“Holes” in the genomes of severely overweight children have revealed a new type of genetic variant that drives obesity and also increases the risk of learning difficulties.

More gene variants that increase the risk of obesity have long been sought. Although obesity, particularly in children, is often blamed on bad parenting, previous studies in identical twins that were raised apart revealed that genes play a major role in who becomes obese.

Pinpointing the culprits has been hard, however: the single-letter genetic variations found to be more common in obese people can only account for a small measure of obesity’s heritability.

So geneticists Stephen O’Rahilly and Sadaf Farooqi at the University of Cambridge, and colleagues, turned to a different kind of genetic variation, known as a deletion, in which entire genes are absent.


They compared the genes of people of normal weight with 300 children who had all become obese by age 10 or younger.

Learning difficulties

They found that these children were far more likely to have large, rare deletions. One of these featured the absence of a gene on chromosome 16 involved in sensing the hormones leptin and insulin, which play critical roles in both metabolism and appetite.

Some of the children had been taken out of their parents’ custody because their weight problems were blamed on bad parenting, but O’Rahilly says “it was pretty clear that this deletion was causing obesity”.

Deletions are part of a larger group of gene variants called copy number variants (CNVs), which also include additional copies of genes, known as insertions.

Previously, CNVs have mainly been linked to psychiatric problems including autism, learning difficulties and schizophrenia.

O’Rahilly’s team also found that the obese children he studied were more likely than the general population to have learning difficulties. Further evidence for a connection between brain development and obesity is also being claimed by a team led by Philippe Froguel of Imperial College London.

Drug targets

His team hasn’t yet published the results, but Froguel says they scanned the genomes of 16,000 adults and children, some obese and some not, for a different deletion on chromosome 16 which had previously been linked to learning difficulties. Every single adult over 30 and half the children with this mutation – 19 in total – were obese, he says.

Although in both studies, the deletions discovered are rare, and so cannot account for all cases of obesity, they are still important, Froguel says. At the very least, the mutations will point to genes and biological pathways that tend to go awry in obesity, offering potential targets for drug therapies.

“Just because something is not common does not mean that the discovery you make from it won’t be applicable to lots of people,” says Andrew Hattersley, a geneticist at Peninsula Medical School in Exeter, UK, who was not involved in either study.

Froguel’s team is already probing larger populations to find out which other rare deletions may cause obesity.

Journal reference: Nature, DOI: 10.1038/nature08689