Studies provide new insights into the genetics of obesity and fat distribution

An international consortium has made significant inroads into uncovering the genetic basis of obesity by identifying 18 new gene sites associated with overall obesity and 13 that affect fat distribution. The studies include data from nearly a quarter of a million participants, the largest genetic investigation of human traits to date. The papers, both from the GIANT (Genetic Investigation of ANthropometric Traits) consortium – which consists of more than 400 scientists from 280 research institutions worldwide – will appear in Nature Genetics and are receiving early online publication.

Joel Hirschhorn, MD, PhD of Children's Hospital Boston and the Broad Institute, a senior author on the overall obesity paper and involved in both, says, "Different people have different susceptibilities to obesity. Some don't rigorously watch what they eat or how much they exercise and still resist gaining weight, while others constantly struggle to keep their weight from skyrocketing. Some of this variability is genetic, and our goal was to increase understanding of why different people have different inherited susceptibility to obesity." Because most of the genes newly implicated in these studies have never been suspected of having a role in obesity, findings from both papers begin to shed light on the underlying biology, which may lead to better categorization and treatment of obesity in the future, Hirschhorn notes.

The overall obesity study looked for genetic determinants of body mass index (BMI), calculated as an individual's weight in kilograms over height in meters squared.

Investigators combined data from 46 studies involving nearly 124,000 people and confirmed the top results in almost 126,000 more individuals to identify a total of 32 sites consistently associated with BMI, 18 of which are new. One of the novel variants is in the gene encoding for a receptor protein that responds to signals from the gut to influence insulin levels and metabolism. Another variant is near a gene known to encode proteins affecting appetite.

"One of the most exciting parts of this work is that most of the BMI-associated variants identified are in or near genes that have never before been connected to obesity. Through this work we are discovering that the underlying biological underpinnings of obesity are many, varied and largely uncharacterized," says Elizabeth K. Speliotes, MD, PhD, MPH, of Massachusetts General Hospital and the Broad Institute, the first author of the BMI study and also involved in both studies.

Although the effects of each individual variant were modest, individuals who carried more than 38 BMI-increasing variants were on average 15 to 20 pounds heavier than those who carried fewer than 22 such variants. However, even in combination these variants explain only a small fraction of the overall variation in body weight. The researchers found that the combined genetic information from these variants was only slightly better than flipping a coin in predicting whether an individual would be obese, probably because many other factors, both genetic and environmental, contribute to overall weight.