Largest ever genome-wide study strengthens genetic link to obesity

Their findings, part of the largest genome wide study, were published in two papers today in the journal Nature.

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

Learning more about the genes and biological processes may guide the development of weight-loss therapies, and help doctors tailor the health advice they give to patients.

"Our work clearly shows that predisposition to obesity and increased body mass index is not due to a single gene or genetic change," says senior study author Elizabeth Speliotes, M.D., Ph.D., M.P.H, 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 beat obesity will work for everyone and opens the door to possible ways we could use genetic clues to help defeat obesity," she says.

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

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

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

"Presently we have no way of knowing if obese individuals will develop these obesity-related metabolic diseases and if so which ones," says Speliotes, who is also a gastroenterologist at the U-M Health System. "We envision using these genetic markers to help doctors decide which treatments would work best to keep patients healthy."

A cross-campus group of faculty and staff from the University of Michigan's Department of Human Genetics, Department of Epidemiology, Kidney Epidemiology and Cost Center, Center for Statistical Genetics, Department of Biostatics, Department of Internal Medicine, Department of Computational Medicine and Bioinformatics and the Institute for Social Research contributed to the papers.

Researchers from various institutions are increasingly bringing troves of DNA sequences into huge gene banks in hopes of tackling diseases. The international GIANT consortium is already reaping the benefits of big data sets with papers on new variants linked to BMI and a companion paper in today's Nature on waist-to-hip circumference ratio.

The analyses of genetic link to BMI indicate that the central nervous system has a role in obesity susceptibility, including a pathway that responds to changes in feeding and fasting and that is thought to be targeted by an FDA-approved weight-loss drug.

"Using novel computational methods, we have pointed to new biological pathways that act in the brain to regulate overall obesity, and also to a different set of pathways related to fat distribution that regulate key metabolic processes," says senior author Joel Hirschhorn, M.D., Ph.D., 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.

The researchers note that while some genes involved in obesity could already have been implicated in other aspects of human health, others could 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 a variety of diseases.

"Finding the genes that increase risk of obesity is only the end of the beginning," says senior author Ruth Loos, Ph.D., professor of preventive medicine at Mt. Sinai Hospital, and director of the Genetics of Obesity and related Metabolic Traits Program in the Charles Bronfman Institute for Personalized Medicine.

"A major challenge now is learning about the function of these genetic variations and how they indeed increase people's susceptibility to gain weight," Loos says. "This will be the critical next step, which will require input from scientists with a range of expertise, before our new findings can be used towards targeted obesity prevention or treatment strategies."

Belly fat key to health risk

In a companion study, an analysis of 224,459 individuals helped identify 49 sites in the genome associated with waist-to-hip ratio -- a measure of body fat distribution. People with waistlines larger than hip circumferences have more belly fat surrounding their abdominal organs.

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

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

"We need to know these genetic locations because different fat depots pose different health risks," says Karen Mohlke, Ph.D., professor of genetics at the University of North Carolina School of Medicine and a senior author on the paper that examined waist-to-hip ratio of fat distribution.

"If we can figure out which genes influence where fat is deposited, it could help us understand the biology that leads to various health conditions, 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.