New, ultra-rare gene mutations implicated in eating disorders

September 5, 2017
Schematic shows network of genetically-associated genes that have additional evidence for involvement in appetite or feeding behaviors. Researchers at the University of Iowa Carver College of Medicine and the Eating Recovery Center in Dallas, Texas, used whole exome sequencing, machine learning, and network analysis, to identify new, ultra-rare gene mutations within specific biological pathways that may contribute to eating disorders. The study also shows that targeting one of the pathways with a drug already approved for diabetes reduces food consumption in a mouse model of binge eating, suggesting that the findings might be useful for developing new, targeted treatments for eating disorders. The study was published recently in the journal PLOS ONE. Credit: CC PLOS ONE

By combining whole exome sequencing, machine learning, and network analysis, researchers have identified new, ultra-rare gene mutations within specific biological pathways that may contribute to eating disorders.

The study, conducted by researchers at the University of Iowa Carver College of Medicine and the Eating Recovery Center in Dallas, Texas, also shows that targeting one of the pathways with a drug already approved for diabetes reduces food consumption in a mouse model of binge eating, suggesting that the findings might be useful for developing new, targeted treatments for eating . The study was published recently in the journal PLOS ONE.

"For many psychiatric conditions there is a lot of stigma and misunderstanding. That is certainly true of eating disorders," says Jacob Michaelson, PhD, UI assistant professor of psychiatry and senior author of the study. "Science can help remove that stigma with studies like ours showing that eating disorders are fundamentally biological in nature and that, just like other diseases, there may be ways to prevent or treat eating disorders if we understand the biological causes."

Eating disorders (EDs) are very common, affecting up to 30 million Americans. They disproportionately affect young people, and have among the highest rates of morbidity and mortality of all psychiatric illnesses.

Although genetics are known to play an important role, accounting for an estimated 50 to 80 percent of the risk of developing an ED, very few specific have been implicated in the development of EDs. The UI study takes a new approach that combines genetic sequencing with machine learning to investigate the genetics of these disorders.

First, the team sequenced the protein-coding region of every gene from 93 unrelated individuals affected by various EDs, including anorexia nervosa, , and binge eating disorder. They used this whole exome sequencing information to identify previously unobserved and ultra-rare mutations that are also predicted to be damaging to the encoded protein.

Next, the researchers compared the patients' genetic data to ExAC, a large data set of exomes from more than 60,000 people. After removing exomes from individuals with any type of psychiatric diagnosis, the researchers did a simple comparison between the ED patients and the database for every human gene.

"We looked at our data and asked if the number of damaging variants we see within a gene is a lot more than we would expect based on the baseline from the ExAC database," Michaelson explains. "We found a number of genes that were statistically enriched for damaging variation in our cohort."

The team also found a strong over-representation of genes already identified by other research studies as being connected to eating disorders, appetite, or feeding behavior.

To home in on which of the genes are most likely to be involved in EDs, the team developed several machine learning models that can predict, based on information from thousands of published studies, how likely any gene is to contribute to the development of an ED. Genes that are identified by this approach and that show genetic evidence from the sequencing data are particularly strong candidates.

Finally, was used to identify the interrelationships between the genes from the study and other genes. This analysis revealed several distinct biological pathways that have a much larger burden of the damaging genetic variants in the ED sample than in people without eating disorders.

"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.

In particular, the study found that the damaging variants clustered into two major pathways. First is neuropeptide/neurotrophic factor signaling , which works in the gut to facilitate digestion and nutrient absorption, and in the brain to regulate appetite. The second pathway is inflammation. Inflammatory states cause appetite suppression and have been linked to EDs in the past.

Using a of , the team then tested the therapeutic effect of targeting the neuropeptide pathway. They gave the animals a drug that activates the GLP1 receptor in the pathway. The mice significantly reduced their food intake. Because drugs in this class are already FDA approved for other conditions, including diabetes and weight management, the researchers hope to test it in human patients with EDs.

"One of the major findings is that patients with bulimia nervosa have a high burden of mutations in the GLP1-GLP1 receptor signaling pathway," Lutter says. "There are medications that work on the GLP1 receptor that I would like to test in patients with bulimia to see if it helps."

Explore further: Eating disorders linked to increased risk of theft and other criminal behavior

More information: Michael Lutter et al, Novel and ultra-rare damaging variants in neuropeptide signaling are associated with disordered eating behaviors, PLOS ONE (2017). DOI: 10.1371/journal.pone.0181556

Related Stories

Eating disorders linked to increased risk of theft and other criminal behavior

August 9, 2017
In an analysis of nearly 960,000 females, individuals with eating disorders were more likely to be convicted of theft and other crimes.

Eating disorder gene alters feeding and behavior in female mice

October 13, 2016
Giving mice a gene mutation linked to eating disorders in people causes feeding and behavior abnormalities similar to symptoms often seen in patients with eating disorders. Only female mice are affected by the gene mutation, ...

Genetic risk factor for binge eating discovered

October 26, 2016
Researchers have identified a gene (CYFIP2) associated with binge eating.

Compassion key to treating eating disorders

August 29, 2017
Self-compassion is an important part of recovery for people with eating disorders, University of Queensland researchers have found.

Two genes linked to increased risk for eating disorders

October 8, 2013
Eating disorders like anorexia nervosa and bulimia often run in families, but identifying specific genes that increase a person's risk for these complex disorders has proved difficult.

Gene loss creates eating disorder-related behaviors in mice

April 9, 2015
Building on their discovery of a gene linked to eating disorders in humans, a team of researchers at the University of Iowa has now shown that loss of the gene in mice leads to several behavioral abnormalities that resemble ...

Recommended for you

Genome editing enhances T-cells for cancer immunotherapy

November 20, 2017
Researchers at Cardiff University have found a way to boost the cancer-destroying ability of the immune system's T-cells, offering new hope in the fight against a wide range of cancers.

A math concept from the engineering world points to a way of making massive transcriptome studies more efficient

November 17, 2017
To most people, data compression refers to shrinking existing data—say from a song or picture's raw digital recording—by removing some data, but not so much as to render it unrecognizable (think MP3 or JPEG files). Now, ...

US scientists try first gene editing in the body

November 15, 2017
Scientists for the first time have tried editing a gene inside the body in a bold attempt to permanently change a person's DNA to try to cure a disease.

Genetic mutation in extended Amish family in Indiana protects against aging and increases longevity (Update)

November 15, 2017
The first genetic mutation that appears to protect against multiple aspects of biological aging in humans has been discovered in an extended family of Old Order Amish living in the vicinity of Berne, Indiana, report Northwestern ...

Genetic variant prompts cells to store fat, fueling obesity

November 13, 2017
Obesity is often attributed to a simple equation: People are eating too much and exercising too little. But evidence is growing that at least some of the weight gain that plagues modern humans is predetermined. New research ...

Discovering a protein's role in gene expression

November 10, 2017
Northwestern Medicine scientists have discovered that a protein called BRWD2/PHIP binds to histone lysine 4 (H3K4) methylation—a key molecular event that influences gene expression—and demonstrated that it does so via ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.