A massive study among 645,626 individuals in the United States, UK, and Mexico has found a rare gene variant that appears to offer "substantial protection" against weight gain. Roughly 1 in 2,500 people appear to carry a particular mutation of a gene called GPR75, leading to only one working copy of it. Being in this rare group of people is associated with a lower body weight and 54 percent lower odds of obesity. These results are consistent across multiple ancestries, environmental exposures and genetic backgrounds, and they strongly suggest GPR75 is one of 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 therefore reveal their effects. Instead of sequencing each and every gene in the human genome, exome sequencing focuses only on exons, which make up about one percent of all DNA. Exons are the pieces that provide instructions for proteins, which means when you sequence this entire subset you can identify mutations in protein-coding regions of any gene. Such variations are generally quite rare, but when they are found, they "self-identify" causative genes. "The principles of discovery exemplified in the study of Akbari et al. go beyond that of body weight control and obesity," metabolic disease researchers Giles Yeo and Stephen O'Rahilly, who weren't involved in the study, write in a related Perspective piece. "It is likely that human exome sequencing at scale will become an increasingly important entry point for the discovery of mechanistic insights into mammalian biology." Using this method, the team identified 16 genes that were linked to both exon mutations and a person's body mass. Four of the genes had already been found in previous studies on weight gain, and are known to influence appetite, which suggests the authors are on the right track. Of all the mutations, variations in the GPR75 gene had the largest effect on a person's body mass index. People carrying mutations that only inactivated one copy of this gene weighed 5.3 kilograms less on average. In further lab tests, when mice lacked a single copy of this gene, the animals gained 25 percent less weight than those with the fully functioning GPR75 gene. When mice lacked both copies of the gene, on the other hand, they gained 44 percent less weight. "Although it remains unclear 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 might be expected to result in a loss of body weight," write Yeo and O'Rahilly. There are still many questions that need to be answered about GPR75, but the new finding is a promising start. In the past, other studies have identified certain "thin" genes in humans that stop mice from putting on weight. Still, figuring out if that link is causal or merely a coincidence is tricky business, especially as these genes are probably working in concert with other genetic and environmental factors to control our body weight. Source
