Largest genome-wide study ever strengthens genetic link to obesity – sciencedaily


There are many reasons why people gain different amounts of weight and why fat is stored in different parts of their body. Now, researchers are pointing to a genetic reason for a tendency to gain weight.

Their findings, which are part of the largest genome-wide study, were published today in two articles in the journal Nature.

By analyzing genetic samples from more than half a million individuals as part of the GIANT research project, which aims to identify the genes that regulate human body and size, the researchers have discovered more than 100 locations in the genome that play a role in various obesity traits.

Knowing more about genes and biological processes can guide the development of weight loss therapies and help physicians tailor the health advice they give to patients.

“Our work clearly shows that the predisposition to obesity and to increased body mass index is not due to a single gene or a genetic change,” says Elizabeth Speliotes, lead author of the study. , MD, Ph.D., MPH, Assistant Professor of Internal Medicine and Computational Medicine. and bioinformatics at the University of Michigan Health System.

“The large number of genes makes it less likely that one solution to beating obesity will work for everyone and opens the door to possible ways to use genetic clues to help beat obesity,” she says. .

Speliotes and his colleagues studied the genetic basis of body mass index (BMI), a common measure of overall obesity, in up to 339,224 people.

Across the genome, which is the complete set of a person’s genes, they found 97 sites associated with obesity. The number triples the number of previously known regions.

When better understood, these genetic mechanisms could not only help explain why not all obese people develop related metabolic diseases, such as type 2 diabetes and high cholesterol, but could also lead to possible ways to treat it. obesity or prevent metabolic diseases in such people. who are already obese.

“Currently, we have no way of knowing if obese people will develop these obesity-related metabolic diseases and if so which ones,” says Speliotes, who is also a gastroenterologist at UM Health System. “We plan to use these genetic markers to help doctors decide which treatments would work best to keep patients healthy.”

An inter-campus group of faculty and staff from the Department of Human Genetics at the University of Michigan, Department of Epidemiology, Center for Epidemiology and Kidney Costs, Center for Statistical Genetics, Department of Biostatics, Department of Internal Medicine , Department of Computational Medicine and Bioinformatics and the Social Research Institute contributed articles.

Researchers from various institutions are bringing more and more treasures of DNA sequences into huge gene banks in the hope of fighting disease. The international GIANT consortium is already reaping the benefits of large datasets with articles on new BMI-related variants and a companion article in Nature today on the waist-to-hip ratio.

Analyzes of the genetic link to BMI indicate that the central nervous system has a role in susceptibility to obesity, including a pathway that responds to changes in diet and fasting and that would be targeted by a weight loss drug approved by the FDA.

“Using new computational methods, we have highlighted new biological pathways that work in the brain to regulate overall obesity, as well as a different set of pathways related to fat distribution that regulate key metabolic processes. “says senior author Joel Hirschhorn, MD, Ph.D., professor of pediatrics at Concordia and professor of genetics at Boston Children’s Hospital and Harvard Medical School, and co-director of the Broad Institute Metabolism Program.

The researchers note that while some genes involved in obesity may already have been involved in other aspects of human health, others may be part of pathways that are not yet understood. A better understanding of their functions related to body fat and obesity could provide a better picture of the roles these genes play in various diseases.

“Finding the genes that increase the risk of obesity is only the end of the beginning,” says lead author Ruth Loos, Ph.D., professor of preventive medicine at Mt. Sinai Hospital and director of genetics obesity and associated metabolic traits. Charles Bronfman Institute Program for Personalized Medicine.

“A major challenge now is to discover the function of these genetic variations and how they actually increase people’s susceptibility to weight gain,” says Loos. “This will be the crucial next step, which will require the contribution of scientists with a wide range of expertise, before our new findings can be used for targeted obesity prevention or treatment strategies.”

Belly fat is the key to health risk

In a follow-up study, an analysis of 224,459 individuals identified 49 sites in the genome associated with waist-to-hip ratio, a measure of the distribution of body fat. People whose waist circumference is larger than the hip circumference have more abdominal fat around their abdominal organs.

The accumulation of fat, especially around the stomach, increases the risk of cardiovascular and metabolic diseases.

Some sites show stronger effects in women than in men, showing that the genetic regulation of body fat distribution varies between the sexes.

“We need to know these genetic locations because different fat deposits pose different health risks,” says Karen Mohlke, Ph.D., professor of genetics at the University of North Carolina School of Medicine and senior author of the article which examined the size. compared to the hips of the distribution of fat.

“If we can determine which genes influence where fat is deposited, it could help us understand the biology that leads to various health issues, such as insulin resistance / diabetes, metabolic syndrome and heart disease.”

Financial support for the international collaboration was provided in part by the National Institutes of Health and Wellcome Trust UK.


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