It took the genomes of nearly 340,000 people and more than 400 researchers in two dozen countries, but we now have the most comprehensive picture so far of the genetic contributors to obesity.
Two new papers in the journal Nature describe the results of two studies that connected the obesity-related factors of body mass index (the ratio between height and weight) and fat distribution to their potential genetic drivers. The studies did not isolate specific genes—at least not yet—but identified areas in the human genome where people with different BMIs and different patterns of fat distribution varied in their genetic code. Those variants will lead scientists to the genes they code for, and eventually to how those genes work in contributing to obesity.
“I think we have so many more opportunities now to learn about the biology of obesity through genetic contributions to these traits,” says Karen Mohlke, professor of genetics at University of North Carolina and the senior author of the report focusing on body fat distribution.
Those genetic clues may yield new weight-management treatments that are both more powerful and more personalized. “What the data supports is the fact that there are a lot of different causes of obesity,” says Dr. Elizabeth Speliotes, assistant professor of internal medicine and computational medicine and bioinformatics at the University of Michigan and senior author of the paper on body mass index. “If you’re hoping for one cause of obesity, that’s not reality. What causes you to be obese is probably slightly different from what causes me to be obese.”
Currently, however, all obesity is treated pretty much the same way. With the new knowledge gleaned from the genetics of what’s driving different types of obesity, that may change.
In the study involving factors contributing to BMI, Speliotes and her team discovered 97 genetic regions, or loci that account for nearly 3% of the variation among people on BMI. Of those, 56 are entirely new. Many of the regions are in areas that code for nervous system functions, or brain systems. Some aren’t so surprising—they confirm previous studies that have implicated genetic regulators of areas that control appetite, for example—but others were more unexpected. They involved regions responsible for learning, memory and even emotional regulation, hinting that some of weight and obesity may be tied to the addiction and reward pathways that help to reinforce behaviors like eating with feelings of pleasure and satisfaction. “There were definitely a lot more loci involving the brain than I would have guessed,” says Dr. Joel Hirschhorn, director of the center for basic and translational obesity research at Boston Children’s Hospital and Harvard Medical School and one of the co-authors. “That makes obesity much more of a neurobehavioral disorder than just the fact that your fat cells are more efficient or less efficient.”
They also uncovered some truly head-scratching connections between some genetic variants that contributed to higher BMI and lower risk of diabetes, heart disease and triglyceride levels. That suggests that there may be some protective genetic factors that counteract the effects of higher BMI, and exploiting these may be an entirely new way of treating obesity.
The group that zeroed in on the genetic factors directing how body fat is distributed had similar findings. Mohlke and her colleagues looked at the waist-hip ratio and found 49 areas in the genome that varied among the participants, 33 of which were entirely new. Most of the variants involved logical processes such as the formation of HDL and LDL cholesterol, triglycerides and processing of insulin.
What was interesting, however, was the fact that many of these exerted much more power on women than on men, suggesting the need to recognize gender-based differences as a critical factor in future obesity therapies.
The findings, all of the authors stress, are just the beginning of a deeper understanding of what is driving obesity in its many forms, and how best to intervene with more personalized and potentially more effective treatments. Genes, they say, only play a part in obesity, but these studies are the first step toward a better appreciation of how genes are involved in behaviors that influence what and how much we eat. “We don’t know how much impact each of these genetic loci are going to have on whether people will need different treatments,” says Hirschhorn. “But these papers provide the tools to start answering that question. It’s possible that if we know a lot more about how somebody came to be obese, then we will know more about what to do about it.”
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