A large international consortium has made significant inroads into uncovering the genetic basis of obesity, adding six new genetic variants to the two already linked to higher body mass index (BMI) in previous studies. Most of the newly discovered genes had never before been suspected of having a role in body weight and, curiously, many of the genes are active in the central nervous system, suggesting they may exert their effects via the brain. The study, from the Genetic Investigation of Anthropometric Traits (GIANT) consortium, appeared online in Nature Genetics on Dec. 14.
“One of the major insights to come out of this is a new window into the biology of obesity,” says Joel Hirschhorn of Children’s Hospital Boston and the Broad Institute of Harvard and MIT, who led the study together with researchers from the University of Michigan and research institutes in Oxford and Cambridge, U.K. “One of the interesting things is that the genes near these variants are all active in the central nervous system, suggesting that inherited variation in appetite regulation may have something to do with people’s predisposition to obesity.
The study used genetic information from more than 32,000 people of European ancestry, drawn from 15 genomewide association studies of BMI involving a total of 76 international research institutes. A large-scale statistical analysis comparing BMI data with about 2.4 million genetic variations, followed by validation of the most promising results in an additional 59,000 individuals, identified six new genetic variants associated with higher BMI. It also strongly confirmed a role for two genetic variants identified last year “near the FTO and MC4R genes” says Hirschhorn.
The effect of each individual variant was modest, ranging from 0.06 to 0.33 BMI units, and the paper estimates that the 1 percent of people with the most obesity-causing variants will be on average 10 pounds heavier than the 1 percent of people with the fewest variants and 4 pounds heavier than the typical person. Hirschhorn also points out that the GIANT consortium team is likely to have uncovered just a fraction of probably hundreds of genetic regions that each make small contributions to obesity — and that identifying new regions will require both larger studies and additional approaches.
The team also compared their results with those from another large genomewide association study of BMI, led by deCODE Genetics in Iceland. Where comparisons were possible, all of the variants identified by Hirschhorn and colleagues were strongly confirmed by data obtained by the deCODE group. (The deCODE results are described in an accompanying study published in the same issue of Nature Genetics.)
According to Elizabeth Speliotes of Massachusetts General Hospital, joint first author on the paper, it can be a major challenge to find genetic associations with strong enough statistical evidence to be certain of their validity. However, she says, “Thanks in part to the large group effort the regions we report are clearly and reproducibly associated with body mass index.”
The GIANT consortium is now performing large-scale studies to identify more genetic variants contributing to the risk of obesity in both adults and children. “The next round of studies will involve new collaborators and DNA from more than 100,000 people,” says Hirschhorn. “We also hope to do analyses to determine whether genetic variants have the same effects in different ethnic populations, in both genders, and in individuals with extreme obesity compared to overweight or normal-weight individuals.”
Family or twin studies have shown that genetic factors account for 40 to 70 percent of population variation in BMI. But while previous studies have identified “obesity genes” such as the LEP gene, which is mutated in people with leptin deficiency and causes severe obesity, little is known about the genetics underlying more common forms of weight dysregulation.
According to the World Health Organization (WHO), there are more than 1 billion overweight adults worldwide, and at least 300 million of them are obese (as defined by a BMI of 30 or above). But there are still no good treatments, and the need to uncover the biology underlying weight control is becoming increasingly urgent.
“At present, we’ve only identified regions that show natural genetic variations that influence body mass index,” says Speliotes, who is also a fellow at the Broad Institute and an instructor in medicine at Harvard Medical School. “As we learn more about what some of the genes in these regions do, we hope that these discoveries might suggest routes to new therapies for obesity.”