title: Cytoplasmic FMR1-Interacting Protein 2 Is a Major Genetic Factor Underlying Binge Eating.
abstract: Eating disorders are lethal and heritable; however, the underlying genetic factors are unknown. Binge eating is a highly heritable trait associated with eating disorders that is comorbid with mood and substance use disorders. Therefore, understanding its genetic basis will inform therapeutic development that could improve several comorbid neuropsychiatric conditions.
  
  
  
  We assessed binge eating in closely related C57BL/6 mouse substrains and in an F2cross to identify quantitative trait loci associated with binge eating. We used gene targeting to validate candidate genetic factors. Finally, we used transcriptome analysis of the striatum via messenger RNA sequencing to identify the premorbid transcriptome and the binge-induced transcriptome to inform molecular mechanisms mediating binge eating susceptibility and establishment.
  
  
  
  C57BL/6NJ but not C57BL/6J mice showed rapid and robust escalation in palatable food consumption. We mapped a single genome-wide significant quantitative trait locus on chromosome 11 (logarithm of the odds = 7.4) to a missense mutation in cytoplasmic FMR1-interacting protein 2 (Cyfip2). We validated Cyfip2 as a major genetic factor underlying binge eating in heterozygous knockout mice on a C57BL/6N background that showed reduced binge eating toward a wild-type C57BL/6J-like level. Transcriptome analysis of premorbid genetic risk identified the enrichment terms morphine addiction and retrograde endocannabinoid signaling, whereas binge eating resulted in the downregulation of a gene set enriched for decreased myelination, oligodendrocyte differentiation, and expression.
  
  
  
  We identified Cyfip2 as a major significant genetic factor underlying binge eating and provide a behavioral paradigm for future genome-wide association studies in populations with increased genetic complexity.
authors.affiliation: Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University, Boston, Massachusetts.
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Kirkpatrick
authors.affiliation: Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University, Boston, Massachusetts; Graduate Program in Biomolecular Pharmacology, Boston University, Boston, Massachusetts.
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Goldberg
authors.affiliation: Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University, Boston, Massachusetts; Graduate Program in Biomolecular Pharmacology, Boston University, Boston, Massachusetts; Transformative Training Program in Addiction Science, Boston University, Boston, Massachusetts.
authors.forename: Neema
authors.initials: N
authors.lastname: Yazdani
authors.affiliation: Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University, Boston, Massachusetts.
authors.forename: R Keith
authors.initials: RK
authors.lastname: Babbs
authors.affiliation: Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University, Boston, Massachusetts; Ph.D. Program in Biomedical Sciences, Graduate Program in Genetics and Genomics, Boston University, Boston, Massachusetts; Transformative Training Program in Addiction Science, Boston University, Boston, Massachusetts.
authors.forename: Jiayi
authors.initials: J
authors.lastname: Wu
authors.affiliation: Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University, Boston, Massachusetts; Ph.D. Program in Bioinformatics, Boston University, Boston, Massachusetts.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Reed
authors.affiliation: Computational Biomedicine, Boston University, Boston, Massachusetts; Ph.D. Program in Bioinformatics, Boston University, Boston, Massachusetts.
authors.forename: David F
authors.initials: DF
authors.lastname: Jenkins
authors.affiliation: Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University, Boston, Massachusetts; Graduate Program in Biomolecular Pharmacology, Boston University, Boston, Massachusetts.
authors.forename: Amanda F
authors.initials: AF
authors.lastname: Bolgioni
authors.affiliation: Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University, Boston, Massachusetts.
authors.forename: Kelsey I
authors.initials: KI
authors.lastname: Landaverde
authors.affiliation: Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University, Boston, Massachusetts.
authors.forename: Kimberly P
authors.initials: KP
authors.lastname: Luttik
authors.affiliation: Department of Psychiatry, Boston University School of Medicine, Boston University, Boston, Massachusetts.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Mitchell
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine.
authors.forename: Vivek
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Computational Biomedicine, Boston University, Boston, Massachusetts.
authors.forename: W Evan
authors.initials: WE
authors.lastname: Johnson
authors.affiliation: Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Megan K
authors.initials: MK
authors.lastname: Mulligan
authors.affiliation: Laboratory of Addictive Disorders, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University, Boston, Massachusetts.
authors.forename: Pietro
authors.initials: P
authors.lastname: Cottone
authors.affiliation: Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University, Boston, Massachusetts. Electronic address: camron@bu.edu.
authors.forename: Camron D
authors.initials: CD
authors.lastname: Bryant
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D056912:Binge-Eating Disorder / Q000235:genetics* / Q000378:metabolism; D002032:Bulimia / Q000235:genetics / Q000378:metabolism; D003192:Compulsive Behavior / Q000235:genetics / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D005260:Female; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology*; D040641:Quantitative Trait Loci; D059467:Transcriptome
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C529497:Cyfip2 protein, mouse; D009419:Nerve Tissue Proteins
keywords: Anxiety; Binge; Eating disorders; GWAS; Myelin; Prader-Willi syndrome