Studies reveal disorders like anorexia nervosa have both genetic and psychiatric correlations
For many decades, the popular narrative surrounding anorexia nervosa was that it was an emotional disorder springing from profound cultural pressures combined with dysfunctional family dynamics. Teenage girls, typically, would refuse to eat in an obsessive bid to lose weight. They would imagine themselves to be fat, even if mirrors and scales demonstrated otherwise. Because of the surfeit of images of rail-thin preteen models cluttering the pages of trendy fashion magazines, it was easy to imagine this theory to be true. It made sense if some clinicians regarded anorexia as the inevitable result of a “you-can-never-be-too-rich-or-too-thin” culture.
Today, researchers are developing a much more nuanced understanding of not only anorexia, but other eating disorders like bulimia and binge eating. Increasingly, evidence suggests that genetics is a primary driver.
In 2019, one of the largest studies ever conducted on anorexia identified eight genetic variants associated with the disorder. The study, published in Nature Genetics, combined data collected by more than 100 researchers from around the world. Looking at 16,992 anorexia nervosa cases and 55,525 controls of European ancestry from 17 countries across North America, Europe, Australia, and Asia, the study found that the genetic basis of anorexia nervosa overlaps with other psychiatric disorders such as obsessive-compulsive disorder, depression, anxiety, and schizophrenia .
“This provides concrete evidence that genes are involved in risk for developing anorexia nervosa,” says principal investigator Cynthia M. Bulik, founding director of the University of North Carolina Center of Excellence for Eating Disorders and a professor in the Department of Psychiatry at the University of North Carolina at Chapel Hill (Figure 1). “Second, the significant genetic correlations we observed revealed clearly that there were both psychiatric AND metabolic genetic correlations.”
In short, says Bulik, anorexia is a “metabo-psychiatric disorder.”
New Understanding of a Deadly Disorder
It is a colossal finding in the field, as eating disorders are estimated to affect nearly 9% of the world’s population, with profound consequences . About 1% grapple with anorexia, while 2%–3% have bulimia nervosa, characterized by binge-eating followed by vomiting or purging, and another 2%–3% binge eat. Nearly 10% of those with eating disorders end up dying as a result . And eating disorders are not just a problem with teenage girls. Eating disorders affect people of all ages, genders, and races. Anorexia, according to the National Institute of Mental Health, is the most deadly mental illness in the United States, second only to opioid abuse.
“Our conceptualizations and treatments have primarily focused on the psychiatric aspects of anorexia,” says Bulik, who is also the director of the Centre for Eating Disorders Innovation at the Karolinska Institutet in Stockholm. “Accordingly, our success in treating the disorder is poor with only about 30% of individuals achieving full recovery. In addition, it is very common for people to rapidly lose weight after inpatient renourishment and often that cycle repeats itself several times during the course of treatment.”
Results of the latest studies suggest, she says, “that we need to focus our attention on not just psychiatric factors but also metabolic factors that influence the extreme weight loss and the ‘weight relapse’ that we often see.”
In an effort to further uncover the genetic links behind eating disorders, Bulik is spearheading the Eating Disorders Genetics Initiative with more than US$7 million from the National Institute of Health and additional funding from Sweden, the United Kingdom, and other countries. Researchers hope to include 100,000 people with anorexia nervosa, bulimia nervosa, and binge eating disorder. Bulik is hoping that more studies might lead to new drug treatments.
Nature and Nurture
In addition to linking eating disorders to genetics, other researchers are exploring the interplay of both genetics and the environment. In the face of certain stressors, it appears that some people who are genetically predisposed to the condition may develop the disorder.
Lori Zeltser, a developmental neuroscientist and associate professor of pathology and cell biology at Columbia University (Figure 2), has studied the brains of developing mice, trying to identify feeding circuits that increase susceptibility to obesity in adulthood. Zeltser published a paper in a 2016 issue of Translational Psychiatry in which she reported on mice with a variant in a gene that in people is linked to anorexia. On its own, the variant didn’t seem to make much of a difference in mouse behavior. But when the mice were given diets restricting calories by 20%–30% and then subjected to stress which included isolation, they stopped eating .
“Some people try to draw a false dichotomy by arguing the primacy of either nature or nurture,” says Zeltser. “Our research using mouse models suggests that it is the combination of genetic and environmental risk factors that drives susceptibility to anorexia.”
Her research raises interesting questions about how environmental stressors, including stress spurned on by life lived in a social media world (or more recently, life lived in isolation during a pandemic), might lead some kids toward anorexia. Especially if those kids happened to be trying out a fad diet to lose a few pounds.
“One lesson from our studies is that both the type and timing of the stress matters,” says Zeltser. “We have used social isolation stress in mice as a surrogate for social phobias often observed in patients with anorexia. We are finding that chronic exposure to social isolation affects feeding behaviors in response to stress. Interestingly, beginning this isolation in adolescence vs. adulthood has different effects on stress responses in males and females. The social isolation experienced during this pandemic will likely impact susceptibility to disordered eating, but the direction of the effects (i.e., promoting vs. inhibiting eating) will likely depend on the age and biological sex of the individual, severity of the isolation and genetic factors.”
