Ruth Loos, PhD
Diet and physical activity are not the only factors that determine how easily a person gains or loses weight. A recent study led by researchers at the Icahn School of Medicine at Mount Sinai and other institutions of the Genetic Investigation of ANthropometric Traits (GIANT) consortium has found that 13 genes may play an important role, as well.
According to the study, published in the January 2018 issue of Nature Genetics, these 13 genes carry variations associated with body mass index (BMI).
“Our study has identified genes that play a crucial role in the neuronal control of body weight,” says lead researcher Ruth Loos, PhD, Professor of Environmental Medicine and Public Health at the Icahn School of Medicine at Mount Sinai, and Director of the Genetics of Obesity and Related Metabolic Traits Program at The Charles Bronfman Institute for Personalized Medicine. “They act in the brain in pathways that may affect people’s food intake, hunger, and satiety. Individuals who inherit these genetic variations may find it harder to eat less or stop eating, compared to those who did not inherit these variations.”
The study, led by Dr. Loos and Joel Hirschhorn, MD, PhD, Concordia Professor of Pediatrics and Professor of Genetics at Boston Children’s Hospital and Harvard Medical School, and Co-director of the Broad Institute Metabolism Program, also involved the collaboration of more than 250 international research institutions that comprise the GIANT consortium.
In the past decade, researchers in the 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, 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.
Genetic data from more than 700,000 individuals and 125 different studies were combined to form the largest genetic association study to date. The researchers identified a total of 14 genetic variations in 13 genes, including a “stop” variation in a gene called MC4R that causes carriers to weigh 15 pounds more, on average, than individuals who do not carry the “stop” variation.
Genes contain the information needed to make proteins. In the case of a “stop” variation, the translation from gene to protein is halted, and the protein is shorter than normal. About 1 in 5,000 individuals carries the “stop” variant in MC4R, which causes the gene not to produce 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.
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 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.
Genes are not the only factor in determining body weight, and it is important to be physically active and maintain a healthy diet, Dr. Loos says. However, she says, “Our study has provided new potential targets for therapeutic interventions, and may even help personalize treatment for carriers of the genetic variations.”