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Tuesday, April 23, 2019

The genetics of obesity

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The genetics of obesity

Obesity is a very complex condition and involves a multitude of metabolic pathways, each regulated by  several genes. A disorder of one gene can lead to severe obesity but the rate of occurrence of these single gene defects is so low that they cannot explain the current pandemic of obesity.  For example, a rare defect in the gene which encodes for a protein, bearing the awkward title melanocortin-4 receptor (MC4-R) can lead to obesity. But even among morbidly obese persons, this gene defect is only found in 4% of this population. Thus a single gene defect is never going to explain the obesity issue.

However, twin studies have repeatedly shown that obesity is highly heritable to a level of about 70%. So if one gene defect can’t explain this inherited susceptibility to obesity, maybe data on multiple genes might assist us. A recent study by UK and US scientists[1], has begun to throw some light on how we might begin to predict the susceptibility to obesity based on our genes.

The first step in their quest was to explore a published database on 300,000 individuals whose body-weight was known and who had their entire genetic code searched for over 2.1 million common genetic variants. No single variation explained any significant risk of obesity. Thus the next step was to take all of these 2.1 million common genetic variants and see if they could compute a polygenic score which would be predictive of obesity. They used advanced computational methodologies to devise 6 candidate scoring systems. To determine which was best, they turned to the UK Biobank which has full genetic data and body weight data on over 120,000 subjects. Their best performing scoring system could now be put to the test.

They used four different data sets to explore the predictability of their polygenic score  in quite different groups. To understand their scoring system, they could first dismiss all those common gene variants which had simply no link with obesity. Thus our hair and eye colours are genetically determined and different genetic variants explained redheads from blondes to brunettes. So they were scrapped along with lots of others. They were left with genes that had a very, very minor effect on obesity right up to some genetic variants with a more significant link with obesity but still, on their own, would have no real predictive power. The more of the higher linked variants you had, the higher your polygenic score. So every individual in the UK Biobank got a score ranging from low to high. They divided the 300,000 subjects into ten groups (deciles) with increasing polygenic scores and they showed a very strong link between the score and body weight.  Half the people with the lowest score had a normal body mass index whereas among those in the top 10% of the polygenic score, only 17% were of normal weight. Conversely, among those classified as obese, only 9% belonged to the lowest scoring decile while 38% were at the top end of the score. Across the ten deciles of polygenic score there was a linear increase in  bodyweight, BMI and the incidence of severe obesity.

The next data sets they turned to were ones that included subjects who underwent bariatric surgery for the treatment of their morbid obesity. A high polygenic score was associated with a 5.0-fold increased risk of severe obesity treated with bariatric surgery. To understand the evolution of obesity over time, they then turned to the Framingham Offspring and Coronary Artery Risk Development in Young Adults (CARDIA). This gave data on 3,722 individuals who at baseline had no case of severe obesity. Over the next 27 years they were weighed 8 times. Over that period some subjects went on to develop severe obesity. Among those in the lowest 10% of the polygenic score just over 1% went on to develop severe obesity. In contrast, those in the top 10% of the polygenic score, 16% went on the become severely obese. The final database they used was one of UK babies born in the years 1991-1992 who were followed up to their 18th birthday (Avon Longitudinal Study of Parents and Children). The difference in birthweight between the top and bottom 10% of the polygenic score was just 0.06 kg. By 8 years of age the difference was 3.5 kg and by 18 years of age the difference had risen to 12.3 kg.  

This has shown that we are fast becoming capable of defining genetic profiles which predicts the likelihood development of a normal weight or a severe obesity problem. But before you jump up and down and blame your genes, remember the key saying: “Genes load the obesity gun. But only the environment pulls the trigger”. That said, a knowledge of the likely risk of sever obesity might motivate people with a high score to watch their calories more closely than most


[1] Khera et al., 2019, Cell 177, 587–596

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