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

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          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.

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          Most cited references45

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          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

          Yoav Benjamini, Yosef Hochberg (1995)
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            Gene Ontology: tool for the unification of biology

            Michael Ashburner, Catherine A. Ball, Judith Blake … (2002)
            Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing. To this end, three independent ontologies accessible on the World-Wide Web (http://www.geneontology.org) are being constructed: biological process, molecular function and cellular component.
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              Prevalence, heritability, and prospective risk factors for anorexia nervosa.

              Mogens Pedersen, Patrick F Sullivan, Helena Furberg … (2006)
              Anorexia nervosa (AN) is a serious mental illness with marked morbidity and mortality. To explore the prevalence, heritability, and prospectively assessed risk factors for AN in a large population-based cohort of Swedish twins. During a 4-year period ending in 2002, all living, contactable, interviewable, and consenting twins in the Swedish Twin Registry (N = 31 406) born between January 1, 1935, and December 31, 1958, underwent screening for a range of disorders, including AN. Information collected systematically in 1972 to 1973, before the onset of AN, was used to examine prospective risk factors for AN. Population-based sample of twins in Sweden. Cases of AN were identified as those individuals who met full DSM-IV criteria by means of clinical interview of the Swedish Twin Registry, who had a hospital discharge diagnosis of AN, or who had a cause-of-death certificate including an AN diagnosis. The overall prevalence of AN was 1.20% and 0.29% for female and male participants, respectively. The prevalence of AN in both sexes was greater among those born after 1945. Individuals with lifetime AN reported lower body mass index, greater physical activity, and better health satisfaction than those without lifetime AN. Anorexia nervosa was inversely associated with the development of overweight (odds ratio, 0.29; 95% confidence interval [CI], 0.16-0.54 [P<.001]). The heritability of narrowly defined DSM-IV AN (additive genetic effects) was estimated to be a(2) = 0.56 (95% CI, 0.00-0.87), with the remaining variance attributable to shared environment (c(2) = 0.05; 95% CI, 0.00-0.64) and unique environment (e(2) = 0.38; 95% CI, 0.13-0.84). Neuroticism measured about 3 decades before the diagnostic assessment was significantly associated with the development of later AN (odds ratio, 1.62; 95% CI, 1.27-2.05 [P<.001]). The prevalence of AN was higher in both male and female participants born after 1945. Individuals who survive AN and who no longer have body mass indexes in the AN range appear to be at lower risk for the development of overweight. Prospectively assessed neuroticism was associated with the subsequent development of AN, the liability to which is under considerable genetic influence.
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                Author and article information

                Contributors
                Dabney Hofammann: Role: Writing – original draft
                Hubert Vaudry: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 28 August 2017
                Publication date Collection: 2017
                Volume: 12
                Issue: 8
                Electronic Location Identifier: e0181556
                Affiliations
                [1 ] Eating Recovery Center of Dallas, Plano, Texas, United States of America
                [2 ] Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, Iowa, United States of America
                [3 ] Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
                [4 ] Department of Pharmacology, University of Iowa, Carver College of Medicine, Iowa City, Iowa, United States of America
                Universite de Rouen, FRANCE
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-9713-0992
                Article
                Publisher ID: PONE-D-17-09112
                DOI: 10.1371/journal.pone.0181556
                PMC ID: 5573281
                PubMed ID: 28846695
                SO-VID: 3e76f3cb-221f-4fc9-b708-171f6615b1cc
                Copyright © © 2017 Lutter et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 7 March 2017
                Date accepted : 3 July 2017
                Page count
                Figures: 3, Tables: 1, Pages: 15
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100005310, Klarman Family Foundation;
                Award Recipient :
                Funded by: University of Iowa Foundation
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000025, National Institute of Mental Health;
                Award ID: MH093684
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000025, National Institute of Mental Health;
                Award ID: MH105527
                Award Recipient :
                ORCID: http://orcid.org/0000-0001-9713-0992
                This work was supported by funding from the Klarman Family Foundation Grants Program in Eating Disorder Research (ML), University of Iowa Foundation, Department of Psychiatry (ML), and NIMH grants MH093684 (CJM), and MH105527 (JJM).
                Categories
                Subject: Research Article
                Subject: Medicine and Health Sciences
                Subject: Mental Health and Psychiatry
                Subject: Eating Disorders
                Subject: Medicine and Health Sciences
                Subject: Mental Health and Psychiatry
                Subject: Eating Disorders
                Subject: Anorexia Nervosa
                Subject: Biology and Life Sciences
                Subject: Physiology
                Subject: Physiological Processes
                Subject: Eating
                Subject: Medicine and Health Sciences
                Subject: Physiology
                Subject: Physiological Processes
                Subject: Eating
                Subject: Medicine and Health Sciences
                Subject: Mental Health and Psychiatry
                Subject: Eating Disorders
                Subject: Bulimia Nervosa
                Subject: Biology and Life Sciences
                Subject: Organisms
                Subject: Animals
                Subject: Vertebrates
                Subject: Amniotes
                Subject: Mammals
                Subject: Rodents
                Subject: Mice
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Peptides
                Subject: Research and Analysis Methods
                Subject: Database and Informatics Methods
                Subject: Biological Databases
                Subject: Mutation Databases
                Subject: Biology and Life Sciences
                Subject: Genetics
                Subject: Mutation
                Subject: Mutation Databases
                Subject: Biology and Life Sciences
                Subject: Behavior
                Custom metadata
                Data Availability All phenotype and genotype files are available from dbGaP under study ID phs001414.v1.p1.

                ScienceOpen disciplines: Uncategorized
                Data availability:
                ScienceOpen disciplines: Uncategorized

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