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RResearchers have long since probed DNA to find a big time bomb linked to the disease. But in their quest to predict the risk of common conditions, they are increasingly looking for thousands of genetic variants that are themselves weak – but can collectively use a powerful detonation force.
Everything is done to create what are known as polygenic risk scores, which attempt to measure the impact of a multitude of genetic modifications on a person's chances of getting diabetes or having a heart attack. The latest predictor of this type, unveiled Thursday in the journal Cell, aims to predict the chances of a person to become obese.
The score, tested on data from 300,000 people, found that the 10% of adults who received the worst genetic risk map for obesity weighed an average of 29 pounds – and 25 times more likely to become severely obese – the 10% of those with the genes most likely to keep them lean.
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Built by a team of researchers affiliated with Harvard, the score seems to be more powerful than any previous genetic tests of obesity. But there is still no commercial version. And it remains to be seen whether it will be powerful enough to be clinically useful, as a means of informing adults why they are heavy or of identifying high-risk children and intervening before they become obese.
Dr. Sekar Kathiresan, Massachusetts General Hospital cardiologist and geneticist at the Broad Institute, who led the new research, sees the possibility of using his score as a screening tool in what he called "a period of time." However, he acknowledged that he did not yet know what interventions should be offered to children identified as being at high risk by his test – and that he did not know. it has not been shown that such interventions would make a difference.
The researchers began by compiling a list of 2.1 million common genetic variants and used computer algorithms to calculate several possible scores, each of them gauging obesity a little differently. They chose the best score by seeing how they got away with the data from UK Biobank, a UK initiative to collect genetic information and supported by the government.
And when did they test the winner? The genetic variation was striking.
"It really means that 10% of the population inherited a genetic factor that makes them heavier by 20 to 30 pounds," said Kathiresan.
Genetics is not destiny, however. Kathiresan and her team found that about 17% of the deciles of people at highest risk still had normal weight.
Some experts have urged caution in rushing to adopt polygenic risk scores, warning that confounding environmental influences are too strong – and science too immature – for such genetic prediction tools to be ready for prime time.
In the case of obesity, for example, it is thought that genes and the environment exert an almost equivalent influence. And a polygenic risk score only partially accounts for the genetic influence. Common genetic variants accounted for less than a quarter of the heritability of body mass index in the data set used in the research, said Kathiresan and her team in their article.
The result? The polygenic risk score can only represent a small fraction of the overall risk.
"If you have a score that accounts for only 10% of the overall susceptibility to obesity, you can never accurately predict future obesity," said Ruth Loos, a genetic epidemiologist and professor at the Mount Sinai School of Medicine Icahn, who was skeptical a score would be helpful.
Such limitations have not stopped the enthusiasm generated by the new forecasting tools.
Kathiresan published last summer a different polygenic risk score that aimed to assess the risk of heart attack. It has also been found that 5% to 8% of those who scored in the search had at least a tripled risk. Kathiresan said her lab is now collaborating with Color, a San Francisco-based company that sells clinical genetic testing at the heart of a health-based business. They are building on this research to develop a commercial test to measure the polygenic risk of coronary heart disease.
The Broad Institute, based in Cambridge, Mass., Has also filed intellectual property protection claims related to the laboratory's lab scores research, said Kathiresan. The research to develop the new obesity score was funded by various government, academic and philanthropic grants, part of the analysis being funded by units of pharmaceutical companies Merck and Johnson & Johnson.
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