Second Genetic Link to Weight and Obesity

05/05/08 A study of 90,000 people has uncovered new genetic variants that influence fat mass, weight and risk of obesity. The variants act in addition to the recently described variants of the FTO gene: adults carrying variants in both genes are, on average, 3.8 kg (or 8.5 lb) heavier.

The variants map close to a gene called MC4R: mutations in this gene are the most common genetic cause of severe familial obesity. The study highlights the power of large collections of volunteer samples to uncover common variants that influence health.

"By working together with many international groups we have been able to assemble a sample collection which was large enough to allow this finding to be made," explains Dr Ruth Loos, leading author from the Medical Research Council Epidemiology Unit. "Several groups had shown that rare, highly disruptive variants in the MC4R gene were responsible for very severe, genetic forms of obesity: this collaboration has uncovered more common variants that affect more people."

The study, published in Nature Genetics, is led by investigators from the Cambridge GEM consortium (Genetics of Energy Metabolism) and Oxford University and is a collaboration between 77 institutions from the UK, USA, France, Germany, Italy, Finland and Sweden.

The team studied more than 77,000 adults and found that two copies of genetic variants resulted in an average increase in weight of about 1.5 kg.

This is the second set of common variants that are associated with weight and obesity, following the study, involving many of the same team, published in April 2007 that uncovered a role for the FTO gene. People who carry two copies of an FTO variant are about 2-3 kg heavier than those who have no copies of the variant.

Importantly, the effects of the new gene add to those of FTO; people who carried both the FTO variant and new variants were on average 3.8 kg (8.5 lb) heavier.

"This is a great example of how cooperation can bring about new findings that can be missed when researchers work in isolation," explains Dr Inês Barroso, Investigator at the Wellcome Trust Sanger Institute and one of the senior authors on the study. "The precise role in obesity of genetic variants in FTO and near MC4R remains to be discovered, but we can now begin to understand the biological consequences of these variants. This is where this research will make a difference."

MC4R protein plays a pivotal role in many aspects of physiology, including regulation of appetite and energy expenditure. The severe form of MC4R-related obesity is a consequence of alterations in the gene sequence, resulting in an inactive or less active MC4R protein.

By contrast, the new variants lie some distance from the MC4R gene. The team suspect that the sequence variant changes activity of the MC4R gene, perhaps by disrupting DNA regions required for normal activity of MC4R.

"Through this new and powerful genetic approach we are increasingly finding that the genes known to play a role in severe - but rare - diseases are also implicated in much more common disease," explains Professor Mark McCarthy, Robert Turner Professor of Diabetes at the University of Oxford, UK. "The common variants we are uncovering do not have such a dramatic effect on the normal functioning of the gene as do the rare mutations in MC4R that can cause rare examples of very serious, early onset obesity."

Dramatically, in a study of almost 6000 children, they found that the effects were almost double those seen in adults. Between the ages of four and seven, this additional increase in weight was the result, almost exclusively, of gain of fat tissue, and not due to gain in muscle or other solid tissues.

This more dramatic effect in young children reflects the more extreme consequences seen with rare variants of MC4R that severely disrupt its activity, suggesting that the novel variants do indeed exert their effect through action on MC4R.

"Our work to understand common disease, such as obesity, depends on the participation of thousands of people - members of the public who provide samples," explains Professor Nick Wareham, Director of the MRC Epidemiology Unit. "Without their willing participation, we could never achieve the power in our research to make striking findings like this.

"For each discovery, our efforts and the contribution of the participants will lead to improved healthcare for the population at large."

The team will now look to uncover how the DNA variants affect activity of the MC4R protein, which is a key player in orchestrating information from the body to control appetite and energy expenditure to keep body weight in balance. The team propose that altered activity of MC4R, imposed by the variants, might reduce its ability to carry out this important role.

The team emphasize that, although gene variants can affect weight, body mass index and obesity, they are only part of the story: lifestyle actions such as good diet and regular exercise are vital to control of weight.

This research programme was supported by the Medical Research Council, the Wellcome Trust, Diabetes UK, Cancer Research United Kingdom, BDA Research, UK National Health Service Research and Development, the European Commission, the Academy of Finland, the British Heart Foundation, the National Institutes of Health, the Novartis Institutes for BioMedical Research, GlaxoSmithKline, and the German National Genome Research Net.

Additional support was provided to individuals by the US National Institute of Diabetes and Digestive and Kidney Diseases, the Throne-Holst Foundation, the Vandervell Foundation, American Diabetes Association, Unilever Corporate Research and the British Heart foundation.