Mass General researchers have helped to develop a powerful new tool that could lead to new opportunities to understand and prevent obesity.

By analyzing millions of DNA variations in the human genome, researchers have developed a “polygenic score” for obesity, a quantitative tool that predicts an individual’s inherited risk for becoming overweight.

Amit V. Khera, MD
Amit V. Khera, MD

The researchers found that a genetic predisposition to obesity begins to appear in early childhood and is often clearly evident by early adulthood — suggesting an opportunity for early intervention.

“We’ve known for a long time that some people are born with DNA predisposing them to obesity,” says co-first author Amit V. Khera, MD, a clinician and researcher at the Massachusetts General Hospital Center for Genomic Medicine and an associate scientist at the Broad Institute. “Now, we can quantify those differences in a meaningful way, and potentially explore new routes for achieving better health.”

In addition to Dr. Khera, the research team was co-led by Mark Chaffin and Sekar Kathiresan, MD, of the Broad Institute of MIT and Harvard, Massachusetts General Hospital and Harvard Medical School.

The findings were published in the journal Cell.

Read more about obesity research and programs at Mass General:
Getting Ahead of Childhood Obesity
Obesity Research Sheds New Light On Weight Problems
Healthy Eating Key to MGH Diet Effort in Chelsea

Destigmatizing Obesity

Obesity is a major global health issue, often stigmatized as a disease related to poor lifestyle choices and lack of willpower. This stigma can create significant barriers to effective healthcare. However, quantifying a strong biological predisposition among many individuals who struggle with severe obesity could help to destigmatize the condition and offer new opportunities for prevention.

To develop the polygenic score, the researchers compiled data on the impact of more than 2.1 million places in the genome on body weight, gathered from the largest published genome-wide association study on obesity. New computational algorithms distilled that information into a single number for each individual. The team validated the scoring algorithm based on data from 119,951 individuals in the UK Biobank, and then used it to explore obesity in additional groups totaling more than 300,000 individuals from the UK Biobank, the Framingham Offspring and Coronary Artery Risk Development in Young Adults study, and the Avon Longitudinal Study of Parents and Children.

DNA Is Not Destiny

The polygenic scores for all study participants correlated with a clear difference in weight. The 10 percent of the adult population with the highest polygenic scores — corresponding to 32 million Americans — weighed nearly 30 pounds more on average than those with the lowest scores, and were 25 times as likely to be severely obese. They were also at increased risk for cardiometabolic diseases such as diabetes and coronary artery disease.

“Prevention strategies could be especially impactful early in life for these individuals.”

“A high polygenic score doesn’t necessarily mean someone is fated to become obese,” says Dr. Kathiresan, an institute member and director of the Cardiovascular Disease Initiative at the Broad Institute, director of Mass General’s Center for Genomic Medicine, and professor of medicine at Harvard Medical School.

“DNA is not destiny,” he adds. “We know that a healthy lifestyle can offset a genetic predisposition, although those with a high genetic risk likely have to work much harder to maintain a normal weight. Prevention strategies could be especially impactful early in life for these individuals.”