The University of Southampton

Second genetic link to obesity identified

7 May 2008

Scientists from Southampton have taken part in a large international study of almost 90,000 people, which has identified a second genetic variant that influences body fat, weight and risk of obesity.

The first commonly occurring, genetic marker of obesity in the population was called FTO, and discovered in 2007. This new marker 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 4kg heavier than those who don’t carry these genetic variations. The results are published in ‘Nature Genetics’.

The study involved scientists from the MRC (Medical Research Council) Epidemiology Resource Centre at the University of Southampton and was led by the MRC Epidemiology Unit, University of Cambridge and Wellcome Trust Sanger Institute, Cambridge. It included 79 other research institutions from the United Kingdom, USA, France, Germany, Italy, Finland and Sweden.

Director of the MRC Epidemiology Resource Centre, Professor Cyrus Cooper, explains: “This discovery was enabled by the pooling of research data from international teams of scientists. It demonstrates how large collections such as the Hertfordshire Cohort Study, can contribute to consortia aiming to discover common genetic variants that can influence health.”

Lead author Dr Ruth Loos, of the Medical Research Council Epidemiology Unit, University of Cambridge 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 less rare variants that affect more people.”

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 activity of the MC4R gene, perhaps by disrupting DNA regions required for its normal activity.

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.

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