Anorexia has one of the highest mortality rates of any psychiatric disorder, and scientists are still perplexed by its causes. Now, however, a new study has examined the genomes of tens of thousands of people and identified eight chromosome locations that may increase vulnerability to the illness. Some of these locations have been linked to metabolic problems—suggesting the causes of anorexia may not be purely psychological.

Anorexia nervosa, as it is officially known, is an eating disorder primarily associated with an extremely low body mass index (BMI), usually accompanied by an aversion to eating and a distorted body image. It affects about 1 to 4 percent of women and 0.3 percent of men. Previous studies in twins suggest it has a 50 to 60 percent heritability, meaning 50 to 60 percent of the variability of the traits associated with anorexia can be explained by genetic differences among people, with the remainder linked to the environment or other influences. One of the disorder’s most insidious features is that many patients are able to restore their body to a normal weight but have trouble keeping the pounds on.

“We all know how hard it is to lose weight. Yet somehow [people with anorexia] have this capacity to get down to a dangerously low weight and stay there,” says study co-author Cynthia Bulik, a professor of eating disorders at the University of North Carolina at Chapel Hill and the Karolinska Institute in Sweden. “It has been explained psychologically—but it would take such an enormous amount of willpower to do that.” In treatment centers, patients can be nourished to a healthy BMI, Bulik says, but “we send them back out, and their weight just starts dropping like a stone again.” The trend seems almost the inverse of obesity, in which patients can lose weight quite easily, but it often returns. “We don't know what the mechanism is here yet,” she says. “It’s just something that we've seen clinically for years but haven’t thought about as potentially [involving] opposite ends of the same underlying process.”

Bulik and her colleagues published a study in 2017 that analyzed the genomes of about 3,500 people with anorexia. In it, they identified the first chromosome location, or locus, to be correlated with the disorder, hinting at a possible metabolic link. Their new study analyzed dozens of data sets containing a total of nearly 17,000 people with anorexia and more than 55,000 healthy controls. The subjects were from 17 countries, and all of them had European ancestry.

This time, the researchers identified eight genetic loci linked to the disorder, although Bulik says there are likely hundreds. Some of the eight were associated with psychiatric illnesses—but others were associated with metabolic traits, even after the researchers controlled for BMI. This result suggests the risk of developing anorexia may be linked to metabolic factors, the researchers report in the study, which was published in July in Nature Genetics.

“There’s no question that this is an extremely important study and is aiming to take state-of-the-art methods and use them to examine the genetic risk factors that may be at the base of the challenging disorder of anorexia nervosa,” says Evelyn Attia, a professor of psychiatry at Columbia University Irving Medical Center, who was not involved in the work. The findings are correlational, however, and do not conclusively prove that metabolic factors are among the causes of the disorder, Attia notes.

Nevertheless, the study’s conclusions increase our understanding of genetic contributors to anorexia. Pharmacogeneticists may be able to use them as a starting point to develop new treatments, Bulik says. “Right now, we have no medications effective in treatment of this illness,” she says. “We’re starting at zero.”

Attia agrees that learning more about the genetics involved is a helpful first step toward therapies. “We’re in the early phase of using these genetic results to directly inform new treatments,” she says. But she adds that understanding more about what contributes to the development of this complex illness—notoriously hard to treat despite being known for centuries—is “tremendously exciting.”

Environmental influences are also thought to play a role in anorexia’s development, but they are difficult to measure. Dieting is a known risk factor—most people who diet, however, do not go on to develop the disorder. “Most of us, when we get hungry, we feel worse. And we get kind of grumpy and irritable and start foraging and do whatever we can to find food,” Bulik says. Yet “people who are predisposed to anorexia often say that they feel sort of irritable and anxious at baseline, and starvation actually makes them feel better.” Understanding this paradox would go a long way toward improving treatment, she says.

Anne Becker, a professor of global health and social medicine at Harvard Medical School, has conducted studies of body image and eating disorders among women in Fiji. Becker traveled to the archipelago nation in the early 1980s, describing its strong food culture and lack of weight stigma. She went back in 1995 and 1998—before and after television became widespread in the country—and noted a striking increase in the number of girls who reported “purging” themselves to look more like women they saw on TV.

Becker says science still has an incomplete understanding of how social norms, food insecurity and social determinants of poor health affect vulnerability to the disorder. She praises Bulik and her colleagues for their rigorous study of the genetic factors involved, adding, “I hope, in the future, that such studies can also encompass more global diversity and, especially, populations in the global south, which have been neglected in eating disorders research.” 

Environmental factors may contribute to the pursuit of thinness at the core of anorexia nervosa but do not, by themselves, cause eating disorders, Attia says. Currently, in Western society, “we are in an environment flooded with images of idealized thin bodies,” she says “[yet] rates of anorexia nervosa in Europe and North America are relatively low and have not changed much in recent years.” The social context may simply increase the risk of eating disorders such as anorexia among individuals who are biologically susceptible to them.

To look deeper, Bulik says she and her team plan to increase the size of their study sample and to diversify it by including more people of African and Asian ancestry. Although their latest paper had a large number of subjects, it was still relatively small by the standards of such genetic-association studies. And there are many other eating disorders besides anorexia whose genetic involvement has yet to be explored.

But this study is an important step. “For now, this [research] actually gives an explanatory model to a lot of patients and families who have just been perplexed by this illness for a long time,” Bulik says. “It can be really encouraging when they’re on that difficult path of recovery and really need that kind of help.”