Researchers have long probed DNA for one big ticking time bomb linked to disease. But in the quest to predict risk for common conditions, they’re increasingly looking for thousands of genetic variants that on their own are wimpy — but may collectively wield a powerful detonation force.
It’s all being done to build so-called polygenic risk scores, which attempt to gauge how a multitude of genetic alterations affect a person’s chances of everything from developing diabetes or having a heart attack. The latest such predictor, unveiled on Thursday in the journal Cell, aims to forecast a person’s chances of becoming obese.
The score, tested using data from 300,000 people, found that the 10% of adults who were dealt the worst hand of genetic cards when it comes to obesity risk were 29 pounds heavier on average — and 25 times as likely to become severely obese — than the 10% of those with genes most likely to keep them lean.
Built by a team of Harvard-affiliated researchers, the score looks to be more powerful than any past genetic test for obesity. But there’s no commercial version of it yet. And it remains to be seen whether it’ll be powerful enough to be useful in the clinic, as a way to inform adults why they’re heavy or to identify high-risk children and intervene before they become obese.
Dr. Sekar Kathiresan, a cardiologist at Massachusetts General Hospital and a geneticist at the Broad Institute who led the new research, sees potential for his score to be used as a screening tool in what he called “a golden period” of early childhood, between birth and age 8. He acknowledged, however, that it’s not yet known which interventions should be delivered to kids identified as high-risk by his test — nor has it been shown that any such interventions would make a difference.
The researchers started with a list of 2.1 million common genetic variants and used computer algorithms to derive several possible scores that each gauged obesity risk a little bit differently. They picked the best score by seeing how they fared with data from the U.K. Biobank, a government-backed effort in the United Kingdom to gather genetic information.
And when they tested out the winner? The genetic variation was striking.
“What this really means is 10% of the population has inherited a genetic factor that makes them 20-30 pounds heavier,” Kathiresan said.
Genetics are not destiny, however. Of the decile of people dealt at highest risk, about 17% of them still had a normal weight, Kathiresan and his team found.
Some experts have urged caution in the rush to embrace polygenic risk scores, warning that the confounding environmental influences are too strong — and the science too immature — for such genetic prediction tools to be ready for primetime.
In obesity, for instance, genes and the environment are thought to exert a roughly equivalent influence. And a polygenic risk score only partially captures genetic influence. Common genetic variants explained less than a quarter of the heritability of body mass index in the dataset used in the research, Kathiresan and his team estimated in their paper.
The result? The polygenic risk score may only capture a small fraction of overall risk.
“If you have a score that only represents 10% of the overall obesity susceptibility, you can never accurately predict future obesity,” said Ruth Loos, a genetic epidemiologist and professor at the Icahn School of Medicine at Mount Sinai, who was skeptical that such a score would be useful.
Such limitations haven’t stopped the excitement around the new prediction tools.
Last summer, Kathiresan rolled out a different polygenic risk score that aimed to gauge heart attack risk — along with the finding that 5% to 8% of people assigned scores as part of the research had a risk that was at least tripled. Now, Kathiresan said, his lab is collaborating with Color, a San Francisco area company that sells clinical genetic tests as the core of a business built around population health. They’re building off that research to develop a commercial test to gauge polygenic risk for coronary artery disease.
The Cambridge, Mass.-based Broad Institute has also filed for intellectual property protections related to his lab’s polygenic score research, Kathiresan said. The research to develop the new obesity score was funded by a variety of government, university, and philanthropic grants, with one part of the analysis supported by units of the drug companies Merck and Johnson & Johnson.