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expert reaction to study on genetic markers to predict obesity risk

Research published in CELL describes a scoring system based on genetic markers that attempts to predict an individual’s risk for obesity.

Prof David Curtis, Honorary Professor, UCL Genetics Institute, said:

“I’m afraid it’s not true that this study shows that the polygenic risk score accurately predicts obesity or BMI. It accurately predicts the mean, or average, of the BMI across thousands of people with a particular score. But people with a given score will have a very wide range of BMI values around that mean so knowing somebody’s score tells you very little about their BMI. In fact, there is a huge overlap in BMI values between the people with extremely high and low scores. The scores do not distinguish between those who are and are not obese. From their results the score explains less than 10% of the variance in obesity so more than 90% is due to other factors. As they say themselves, there are countries where obesity rates have increased over 100-fold. But the genes haven’t changed, so obviously it’s the other things, such as diet and exercise, which have much larger effects. And those are the things we can do something about.

“In fact, it’s hard for me to see what benefit there is in identifying people at somewhat higher or lower genetic risk of obesity. Whether you’re at higher risk or lower risk the lifestyle advice is exactly the same. A good diet and exercise will be beneficial whatever polygenic risk score you have.”

Prof Tim Frayling, Professor of Human Genetics, University of Exeter, said:

“This new study uses information from across our genomes to test whether or not knowing our genetic information can predict how much excess weight we will carry. The study showed that differences between people’s genetic makeup is associated with substantial differences in their weight – the luckiest 10% of people – those with fewest “fat genes” – were 2 stone lighter than the 10% with the most “fat genes”. The study improves on previous work that showed similar effects, but only when comparing the 2% of people with the most to the 2% with the fewest “fat genes”.

“This study is important because it shows that obesity starts from an early age – the authors showed that more than 80% of the effect was there from as young as 8 years old, showing that a genetic predisposition to gaining weight starts very early in childhood. This might be important in enabling health care professionals help the young people most at risk avoid putting on too much weight, but more studies are needed to see how genetics adds to standard measures such as parents’ weight.”

Dr Katarina Kos, Senior Lecturer in Adipose Tissue Biology, University of Exeter Medical School, said:

“The genetic risk prediction of obesity is somehow limited, as shown in this paper which uses a mathematical model to look at 2 million genes with a promising link to obesity. This newly identified and tested obesity score, whilst somewhat useful in prediction of those with moderate obesity, could predict only 5.6% of people who are severely obese and only 15% of young people with these genes became severely obese. Fundamentally, any genetic risk prediction is restricted by the contribution of heritability, which the authors cite to be around 17-27%.  

“There is good evidence of an increased health risk with obesity. Equally, many clinical trials show that this risk can be significantly reduced by lifestyle modification. People with an unhealthy midriff fat distribution are at particular health risk and this should be considered rather than assessing obesity by BMI only. However, because of the overwhelming evidence of ill health attributed to obesity, it would not be prudent to limit healthy eating and lifestyle advise only to those with a high-risk score. This would, in an ever more ‘tempting and sedentary challenging’ environment, make an increasingly greater number of people affected. Equally, one would not want to rely on ‘healthier genes’ and test whether one gets away with an unhealthier lifestyle.”

Dr Rishi Caleyachetty, Assistant Professor, Warwick Medical School, University of Warwick, said:

“Despite the different circumstances resulting in obesity epidemics in many parts of the world, some common themes emerge. Dr Amit Khera and colleagues clearly show the genetic susceptibility to become severely obese in European populations.

“An important limitation of this study was that it was based primarily on European populations. Future research on polygenic scores for severe obesity need to include diverse populations from low-income and middle-income countries, given that 62% of the world’s obese population live in these countries”.

“While outstanding questions include whether genetic predisposition to severe obesity can be reduced, these findings should put further pressure on health departments and ministries to recognise obesity as a disease.”

Prof Albert Tenesa, Professor of Quantitative Genetics, MRC-Human Genetics Unit, University of Edinburgh, said:

“Although better genetic predictors of obesity have been developed in the past, the contribution of this work arises from the use of genetic predictors of obesity to predict weight in growing children. Future work will require to assess whether the genetic predictors of obesity are also correlated to childhood obesity.”

‘Polygenic Prediction of Weight and Obesity Trajectories from Birth to Adulthood’ by Khera et al. was published in Cell at 16:00 UK time on Thursday 18th April 2019.

Declared interests:

Prof David Curtis: “No COIs”

Prof Tim Frayling: “No”

Dr Katarina Kos: “No other interest to declare”

Dr Rishi Caleyachetty: “I have no conflict of interest.”

Prof Albert Tenesa: “I have no conflict of interests”

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