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

Autor: Kirkpatrick SL; Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University, Boston, Massachusetts., Goldberg LR; 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., Yazdani N; 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., Babbs RK; Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University, Boston, Massachusetts., Wu J; 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., Reed ER; 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., Jenkins DF; Computational Biomedicine, Boston University, Boston, Massachusetts; Ph.D. Program in Bioinformatics, Boston University, Boston, Massachusetts., Bolgioni AF; 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., Landaverde KI; Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University, Boston, Massachusetts., Luttik KP; Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University, Boston, Massachusetts., Mitchell KS; Department of Psychiatry, Boston University School of Medicine, Boston University, Boston, Massachusetts., Kumar V; The Jackson Laboratory, Bar Harbor, Maine., Johnson WE; Computational Biomedicine, Boston University, Boston, Massachusetts., Mulligan MK; Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee., Cottone P; Laboratory of Addictive Disorders, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University, Boston, Massachusetts., Bryant CD; Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University, Boston, Massachusetts. Electronic address: camron@bu.edu.
Jazyk: angličtina
Zdroj: Biological psychiatry [Biol Psychiatry] 2017 May 01; Vol. 81 (9), pp. 757-769. Date of Electronic Publication: 2016 Oct 25.
DOI: 10.1016/j.biopsych.2016.10.021
Abstrakt: 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 F 2 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.
(Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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