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

Stacey L. Kirkpatrick, Lisa R. Goldberg, Neema Yazdani, R. Keith Babbs, Jiayi Wu, Eric R. Reed, David F. Jenkins, Amanda F. Bolgioni, Kelsey I. Landaverde, Kimberly P. Luttik, Karen S. Mitchell, Vivek Kumar, W. Evan Johnson, Megan K. Mulligan, Pietro Cottone, Camron D. Bryant

Research output: Contribution to journalArticle

26 Scopus citations

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.

Original languageEnglish (US)
JournalBiological Psychiatry
DOIs
StateAccepted/In press - Aug 4 2016

Keywords

  • Anxiety
  • Binge
  • Eating disorders
  • GWAS
  • Myelin
  • Prader-Willi syndrome

ASJC Scopus subject areas

  • Biological Psychiatry

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    Kirkpatrick, S. L., Goldberg, L. R., Yazdani, N., Babbs, R. K., Wu, J., Reed, E. R., Jenkins, D. F., Bolgioni, A. F., Landaverde, K. I., Luttik, K. P., Mitchell, K. S., Kumar, V., Johnson, W. E., Mulligan, M. K., Cottone, P., & Bryant, C. D. (Accepted/In press). Cytoplasmic FMR1-Interacting Protein 2 Is a Major Genetic Factor Underlying Binge Eating. Biological Psychiatry. https://doi.org/10.1016/j.biopsych.2016.10.021