By combining data from over 700,000 individuals, a consortium of researchers was able to discover rare and low-frequency coding variants associated with body mass index (BMI). Specifically, they identified 14 coding variants in 13 genes, of which 8 variants were in genes newly implicated in human obesity. Their research is reported in the January issue of Nature Genetics.
In the past decade, researchers in the Genetic Investigation of Anthropometric Traits (GIANT) consortium have performed genome-wide screens in hundreds of thousands of individuals to identify genetic variations associated with obesity and BMI. In this new study, however, the consortium focused on a specific set of genetic variations that are likely to affect the function of genes and their proteins.
The genetic data from more than 125 different studies was combined to form a large genetic association study. Of the 14 genetic variations in 13 genes identified, one was a risk copy variation that causes carriers to weigh 15 pounds more, on average, than individuals who do not carry the variation. The gene is called MC4R and approximately 1 in 5,000 individuals carries this risk copy, which causes the gene not to produce any of the protein needed to inform the brain to stop eating.
While this variant was identified two decades ago in individuals with extreme and early-onset obesity, the new study shows that it also affects body weight in the general population. Furthermore, the researchers identified two variants that may affect the function of a gene called GIPR. Approximately 1 in 400 individuals carries a protective copy of either variant and they tend to weigh an average of 4.5 pounds less than non-carriers.
"Our study has identified genes that play a crucial role in the neuronal control of body weight. They act in the brain in pathways that may affect people's food intake, hunger, satiety, etc. Individuals who inherit these genetic variations may find it harder to eat less or stop eating, as compared to those who did not inherit these variations," said Ruth Loos, professor at The Charles Bronfman Institute for Personalized Medicine at the Icahn School of Medicine at Mount Sinai. "It is also the first time a genetic association study for BMI identifies genes that act in pathways that affect energy expenditure and fat cell biology."
The investigators used computational analysis to further hone in on genes that likely play a key role in obesity. "By considering the genes as a group rather than one-by-one, we could highlight specific genes that both had strong support from genetics and that likely carry out functions that we predict to be important in controlling body weight," said Joel Hirschhorn, Concordia Professor of Pediatrics and Professor of Genetics at Boston Children's Hospital and Harvard Medical School, Co-Director of the Metabolism Program at the Broad Institute and the GIANT consortium.