Genetics of obesity

“Eating too much and putting on weight may be more to do with one’s state of mind rather than a metabolic imbalance,” The Independent reported today. It said that a study has found six new genes associated with obesity, five of which are active in the brain. This has lead scientists to believe that new treatments could involve changing people’s psychological rather than their physical desire to eat.

This large, well-conducted study contributes greatly to understanding how genes affect body mass index (BMI).

The fact that several of these genes were “highly expressed” in the brain tissue suggests that there may be a role of the brain in predisposing some people to obesity, however exactly how such a predisposition works is not yet clear.

It should be pointed out that the variations identified in this research are common in the population, and each contributes a small amount to BMI.

Where did the story come from?

Dr Cristen J Willer from the University of Michigan and a large number of colleagues from the Genetic Investigation of ANthropomorphic Traits (GIANT) consortium, from universities in the US and Europe carried out this research.

It was funded by the US National Institutes for Health, and many charities and pharmaceutical companies. The study was published in the peer-reviewed scientific journal Nature Genetics .

What kind of scientific study was this?

This research was aimed at identifying genetic variations associated with BMI. It is known that a person’s weight is affected by environmental and genetic factors. Studies have suggested that 40-70% of the variation in BMI in the population is due to genetic factors, and it is believed that many different genes contribute to this effect. To date, variations in or near two genes called FTO and MC3R have been found to contribute a small amount to BMI variation, and the researchers in this study wanted to identify more.

In this meta-analysis, the researchers pooled the results of a number of genome-wide analyses (GWAs), which are genetic case-control studies. GWAs look at small genetic variations called SNPs (single nucleotide polymorphisms) scattered throughout the DNA, and try to identify any SNPs that are more common in people who have the condition they are studying (in this case, a higher BMI) than in people who do not.

The researchers obtained data from 15 GWAs, which included 32,387 people of European ancestry, and used statistical methods to pool all this data together. They identified all of the genetic variations that seemed to be associated with a higher BMI, and selected the 35 variants that showed the greatest effect. They then tested these 35 variants in a further 59,082 people and identified those variants that still showed an association with higher BMIs in this group.

The researchers also looked at the relationship between these variants and characteristics including overweight (BMI≥25kg/m2) and obesity (BMI≥30kg/m2). The researchers also checked whether the genes in these associated regions were expressed in various tissues of the body.

What were the results of the study?

On pooling the results of the 15 GWAs, the researchers identified genetic variations in or near the FTO and MC3R genes that were associated with a higher BMI. This confirmed the findings of previous studies. People who had one copy of the FTO variation had a BMI that was on average 0.33 units higher than those who had no copies, and people who had one copy of the MC3R variation had BMIs 0.26 units higher.

The researchers also identified genetic variations in six areas of the DNA that were associated with higher BMI. These variations were in or around the TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2, and NEGR1 genes.

Each individual variant was associated with an increase of between 0.06 units and 0.26 units of BMI in people who carried one copy.

Individually, the eight variants increased the odds of being overweight by between 3% and 14%, and of being obese by between 3% and 25%. When the researchers looked at where the TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2, NEGR1 genes were active in the body, all of them except MTCH2 were active at a high level in the brain.

What interpretations did the researchers draw from these results?

The researchers concluded that they had confirmed an association between the FTO and MC3R regions and BMI, and identified six new regions also associated with BMI. The genes in these regions that are likely to be causing the increase in BMI are mostly active in the brain, showing that the brain plays a role in “predisposition to obesity”.

What does the NHS Knowledge Service make of this study?

This large and well-conducted study identified several regions of the DNA that are associated with an increase in BMI. Confidence in the findings is increased by the fact that five of the new regions were also identified by another group in a separate study published in the same journal.

There are a few important points to note when interpreting these findings:

• This type of study is used to identify regions or areas of the DNA that are associated with the trait in question, in this case a higher BMI. However, associating a variant with a trait does not necessarily mean that one causes the other, and most of the variants lie in pieces of DNA with no known function. The authors in this study identified the genes near to these variations that seemed likely to be involved, but more research will be needed to identify the variations that are actually causing the increase in BMI observed, and to confirm which genes they affect.
• BMI has what is known as “multifactorial” inheritance. This means that multiple factors are having an effect, both genetic and environmental, and a lot of different genes will each be contributing a small effect. Each of the variants found in this study contributes only a small amount to a person’s overall BMI. The eight variants identified in this study were estimated to account for about 0.8% of the variation in BMI seen in the populations tested – a relatively small amount. Therefore, there will be other genetic variants having an effect, as well as environmental factors such as diet and physical activity.
• These results come from populations with European ancestry and may not apply to populations with different ethnic backgrounds.

This study contributes to the understanding of how genes affect BMI. In the long term, this may contribute to the development of treatments for reducing weight. However, the best methods to do this currently are a healthy diet and exercise.

Sir Muir Gray adds...

Until a new drug comes (and it may be a long time), eat less and walk more; an hour a day extra if you want to lose weight, thirty EXTRA minutes a day to keep you weight constant.

See Sir Muir Gray's advice on walking here.