Obesity study implicates brain genes

SEM (scanning electron microscope) micrograph of fat cells.
Image courtesy of David Gregory and Debbie Marshall/WellcomeImages. Image adapted by Sigrid Hart.

By bringing together multiple research groups from the US and Europe, the Genetic Investigation of ANthropometric Traits (GIANT) consortium has identified six new regions of the genome that are associated with common human obesity. The consortium researchers, including scientists from the Broad Institute of Harvard and MIT, Massachusetts General Hospital, Children's Hospital Boston, Harvard University Genetics, University of Michigan, Oxford and Cambridge Universities, found what could be a connection between genes involved in the central nervous system and a predisposition to obesity. Their results appear in the December 14 advance online issue of Nature Genetics.

The researchers studied the genetics of body mass index (BMI), a measure that uses height and weight to classify people into body mass categories such as overweight or obese. Although factors like diet and exercise influence BMI, studies of twins and families indicate that much of the variability in BMI is heritable, or genetic. So far, work on rare genetic syndromes that cause obesity has not been able to explain why roughly one-third of Americans are obese and two-thirds are overweight, so the researchers examined BMI in populations where common obesity prevails.

Elizabeth Speliotes, co-first author of the Nature Genetics paper and a postdoctoral fellow at the Broad Institute working with senior associate member Joel Hirschhorn, said that the consortium aimed to find variants associated with common obesity rather than the rare mutations that have extreme effects. Indeed, all of the BMI increasing variants that they found are common in the population. "Most people of European ancestry reading this article carry at least one of the genetic factors we describe in our paper," she said.

The researchers identified eight regions of the genome that are reproducibly associated with BMI. Two of these regions are near candidate genes that have previously been associated with obesity - MC4R and FTO. Interestingly, MC4R and a newly identified gene, SH2B1, are part of the melanocortin and leptin pathways, respectively, both of which control appetite regulation. "It is particularly exciting that we uncovered genes involved in the two main pathways that have dominated the animal and human obesity literature for the last fourteen years. That helps confirm that the things coming out of our screen were indeed real and relevant to obesity, " said Speliotes, who is also an instructor in gastroenterology and medicine at Massachusetts General Hospital and Harvard Medical School.

More importantly, the study identified five regions of the genome, known as loci, that had never previously been associated with BMI but now appear be linked with human obesity. "One of the major insights to come out of this is a new window into the biology of obesity," said Hirschhorn, who is also a pediatric endocrinologist at Children's Hospital Boston and an associate professor of genetics at Harvard Medical School.

Speliotes said that replicating and validating these results was critical. "It was important to us that the things that we were reporting were real so we took great efforts to make sure these loci could be replicated." Indeed, their colleagues at deCODE genetics did an independent genome-wide association study of BMI and were able to provide data that validated the GIANT findings at all of the loci they had data for.

Interestingly, several of the consortium's candidate genes may act upon a person's central nervous system. The investigators found that five of the six new candidate genes and both of the two previously associated candidate genes are expressed at high levels in the brain, particularly in the hypothalamus and cortex. "These results could be telling us something about where the master control regulators are that affect common human obesity," Speliotes said. "Certainly, appetite regulation is one possibility, but they could also be involved in energy expenditure, mood, energy balance, or other parameters that the brain controls."

Although the implication of the central nervous system in control of BMI is exciting, further work is needed to uncover how the candidate genes function in obesity. And, as these newly identified regions of the genome are studied in finer detail, researchers may find that they also harbor other, more rare variants that may influence BMI. Such variants could provide insights into the biological basis of both rare and common forms of obesity.

The researchers' success in bringing together fifteen studies into one meta-analysis has encouraged them to pursue an even larger study next. "The next round of studies will involve new collaborators and DNA from more than 100,000 people," said Hirschhorn. "We also hope to do analyses to determine whether genetic variants have the same effects in different ethnic populations, in both genders, and in individuals with extreme obesity compared to overweight or normal weight individuals." The researchers hope that the next round will confirm the results they have already found and unearth new, reproducible associations with BMI. And the team hopes that some of the new candidate genes may become drug targets someday. The more genes they find, the better the chances of finding something that can be readily targeted, according to Speliotes.

Other Broad researchers contributing to this work include Amanda Elliot, Gillaume Lettre, Helen Lyon, Steve McCarroll, Noël Burtt, Lauren Gianniny, Candace Guiducci, Rachel Hackett, Mikko Kuokkanen, David Altshuler, David Hunter, and Leena Peltonen. The investigators on this study are part of the GIANT consortium.