Millions of subtle variations in the human DNA sequence, or genome, hold the key to a host of conditions, from breast cancer to heart disease. Now, researchers say they can analyze such variations to predict who is most at risk of becoming obese.
The new genetic risk score provides the best DNA-based forecast yet for obesity, say other scientists who have reviewed the work. But they also warn that the score has serious limitations, as it only suggests a likely weight range—and a wide one—for each person. And because excess weight gain often kicks in early in life, physicians and parents would need to get the score for children early for it to make a difference.
To develop the new score, researchers used data from a previous genomewide study, which scoured the genomes of more than 300,000 people for 2.1 million genetic variants affecting body mass index (BMI), a ratio of a person’s height and weight often used as a proxy for obesity. Then, they compared that with the known weights and BMIs of those people, calculated the impact of each variant on BMI, and integrated that information into a single number, called a “polygenic risk score.”
Next, the researchers tested how accurately the score predicted BMI and obesity in some 300,000 additional individuals—from newborns to middle-aged people. Among the adults with the highest risk scores, 83% were overweight or obese, the researchers report today in Cell. But 17% of people with those scores had a BMI within the normal range, and 0.2% were underweight, they also note.
The adults with the highest risk scores weighed on average 13 kilograms more than those with the lowest scores, and they were 25 times as likely to be severely obese, or more than 45 kilograms overweight. “What’s striking is not just the weight,” says Sekar Kathiresan, a cardiologist and geneticist at Massachusetts General Hospital in Boston and the Broad Institute in Cambridge, Massachusetts, who led the study. “If you have a high risk score for obesity, you’re at high risk for heart attack, stroke, diabetes, hypertension, heart failure, and blood clots in the legs.”
Another surprising result is how early in life the impact of these scores becomes evident, says Nilanjan Chatterjee, a geneticist at Johns Hopkins University in Baltimore, Maryland. High- and low-risk individuals start to show significant differences in body weight at about 3 years of age; by the time kids turned 18, those with the highest risk weighed on average 12 kilograms more than those with the lowest—a gap similar to that seen among middle-aged people.
Spotting children with a high risk of obesity early could help parents and physicians intervene, Kathiresan says. But what kind of intervention should be put in place is still unclear. Others worry that people with a high genetic risk for obesity won’t be motivated to change their lifestyle, especially if they think that the chance of gaining extra weight is written in their DNA. “If you give an 8-year-old a genetic risk score, what do you expect them to do?” asks Cecile Janssens, an epidemiologist at Emory University in Atlanta. “They still have to go through puberty and all the college partying.”
Ruth Loos, a genetic epidemiologist at the Icahn School of Medicine at Mount Sinai in New York City, echoes this concern. People giving up and blaming their genetics, she says, is “the last thing we want as obesity researchers.”
Researchers also caution that because genetic risk scores so far have largely been generated and validated in data sets made up mainly of people of European descent, the extent to which they can be applied to people of other ethnicities might be limited. These risk scores for obesity are optimal for white people, and their predictive power will drop for other ethnic groups, Kathiresan says.
Loos adds that, because obesity is influenced by both genetic and environmental factors such as diet and exercise, genetic risk scores should be used in combination with other predictors such as family history. Knowing whether one or both parents are obese or were obese during childhood is important, because that could reflect the environment they’ve created for their children—the way they eat, and whether they’re physically active, she says. “Any score that captures genetic predisposition will never accurately predict future obesity. … You need to account for that environmental part.”