Gene mutation for obesity 'rare'

“Childhood obesity could be caused by a genetic mutation,” reported The Daily Telegraph . The newspaper said a study has shown that the condition could be genetic, rather than the result of overfeeding.

This well-conducted and reliable study indicates that, very rarely, some people’s DNA may affect their eating behaviour, making them more likely to become obese. This mutation was rare, with only five out of 300 very severely obese children carrying it. Most cases of childhood obesity will not be caused by this mutation.

This study highlights how complex the issue of obesity is and that there is no single cause. A healthy diet and adequate physical activity remain the most important ways of maintaining a healthy weight, even for those whose genes make them more likely to become obese.

Where did the story come from?

This research was carried out by Elena G Bochukova and colleagues from the University of Cambridge Metabolic Research Laboratories, Addenbrooke’s Hospital in Cambridge and other institutions in the UK. The study was funded by the Wellcome Trust, the Medical Research Council (MRC) Centre for Obesity and Related Disorders and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. It was published in the peer-reviewed science journal Nature .

Some papers, including the Daily Mail and The Times highlighted the fact that genes may be playing a part but that genetics doesn’t usually tell the whole story. The Mail gives more detail, saying that, among the 300 children in the study who had become very fat by the age of 10, five had the mutation and four of these had been on the at-risk register.

What kind of research was this?

In this case-control study, the researchers compared mutations in the DNA of 300 obese UK children with those in 7,366 apparently healthy volunteers. Nearly half of the 300 children with severe early-onset obesity also had developmental delay, meaning they required special educational support, or autism.

The researchers were looking for a mutation type in the children’s DNA known as a copy number variant (CNV). These occur when large chunks of DNA are either duplicated or deleted, and can result in a person having more or fewer copies of certain genes than normal. It is thought that this type of mutation plays an important role in several genetic diseases.

Although the rise in obesity is mainly driven by environmental factors, genetic factors play a major role in determining why a few children are more likely to gain weight. The researchers say that genetic studies of rare causes can identify biological pathways that are also important in determining weight.

What did the research involve?

The 300 obese UK children were randomly selected from another study called the Genetics of Obesity Study cohort. The 7,366 apparently healthy controls were of European ancestry and from a study called the Wellcome Trust Case Control Consortium. Among the 300 UK children with severe obesity, there were 143 children with developmental delay.

All 300 obese children had severe obesity defined as a body mass index (BMI) standard deviation score of more than three, meaning that they were among the top one to two per cent for their age. For example, an eight-year-old child weighed at least 11 stone (70kg) and a 10-year-old child at least 15 stone (95kg).

The researchers explain that previous studies have identified small changes to the genetic code called single nucleotide polymorphisms (SNPs) associated with increased BMI. These are common and together account for only a small percentage of the inherited variation in BMI.

This study looked at larger differences (the CNVs), which the researchers thought might affect obesity. Previous studies have identified rare CNVs that affect leptin and melanocortin, hormones that play a role in regulating energy intake and energy expenditure, including appetite and metabolism.

This study used appropriate methods of analysis and described its methods in several appendices.

What were the basic results?

The researchers found an average (median) of 53 CNVs in children with severe early-onset obesity and 55 in the healthy control children. They then looked at only large deletions (more than 500 kilobases, a base being one letter in the DNA code) and rare deletions (found in less than 1% of participants). These deletions were significantly more common among the 300 cases than among the 7,366 controls (P < 0.001).

When the researchers investigated which specific areas of DNA were affected by deletions, they found that deletions of part of chromosome 16 (called 16p11.2) were more common in cases than controls.

Out of the 300 cases, five were identified as having overlapping deletions on chromosome 16p11.2 compared to just two of 7,366 controls (P less than 5 x 10-5). Children with the deletion had severe obesity from a young age. Two of the cases also had mild developmental delay, and the researchers point out that deletions in this part of the genetic code are already known to be associated with delay.

How did the researchers interpret the results?

The researchers conclude that "this is the first evidence that copy number variants have been linked to a metabolic condition such as obesity. They are already known to cause other disorders such as autism and learning difficulties".

They go on to call for a change in attitudes and practices among those with professional responsibility for the health and wellbeing of children. They say that “severe obesity is a serious medical issue that deserves scientific investigation”.

Conclusion

This research forms part of a growing body of evidence on the rarer genetic causes of severe obesity. Its strengths include the relatively large number of children with this severity of obesity who were studied.

The study also has some weaknesses, one of which is related to its design. Case-control studies are limited because it’s possible that other factors could be involved and may be the cause of the associations seen. For example, the genetic differences were seen in areas of the genetic code already linked with developmental delay and autism. It’s possible that the higher rate of CNVs in the cases group is partially due to the selection of children with developmental delay in this group, rather than being directly linked to obesity. However, if this were the case, it's unlikely that it would change the overall conclusion due to the size of the groups.

The findings have implications for the diagnosis of severe childhood obesity. Some of the children in the study had already been formally placed on the social services at-risk register, on the assumption that the parents were deliberately overfeeding their children and causing their severe obesity. These children have reportedly now been removed from the register. The researchers suggest that, in future, children with very severe obesity should be tested for this genetic cause.

The number of very severely obese children with the genetic deletions on part of chromosome 16 were rare. It should not, therefore, be assumed that all severely obese people have this genetic mutation. It is likely that the majority of obesity is attributable to environmental causes. A healthy diet and adequate physical activity remain the most important ways of maintaining a healthy weight.