Individuals who carry extra copies of specific genes have a tendency to be extremely skinny, researchers from Imperial College London and the University of Lausanne, Switzerland, reported in the journal Nature. The authors added that this is the first study to find evidence of a genetic cause for extreme underweight.

The scientists found that a duplication of part of chromosome 16 is linked to being very thin. According to previous research, those with a missing copy of these genes had a considerably higher risk of becoming morbidly obese – 43 times more likely.

Study leader, Philippe Froguel, said:

“This is the first genetic cause of extreme thinness that has been identified. It’s also the first example of a deletion and a duplication of one part of the genome having opposite effects.”

A child’s or baby’s ‘failure to thrive’ may not necessarily be the parent’s fault, Froguel explained. It may be a genetically-driven phenomenon.

In normal cases, we have two copies of each gene, one from each parent. However, sections of a chromosome may occasionally be deleted or duplicated and the individual has an abnormally high or low dosage of certain genes, the researchers wrote.

Froguel said:

“The dogma is that we have two copies of each gene, but this isn’t really true. The genome is full of holes where genes are lost, and in other places we have extra copies of genes. In many cases, duplications and deletions have no effect, but occasionally they can lead to disease.

So far, we have discovered a large number of genetic changes that lead to obesity. It seems that we have plenty of systems that increase appetite since eating is so important – you can suppress one and nothing happens. This is the first genetic cause of extreme thinness that has been identified.

One reason this is important is that it shows that failure to thrive in childhood can be genetically driven. If a child is not eating, it’s not necessarily the parents’ fault.

It’s also the first example of a deletion and a duplication of one part of the genome having opposite effects. At the moment we don’t know anything about the genes in this region. If we can work out why gene duplication in this region causes thinness, it might throw up new potential treatments for obesity and appetite disorders. We now plan to sequence these genes and find out what they do, so we can get an idea of which ones are involved in regulating appetite.”

Part of chromosome 16 is duplicated in approximately 1 in every 2,000 individuals. Males with this duplication are 23 times and females 5 times more likely to be too thin – with a BMI below 18.5.

The researchers gathered and examined DNA data on over 95,000 people. Of those with the gene duplication, half had been diagnosed with a “failure to thrive” and one quarter had microcephaly.

Failure to thrive is a medical term meaning a low weight for the child’s age, or a low rate of increase in the weight. Microcephaly is a condition in which the brain and head are too small; patients typically have neurological problems and have a shorter-than-normal lifespan.

The authors added that further studies are required to better understand the genes in this area. However, they believe their discovery could pave the way for potential future therapies for obesity and feeding and eating disorders.

The authors wrote in conclusion in the journal’s Abstract:

“The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance.”

Written by Christian Nordqvist