Largest Ever Genome-Wide Study Strengthens Genetic Link To Obesity
Findings help explain why some are more likely than others to gain weight and develop obesity-related diseases
ANN ARBOR, Mich. -- There are many reasons why people gain different amounts of weight and why fat becomes stored in different parts of their bodies. Now, researchers point to a genetic reason for a tendency to put on weight.
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 at Broad Institute of MIT and Harvard and Mt. Sinai Health System 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.”
The analyses of genetic links 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.
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 Biostatistics, 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.
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.
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Reference “Genetic Studies of Body Mass Index Yield New Insights for Obesity Biology,” Nature, doi:10.1038/nature14177, 12 Feb. 2015.
Additional U-M authors: Adam Locke, Bratati Kahali, Corey Powell, Jin Chen, Ellen Schmidt, Anne Jackson, Heather Stringham, Goncalo Abecasis, Michael Boehnke, Cristen Willer, David Weir, Jennifer Bragg-Grisham, Jessica Faul, and Wei Zhao.
Media contacts
Mark Derewicz, University of North Carolina, (919) 923-0959, mark.derewicz@unchealth.unc.edu
Paul Goldsmith, Broad Institute of MIT and Harvard, (617) 714-8600, paulg@broadinstitute.org
Keri Stedman, Boston Children’s Hospital, (617) 919-3110, Keri.Stedman@childrens.harvard.edu
Rebecca Spitz, Mount Sinai Health System, (212) 523-4044, rspitz@chpnet.org
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