New paper shows rare variants in multiple genes associated with severe obesity
To date, mutations in 15 genes are known to cause obesity which usually starts in childhood. In a study just published in the journal Scientific Reports, we worked with Ines Barroso's team at the Sanger Institute to look at a large number of genes in over 4000 children with severe obesity from the GOOS cohort. The methods we used allowed us to look at all the genes at the same time, so we could get a comprehensive picture of the frequency of each disorder.
We found that 7% of people in GOOS have mutations in the genes we already know about. Unusually, we found quite a few new mutations in GNAS, a gene which has previously been associated with a condition called Albright's Hereditary Osteodystrophy (AHO). People with AHO often have distinct clinical features with bone problems and reduced growth, but we found some people with GNAS mutations who lacked these features. This showed us that the clinical spectrum of AHO is quite broad and that a defective GNAS gene can cause obesity without the extra clinical features.
We also looked at a large number of genes that cause obesity in mice, but where the role in people is unknown. We found several genes in which mutations were more prevalent in people from GOOS compared to controls from the UK10K consortium which funded a large part of this work (https://www.uk10k.org/). We are undertaking more research into these genes to see which ones may be causing obesity and which might be potential drug targets in the future. This work shows us that the genetic architecture of severe obesity is very heterogeneous - there are many, many genes involved in controlling body weight!