source. 

Knowing about these connections, says Lau, may also someday help doctors make earlier and more specific diagnoses. “In the clinical sense, we often see the risk factors associated with obesity clustered together. An individual who is overweight or obese often has problems with increased risk of diabetes, so I think this particular study offers insight into why that might be,” he says. The authors also found a few strong correlations between obesity-related regions and the nervous system, which may provide clues into appetite control with further research.

Altogether, differences in those 97 regions accounted for less than 3 percent of variation in the body mass index of obese people, though. Expanding that result based on the authors’ projections for the regions which may still be undiscovered suggests that as much as 21 percent of variation in body mass index could originate from such regions.

Michael Skinner, an expert in epigenetics at Washington State University who was not involved in the study, says that focusing too much on the genetics of this affected group could obscure other true causes of the disease in the majority of the population. “What's causing obesity in the other 80 percent of the people?” he says. “Clearly, it's more than genetics. It would have been nice for them to broaden their investigation to at least mention the fact that other molecular factors like epigenetics may be equally important in terms of the onset of the disease,” he says.  

Skinner is also skeptical of the claim that the data will provide new paths forward for drug development. “The pharmaceutical industry has been trying to do this for 20 years and they have not been very successful because the disease is more complex than a set of mutations,” he says. He points out that the rate of obesity in the U.S. population has grown from less than 5 percent in the 1950s to more than a third of people today, which is faster than genetics alone can explain.  

In the second study in Nature, authors found 49 new regions that influence waist-to-hip ratio, often used to gauge how fat is stored in a person’s body.

“We're excited that there are so many,” Karen Mohlke, a coauthor and geneticist at University of North Carolina, says. “There is a lot of potential. Learning more about the genes responsible for these signals gives us many more opportunities to learn about the biology of how fat is distributed.” Roughly half of all people will carry a predisposition to obesity in each of the identified regions, and 19 of the markers had a greater effect in women than in men.

Mohlke is careful to emphasize the faint influence that these regions still seem to hold over a person’s likelihood of developing obesity, however. “I still think diet and exercise still play a major contribution to obesity, and genes are just one part in explaining the variation between people,” she says.