Novel and ultra-rare damaging variants in neuropeptide signaling are associated with disordered eating behaviors

Michael Lutter; Ethan Bahl; Claire Hannah; Dabney Hofammann; Summer Acevedo; Huxing Cui; Carrie J McAdams; Jacob J Michaelson

doi:10.1371/journal.pone.0181556

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Novel and ultra-rare damaging variants in neuropeptide signaling are associated with disordered eating behaviors

Journal article

Open access

Peer reviewed

Novel and ultra-rare damaging variants in neuropeptide signaling are associated with disordered eating behaviors

Michael Lutter, Ethan Bahl, Claire Hannah, Dabney Hofammann, Summer Acevedo, Huxing Cui, Carrie J McAdams and Jacob J Michaelson

PloS one, Vol.12(8), pp.e0181556-e0181556

2017

DOI: 10.1371/journal.pone.0181556

PMCID: PMC5573281

PMID: 28846695

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Abstract

Eating disorders develop through a combination of genetic vulnerability and environmental stress, however the genetic basis of this risk is unknown. To understand the genetic basis of this risk, we performed whole exome sequencing on 93 unrelated individuals with eating disorders (38 restricted-eating and 55 binge-eating) to identify novel damaging variants. Candidate genes with an excessive burden of predicted damaging variants were then prioritized based upon an unbiased, data-driven bioinformatic analysis. One top candidate pathway was empirically tested for therapeutic potential in a mouse model of binge-like eating. An excessive burden of novel damaging variants was identified in 186 genes in the restricted-eating group and 245 genes in the binge-eating group. This list is significantly enriched (OR = 4.6, p<0.0001) for genes involved in neuropeptide/neurotrophic pathways implicated in appetite regulation, including neurotensin-, glucagon-like peptide 1- and BDNF-signaling. Administration of the glucagon-like peptide 1 receptor agonist exendin-4 significantly reduced food intake in a mouse model of 'binge-like' eating. These findings implicate ultra-rare and novel damaging variants in neuropeptide/neurotropic factor signaling pathways in the development of eating disorder behaviors and identify glucagon-like peptide 1-receptor agonists as a potential treatment for binge eating.

Genetic Predisposition to Disease

Humans

Middle Aged

Computational Biology

Feeding and Eating Disorders - genetics

Male

Neuropeptides - metabolism

Gene Regulatory Networks

Appetite Regulation - genetics

Exome

Young Adult

Feeding and Eating Disorders - metabolism

Adolescent

Adult

Female

Signal Transduction - physiology

Neuropeptides - genetics

Details

Title: Subtitle: Novel and ultra-rare damaging variants in neuropeptide signaling are associated with disordered eating behaviors
Creators: Michael Lutter - Eating Recovery Center of Dallas, Plano, Texas, United States of America
Ethan Bahl - Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, Iowa, United States of America
Claire Hannah - Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, Iowa, United States of America
Dabney Hofammann - Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, Iowa, United States of America
Summer Acevedo - Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
Huxing Cui - Department of Pharmacology, University of Iowa, Carver College of Medicine, Iowa City, Iowa, United States of America
Carrie J McAdams - Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
Jacob J Michaelson - Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, Iowa, United States of America
Resource Type: Journal article
Publication Details: PloS one, Vol.12(8), pp.e0181556-e0181556
DOI: 10.1371/journal.pone.0181556
PMID: 28846695
PMCID: PMC5573281
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library of Science; United States
Grant note: K23 MH093684 / NIMH NIH HHS T32 GM008629 / NIGMS NIH HHS R01 MH105527 / NIMH NIH HHS
Language: English
Date published: 2017
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Communication Sciences and Disorders; Psychiatry; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology
Record Identifier: 9984040438502771

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