Hand adjusting weight scales
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A genome-wide association study (GWAS), coordinated by the Genetic Investigation of Anthropometric Traits (GIANT) consortium, has become the first to directly tie specific genetic variations that may directly impact the function of genes associated with body mass index (BMI). The research, published recently in Nature Genetics, discovered variations in 13 different genes that significantly influence the ability of people to either gain or lose weight.

“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.,” explained senior study investigator Ruth Loos, Ph.D., a professor at The Charles Bronfman Institute for Personalized Medicine at the Icahn School of Medicine at Mount Sinai. “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. 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.”

Over the past decade, researchers in the GIANT consortium have performed GWAS in hundreds of thousands of individuals to identify genetic variations associated with obesity and BMI. However, until now, the genetic variations they identified were mere “flags” on the genome that highlighted DNA sequences of interest. 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—an approach that expedited the discovery of the causal genes that affect body weight.

The study was an international collaboration involving more than 250 research institutions. Genetic data from more than 700,000 individuals and 125 different studies was combined to form the largest genetic association study to date. The researchers identified 14 genetic variations in 13 genes, including a risky copy variation—a phenomenon in which sections of the genome are repeated—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 5000 individuals carry this risk copy, which causes the gene not to produce any of the protein needed to inform the brain to stop eating.

Interestingly, 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. Moreover, the researchers identified two variants that may affect the function of a gene called GIPR. Approximately 1 in 400 individuals carry a protective copy of either variant, and they tend to weigh an average of 4.5 pounds less than noncarriers. Eight of the 13 genes identified were newly implicated in obesity and will require further follow-up to understand the mechanisms through which they affect body weight.

“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, M.D., Ph.D., 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.

By knowing the genes and the biological pathways through which they work, researchers believe they are a few steps closer to understanding why some people gain weight more easily than others, which is critical for developing effective treatments.

“Our study has provided new potential targets for therapeutic interventions, and may even help personalize treatment for carriers of the genetic variations,” Dr. Loos concluded. “While we are a few steps closer to understanding the biology of why some people gain or lose weight more easily than others, further research on each of the identified genes is needed to understand the mechanisms through which they act.”

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