Research conducted by Joanna Steinglass, professor of clinical psychiatry at Columbia University (Figure 3), has revealed differences in MRI brain scans of people with eating disorders and those without. In people with anorexia, MRI scans revealed that the region of the brain associated with selecting foods was the dorsal striatum, which is a key region involved in forming habits. In people without an eating disorder, a different brain region is associated with food choices.
“This is meaningful on its own because it serves to underscore that there are neurobiological differences associated with this illness,” says Steinglass. “We cannot emphasize enough how important it is to remember that the symptoms of eating disorders have a neurobiological basis.”
Steinglass’ research supports the notion that persistent food restriction can become a “habit” that is initially learned through reward processes mediated by the brain’s ventral striatum but that over time switch to the dorsal striatum. There, food choices become less sensitive to an outcome and more closely tied to a trigger, like an urge to smoke a cigarette after a meal.
“By understanding the neurobiological vulnerability of some individuals, we may begin to understand why restricting food intake becomes so entrenched and so difficult to change for individuals with anorexia nervosa,” she says. “During adolescence, a lot is happening in the brain, and there may be aspects of this that create a particular period of vulnerability to the development of anorexia nervosa.”
Steinglass and her colleagues are now conducting a large NIMH-funded study examining how the brain changes during adolescence. By following teens with anorexia nervosa and their healthy peers for two years, they hope to understand whether neural systems guiding eating behavior differ between kids who respond well to initial treatment for anorexia nervosa and those who don’t. Specifically, she says, her group will test whether the neural systems associated with habit formation are contributing to illness.
Other researchers have noted other ways in which the brains of those with eating disorders differ from those without them. Walter Kaye, a psychiatrist who directs the eating disorders program at the University of California, San Diego, led a study looking at how the brains of people with anorexia behave after fasting compared to those without the disorder. In normal people, the reward and motivation brain circuits light up when receiving sugar water after a 16-hour fast. In subjects with anorexia, they don’t, or at least not to the same degree. This leads Kaye to conclude that patients can’t convert their hunger into a desire to eat. And with a diminished reward signal, they may actually interpret food as something risky, rather than rewarding.
“The distortion of signals in the brain in both depression and anorexia impact the awareness of hunger, the motivation to eat and food avoidance,” Kaye said upon the publication of the study.
Second look at treatment
In light of these and other findings regarding this disorder, clinicians on the ground are taking a second look at treatment protocols. Now on the table are not just talk therapies or even family-based treatment, which is widely considered the most effective form of treatment (asking parents to curtail school, work, and hobbies to sit with their children during all meals, demanding that they eat), but also treatments like deep brain stimulation and new drug therapies.
An 18-person study at Johns Hopkins University is offering the psychedelic drug psilocybin to patients since early data suggests it may help smokers and alcoholics combat addiction. Another seven-person study by Rebecca Park at the University of Oxford is looking into the efficacy of deep-brain stimulation in people with severe anorexia, some of whom also have OCD. She posits that disrupting the signaling in neural networks with deep-brain stimulation might help people with anorexia as it seems to help those with OCD. Steinglass says she has also seen progress in her own clinic using a psychotherapy approach that focuses on the cues leading to restrictive eating rather than the outcome. Interventions of this type seemed to help anorexics eat more calories, compared with a control intervention, she says.
New ideas like these promise to dramatically broaden future treatment approaches to eating disorders. “It hopefully will change this concept that these are disorders of will and frustration and control,” says James Greenblatt, assistant clinical professor of psychiatry at Tufts University School of Medicine and Dartmouth College Geisel School of Medicine. (See also “A Devastating Disorder, Poorly Understood” in this issue of IEEE Pulse.)
“It does provide a better sense in the community of, okay, this is not your fault. This is not a disorder of control. There is a genetic underlying that triggers this neurobiological process that distorts how your body responds to food and how your brain thinks about your body.”
- H. J. Watson et al., “Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa,” Nature Genet., vol. 51, no. 8, pp. 1207–1214, online Jul. 15, 2019, doi: 10.1038/s41588-019-0439-2.
- M. Galmiche, P. Dechelotte, G. Lambert, and M. P. Tavolacci, “Prevalence of eating disorders over the 2000–2018 period: A systematic literature review,” Amer. J. Clin. Nutrition, vol. 109, no. 5, pp. 1402–1413, May 2019.
- J. Arcelus, A. J. Mitchell, J. Wales, and S. Nielsen, “Mortality rates in patients with anorexia nervosa and other eating disorders: A meta-analysis of 36 studies,” Arch. Gen. Psychiatry, vol. 68, no. 7, pp. 724–731, 2011.
- M. Madra and L. Zeltser, “BDNF-Val66Met variant and adolescent stress interact to promote susceptibility to anorexic behavior in mice,” Transl. Psychiatry, vol. 6, no. 4, p. e776, Apr. 2016, doi: 10.1038/tp.2016.35.