A nondescript gene that no scientist has studied before determines why some people gain more weight than others. A new study of nearly 40,000 Europeans found that people with mutations in both of their copies of the gene known as FTO are 70 percent more likely to be obese than those with regular copies of the gene. Researchers says that identifying a genetic basis for obesity could lead to novel treatments for the increasingly prevalent condition blamed for life-threatening heart disease and type 2 diabetes, among other disorders.
"Approximately one sixth of the population will have two copies of the variant and that will result in them being three kilograms [6.6 pounds] heavier than the one third of the population who do not have any copies of the variant," says geneticist Andrew Hattersley of the Peninsula Medical School in Exeter, England. "[This] is a genetic variant which is involved in the regulation of weight."
Other genes, such as GAD, ENPP1 and, most recently, INSIG2, have been put forward as playing a role in the genetics of obesity but subsequent research has not borne that out. FTO first came to light when researchers compared the genomes of 1,924 Britons who had type 2 diabetes with those of 2,938 healthy peers and found a correlation in those who had the mutated gene and extra fat.
To ensure the accuracy of that finding, the researchers then culled even more DNA samples from more than 38,750 people, ranging from English adults to Finnish children, to see if FTO variations affected a wide variety of people. "Regardless of your age, your weight, this effect was seen in all those populations," says Timothy Frayling, a geneticist at Peninsula and lead author of the study published in Science online.
The variants of the gene correlate with increases in a person's body mass index (BMI)—a measure of weight versus height. By this index, a person is overweight if his or her BMI reaches 25 kilograms per meter2 and obese if it rises above 30 kilograms per meter2, or roughly 213 pounds for someone who is six feet tall. (Some very muscular people can have high BMI with no health risks.) If a study participant had two copies of mutant FTO, scientists found they had 1.67 times the risk of being obese using this measure. The gene is associated with both higher weight (regardless of differences in height) as well as wider waists and thicker concentrations of fat mass.
FTO itself is an unstudied gene in an unidentified pathway. In other words, scientists basically have no idea what it does. It was originally discovered as part of the genome of a mutant mouse with a fused toe, hence the FT at the beginning of its name. "The gene which has been implicated, FTO, is a gene about which we know very little," admits co-author Mark McCarthy of the University of Oxford. "It has not been implicated in obesity before."
Obesity is on the rise worldwide, correlated with gains in affluence. According to a recent study in JAMA The Journal of the American Medical Association, nearly 100 million men, women and children in the U.S. alone are considered obese. "This particular genetic variant would play a role in about 20 percent of those," Hattersley says. "The genetics is the same as it was 100 years ago when we had far less obesity. So you can never underestimate the effects of lifestyle."
McCarthy says that FTO is unlikely to be the only gene involved in obesity. "This gene alone is not going to explain why some people are 30 or 40 or 50 kilograms [65 to 110 pounds] heavier than other people living in the same town, same street or exposed to the same environment," he says. But obesity appears to be highly heritable, according to recent studies in identical twins. "It's a very complicated mix of genes and environment—and teasing them apart is not very easy," he adds. "Not least because some of the things that you think of as environmental, for example, food preference or the choice to exercise a lot or a little, there's quite a bit of evidence that those themselves are under some genetic control."