Although prevalence of eating disorders cannot be tracked precisely, anorexia nervosa, bulimia nervosa, and binge eating disorder together may affect five percent or more of the U.S. population. Now, scientists have discovered two genetic mutations associated with an increased risk of developing eating disorders. In fact, they show how the two genes interact in the brain, converging on the same signal pathway and producing a similar biological effect.

Having identified this pathway, the researchers hope to establish it as a new target when treating eating disorders.

Needle in a Haystack?

Of the estimated 30,000 to 40,000 genes contained in the human genome, how do scientists find the exact genes associated with a disease like anorexia nervosa? One way is by investigating families affected by eating disorders, which are thought to occur as a result of a complex interaction between genetic predisposition and environmental risk factors.

For the new study, Michael Lutter, M.D., Ph.D., and his colleagues found two families with many affected individuals. In one, the researchers analyzed genes from 20 members that ranged across three generations (10 affected individuals and 10 unaffected), while in a second family, they analyzed genes from eight members (six affected and two unaffected). Anorexia nervosa is an eating disorder in which people intentionally starve themselves. An affected individual creates an obsession around food and weight and often develops compulsive or strange rituals, such as preparing gourmet feasts for others but not partaking themselves or adhering to strict exercise routines.

"It's basically a matter of finding out what the people with the disorder share in common that people without the disease don't have," Lutter explained his team’s methodology in a press release. “From a theoretical perspective, it's straightforward. But the difficulty comes in having a large enough group to find these rare genes. You have to have large families to get the statistical power.”

Genetic Link to Eating Disorders

In their genetic analysis, the researchers discovered a mutation of a gene identified as estrogen-related receptor alpha (ESRRA). ESRRA is known as a transcription factor, which means it is a protein that binds to specific DNA sequences and so regulates the flow of information from DNA to messenger RNA. In essence, it enables the expression of other genes. The mutation found by the researchers decreased ESRRA's ability to act. The researchers also found mutations of another gene, histone deacetylase 4 (HDAC4), which is known to be a transcriptional ‘repressor’ or one that turns off transcription factors, including ESRRA.

The two genes are both known to be regulated by exercise while they are both also involved in metabolic pathways in muscle and fat tissue. Importantly, the team observed the two mutations functioning together in a biological pathway related to the development of eating disorders.

Lutter and his colleagues plan to further investigate the role of these genes and ways to modify their activity in both animal studies and laboratory studies of cultured neurons. They also plan to study more patients with eating disorders to understand if other genes may be involved. Their long-term goal is to develop therapies for treating the eating disorders. The researchers estimate genetic factors contribute to the risk of developing an eating disorder an overwhelming 50 to 80 percent.

Source: Cui H, Moore J, Lutter M, et al. Eating disorder predisposition is associated with ESRRA and HDAC4 mutations. Journal of Clinical Investigation. 2013.