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Genetic Obesity Risk From Polygenic Score May Help With Disease Prevention

NEW YORK (GenomeWeb) – Researchers have developed a polygenic score that can predict, at birth, someone's genetic risk of becoming obese later.

In the US, nearly 40 percent of adults are obese, according to the Centers for Disease Control and Prevention. While obesity is often attributed to unhealthy lifestyle choices, it is also heritable, suggesting that genetic variants influence a person's risk of becoming obese.

To investigate this further, a team led by researchers at the Broad Institute generated a polygenic score using data from a large genome-wide association study of obesity. Adults with the highest risk scores, they reported today in Cell, weighed nearly 30 pounds more on average than individuals with the lowest risk scores and were also at increased risk of other cardiometabolic conditions. The researchers further noted that the effects of the score were small among children, but grew with age, suggesting that early prevention strategies might be effective.

"We've known for a long time that some people are born with DNA predisposing them to obesity," first author Amit Khera, a clinician at the Massachusetts General Hospital Center for Genomic Medicine and an associated scientist at the Broad, said in a statement. "Now, we can quantify those differences in a meaningful way, and potentially explore new routes for achieving better health."

Using data on more than 2.1 million genetic variants from the Genetic Investigation of Anthropometric Traits (GIANT) study, Khera and his colleagues used a newly developed computer algorithm to develop five polygenic scores for obesity. The new algorithm reweighted each variant based on the strength of its statistical significance as well as on its correlation with other nearby variants. It also used a tuning parameter.

They tested these five scores in a cohort of 119,951 middle-aged adults from the UK Biobank and selected the one with the best correlation with BMI for further analysis.

In a separate cohort of 288,016 middle-aged adults from the UK Biobank, the researchers found that individuals who fell in the top score decile had an average BMI of 30.0 and an average weight of 188 pounds, while those in the bottom decile had an average BMI of 25.2 and an average weight of 159 pounds.

The researchers noted, though, that their polygenic score was not deterministic, as 17 percent of individuals within the top decile had BMIs in the normal range. Still, a high polygenic score was more common among those with severe obesity, they added.

In addition to obesity, individuals with high polygenic scores were also at increased risk of six cardiometabolic conditions, including diabetes, hypertension, and coronary artery disease. A high score was also linked to a 19 percent increase in all-cause mortality.

When the researchers tested their predictor among younger cohorts, they found that in newborns, there was a small difference in weight between those with high and low polygenic scores. But that difference grew to nearly 8 pounds by 8 years of age and 27 pounds by 18 years of age.

Additionally, within a cohort of 3,722 young adults who were followed over time — none of whom were obese at baseline — the researchers found that 15.6 percent of those in the top decile developed severe obesity, as compared to 1.3 percent in the bottom decile.

This suggested to the researchers that a risk predictor might be able to identify at-risk individuals in childhood for interventional approaches.

"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," senior author Sekar Kathiresan, director of the Center of Genomic Medicine at MGH and the Cardiovascular Disease Initiative at the Broad, said in a statement. "Prevention strategies could be especially impactful early in life for these individuals."