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Cytoplasmic FMR1-Interacting Protein 2 Is a Major Genetic Factor Underlying Binge Eating

  • Stacey L. Kirkpatrick
    Affiliations
    Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University, Boston, Massachusetts
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  • Lisa R. Goldberg
    Affiliations
    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
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  • Neema Yazdani
    Affiliations
    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
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  • R. Keith Babbs
    Affiliations
    Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University, Boston, Massachusetts
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  • Jiayi Wu
    Affiliations
    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
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  • Eric R. Reed
    Affiliations
    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
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  • David F. Jenkins
    Affiliations
    Computational Biomedicine, Boston University, Boston, Massachusetts

    Ph.D. Program in Bioinformatics, Boston University, Boston, Massachusetts
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  • Amanda F. Bolgioni
    Affiliations
    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
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  • Kelsey I. Landaverde
    Affiliations
    Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University, Boston, Massachusetts
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  • Kimberly P. Luttik
    Affiliations
    Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University, Boston, Massachusetts
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  • Karen S. Mitchell
    Affiliations
    Department of Psychiatry, Boston University School of Medicine, Boston University, Boston, Massachusetts
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  • Vivek Kumar
    Affiliations
    The Jackson Laboratory, Bar Harbor, Maine
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  • W. Evan Johnson
    Affiliations
    Computational Biomedicine, Boston University, Boston, Massachusetts
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  • Megan K. Mulligan
    Affiliations
    Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee
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  • Pietro Cottone
    Affiliations
    Laboratory of Addictive Disorders, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University, Boston, Massachusetts
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  • Camron D. Bryant
    Correspondence
    Address correspondence to Camron D. Bryant, Ph.D., Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, 72 E Concord St, L-606C, Boston, MA 02118; .
    Affiliations
    Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University, Boston, Massachusetts
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      Abstract

      Background

      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.

      Methods

      We assessed binge eating in closely related C57BL/6 mouse substrains and in an F2 cross 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.

      Results

      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.

      Conclusions

      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.

      Keywords

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