Second genetic link to obesity identified

A study of almost 90,000 people has identified a second genetic variant that influences body fat, weight and risk of obesity. The first, a variant of a gene called FTO, was uncovered in 2007. The new variant is closely related to a gene called MC4R. Mutations in MC4R are the most common genetic cause of severe obesity within families.

The study also revealed that people who carry variants of both the FTO and MC4R genes have an increased risk of becoming obese and are on average 3.8kg heavier than those who don't carry these genetic variations. The results are published this week in Nature Genetics. 

Dr Cecilia Lindgren, joint first author (together with Dr. Ruth Loos and Dr. Shengxu Li), of the Wellcome Trust Centre for Human Genetics at the University of Oxford explains: "Several research groups had shown that rare variants in the MC4R gene are responsible for severe, genetic forms of obesity but this collaboration has uncovered variants that affect more people. This discovery was made possible by the pooling of research data from international teams of scientists. It highlights the power of large collections of samples from volunteers in looking for common genetic variants that can influence health."

The study involved scientists from University of Oxford, Cambridge Genetics of Energy Metabolism Consortium, the Wellcome Trust Sanger Institute, the MRC Epidemiology Unit and 77 other research institutions from the UK, USA, France, Germany, Italy, Finland and Sweden.

The protein that the MC4R gene provides instructions to make plays a pivotal role in many aspects of physiology, including regulation of appetite and energy expenditure to keep body weight in balance.

It is already known that the most severe form of MC4R-related obesity is caused by alterations in the MC4R gene that in turn create an inactive or less active MC4R protein. The variants uncovered in this research collaboration are much more common throughout the population than the mutated genes that cause severe conditions. They have a less dramatic effect on the normal function of the gene than the rare mutations that cause extreme obesity.

Rather than being located within the gene itself, these common variants lie some distance from the MC4R gene and so the team suspects that the variant changes gene activity. It might do this by disrupting the DNA regions required for the MC4R gene's normal activity thereby preventing a standard version of the MC4R protein from being made.

The next step for the research collaboration is to figure out exactly how variations in DNA near the MC4R gene influence the activity of the MC4R protein and in doing so disrupt its ability to keep body weight in check.

Dr Lindgren concludes: ''Although this research shows that genetic variants can influence a person's risk of becoming obese, it is important to remember that lifestyle choices like eating healthily and taking regular exercise have an impact too.''