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

ObjectiveEating disorders develop through a combination of genetic vulnerability and environmental stress, however the genetic basis of this risk is unknown.MethodsTo 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.ResultsAn 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, pConclusionsThese 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.