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

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Objective: Eating disorders develop through a combination of genetic vulnerability and environmental stress, however the genetic basis of this risk is unknown. Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish (US)
Article numbere0181556
JournalPloS one
Volume12
Issue number8
DOIs
StatePublished - Aug 2017

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Lutter, M., Bahl, E., Hannah, C., Hofammann, D., Acevedo, S., Cui, H., McAdams, C. J., & Michaelson, J. J. (2017). Novel and ultra-rare damaging variants in neuropeptide signaling are associated with disordered eating behaviors. PloS one, 12(8), [e0181556]. https://doi.org/10.1371/journal.pone.0181556