Eating disorders (EDs) affect up to 30 million Americans and has one of the highest rates of morbidity and mortality of all psychiatric illnesses. While it has been estimated that genetics account for 50 to 80 percent of the risk of developing an ED, very few specific genes have so far been implicated. In a recently published paper in the journal PLOS ONE, researchers have identified new, ultra-rare gene mutations that may contribute to eating disorders.
To make this discovery, researchers at the University of Iowa Carver College of Medicine and the Eating Recovery Center in Dallas, Texas took a new approach that combined whole exome sequencing, machine learning and network analysis.
The study participants included 93 unrelated individuals affected by EDs including anorexia nervosa, bulimia nervosa and binge eating disorder. Using whole exome sequencing, the researchers identified previously unobserved and ultra-rare mutations that they predicted would be damaging to the protein encoded.
The researchers then compared this data to healthy genomes listed in ExAC, a database containing the exomes of more than 60,000 people. The data comparison revealed a number of genes that were statistically enriched for damaging variation in the ED group. The team also found an overrepresentation of genes previously identified as being connected to eating disorders, appetite or feeding behavior.
From there, the team developed several machine learning models that were able to use information from thousands of published studies, to determine how likely any gene is to contribute to ED development.
Finally, network analysis was employed to show the interrelationships between the genes from the study and other genes. This revealed several distinct biological pathways that were statistically more likely to have damaging genetic variants in the ED sample.
"Our findings confirm that novel and ultra-rare damaging genetic variants contribute to the risk of developing an eating disorder and identify two potential biological pathways that can be used to study and potentially treat eating disorders," says Michael Lutter, MD, PhD, a psychiatrist at the Eating Recovery Center of Dallas, and first author of the study.
The two major pathways identified include those in the neuropeptide/neurotrophic factor signaling pathway which facilitate digestion and nutrient absorption in the gut and regulate appetite in the brain. The second is in inflammation which has been known to cause appetite suppression and been linked to EDs in the past.
Using a mouse model of binge eating, they tested the therapeutic effect of targeting the neuropeptide pathway. After taking a drug that activates the GLP1 receptor in the pathway, the mice significantly reduced their food intake.
In the future, the team hopes their findings will help identify novel treatments for eating disorders and remove some of the stigma surrounding them.
Image: Schematic shows network of genetically-associated genes that have additional evidence for involvement in appetite or feeding behaviors. Image courtesy of CC PLOS ONE