Rare genetic mutations that protect against weight gain identified in massive study

A massive study of 645,626 people in the US, UK and Mexico found a rare genetic variant that appears to offer “substantial protection” against weight gain.

About 1 in 2,500 people appear to be carriers of a particular mutation in a gene called GPR75, leading to only one functional copy of it. Belonging to this rare group of people is associated with lower body weight and a 54% lower probability of obesity.

These results are consistent across multiple ancestry, environmental exposures, and genetic backgrounds, and they strongly suggest that GPR75 is one of the many genes involved in weight gain.

The team’s work is based on a relatively new technique called whole exome sequencing, which can help us find mutations in certain genes and thus reveal their effects.

Instead of sequencing every gene in the human genome, exome sequencing focuses only on exons, which make up about one percent of all DNA. Exons are the building blocks that provide instructions for proteins, which means that when you sequence this entire subset, you can identify mutations in the protein-coding regions of any gene.

Such variations are usually quite rare, but when discovered they “self-identify” the genes responsible.

“The principles of discovery exemplified in the study by Akbari et al. Go beyond controlling body weight and obesity,” write metabolic disease researchers Giles Yeo and Stephen O’Rahilly, who were not not involved in the study, from a related perspective. room.

“It is likely that large-scale human exome sequencing will become an increasingly important entry point for the discovery of mechanistic information on mammalian biology.”

Using this method, the team identified 16 genes linked to both exon mutations and a person’s body mass. Four of the genes had already been found in previous weight gain studies and are known to influence appetite, suggesting the authors are on the right track.

Of all the mutations, variations in the GPR75 gene had the greatest effect on a person’s body mass index. People with mutations who only inactivated one copy of this gene weighed an average of 5.3 kilograms less.

In other lab tests, when mice did not have a single copy of this gene, the animals gained 25 percent less weight than those with the fully functional GPR75 gene. In contrast, when mice lacked both copies of the gene, they gained 44% less weight.

“While it is not clear whether the leanness of these animals is due to effects on energy intake, expenditure or both, this study establishes that GPR75 is involved in the control of energy balance and that inhibiting its signaling could lead to body weight loss, “write Yeo and O’Rahilly.

There are still many questions to answer about the GPR75, but the new discovery is a promising start.

In the past, other studies have identified certain “thin” genes in humans that prevent mice from gaining weight. Still, determining whether this link is causal or just a coincidence is a tricky business, especially since these genes likely work in concert with other genetic and environmental factors to control our body weight.

The study was published in Science.