Genetic differences in the behavioral organization of binge eating, conditioned food reward, and compulsive-like eating in C57BL/6J and DBA/2J strains

et al. 2020

Preprint

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Word count in abstract: 247 Word count in main text: 4410 ACKNOWLEDGEMENTS This work was funded by R21DA038738 (C.D.B.), R01DA039168 (C.D.B.), and R01CA221260 (M.I.D., C.D.B.) ABSTRACTObjective. Binge eating is a heritable quantitative trait associated with eating disorders (ED) and refers to the rapid consumption of a large quantity of energy-dense food that is associated with loss of control, anxiety, and depression. Binge Eating Disorder is the most common ED in adults in the US; however, the genetic basis is unknown. We previously identified robust mouse inbred strain differences between C57BL/6J and DBA/2J in binge-like eating (BLE) of sweetened palatable food (PF) in an intermittent access, conditioned place preference paradigm. Methods.To map the genetic basis of BLE, we phenotyped and genotyped 128 C57BL/6J x DBA/2J-F2 mice.Results. We identified a quantitative trait locus (QTL) on chromosome 13 influencing progressive changes in body weight across training days (LOD = 5.5; 26-39 cM). We also identified two sex-combined QTLs influencing PF intake on chromosome 5 (LOD = 5.6; 1.5-LOD interval = 21-28 cM) and 6 (LOD = 5.3; 1.5-LOD interval = 50-59 cM). Furthermore, sex-specific analyses revealed that the chromosome 6 locus was driven by males (1.5-LOD interval: 52-59 cM) and identified a female-selective QTL for BLE on chromosome 18 (LOD = 4.1; 1.5-LOD interval: 23-35 cM). Systems genetic analysis of the chromosome 6 locus for BLE using GeneNetwork legacy trait datasets from BXD recombinant inbred strains identified Adipor2 and Plxnd1 as two positional, functional, biological candidate genes.Discussion. We identified genetic loci influencing BLE. Future studies will phenotype BXD recombinant inbred strains to fine map loci and support candidate gene nomination and validation.

Section: Binge-like Eating (Ble) and Compulsive-like Eating (Cle)mentioning

confidence: 99%

Section: Identification Of Qtls Underlying Differences In Bw and Pf Imentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Systems genetic analysis of binge-like eating in a C57BL/6J x DBA/2J-F2 cross

Yao

et al. 2020

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Cyfip1 haploinsufficiency increases compulsive-like behavior and modulates palatable food intake: Implications for Prader-Willi Syndrome

Ruan

et al. 2018

Preprint

Binge eating (BE) is a heritable trait associated with eating disorders and involves consumption of a large quantity of food in a short time. We identified cytoplasmic FMRP-interacting protein 2 (Cyfip2) as a major genetic factor underlying BE and concomitant compulsive-like behaviors in mice. CYFIP2 is a gene homolog of CYFIP1 -one of four paternally deleted genes in patients with the more severe Type I Prader-Willi Syndrome (PWS). PWS is a neurodevelopmental genetic disorder where 70% of cases involve paternal deletion of 15q11-q13. PWS is defined phenotypically by the emergence of hyperphagia and obesity during childhood as well as cognitive deficits and obsessive-compulsive behaviors. We tested the hypothesis that Cyfip1 haploinsufficiency would enhance premorbid compulsive-like behavior and palatable food (PF) consumption in a parent-of-origin-selective manner.Additionally, because our initial studies involved mice on a C57BL/6N background that possess the BEassociated missense mutation in Cyfip2, we tested mice on a mixed background where mice were homozygous for the C57BL/6J (B6J) allele at the Cyfip2 locus. Cyfip1 haploinsufficiency increased compulsive-like behavior on both backgrounds and PF consumption was greater with paternal inheritance. Gene expression in the hypothalamus revealed a paternal effect of Cyfip1 deletion on transcription of Cyfip1 but not Cyfip2 or Magel2. To summarize, the selective increased compulsive-like behavior and PF consumption in paternally deleted Cyfip1 +/-mice could translate to enhancing hyperphagia in a subset of individuals with neurodevelopmental disorders involving reduced expression or haploinsufficiency of CYFIP1, including PWS but also Fragile X Syndrome and 15q11.2 Microdeletion Syndrome.

Systems genetic analysis of binge‐like eating in a C57BL/6J x DBA/2J‐F2 cross

Yao

Genes Brain and Behavior

et al. 2021

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Binge eating is a heritable trait associated with eating disorders and refers to the rapid consumption of a large quantity of energy‐dense food that is, associated with loss of control and negative affect. Binge eating disorder is the most common eating disorder in the United States; however, the genetic basis is unknown. We previously identified robust mouse inbred strain differences between C57BL/6J and DBA/2J in binge‐like eating of sweetened palatable food in an intermittent access, conditioned place preference paradigm. To map the genetic basis of changes in body weight and binge‐like eating (BLE) and to identify candidate genes, we conducted quantitative trait locus (QTL) analysis in 128 C57BL/6J x DBA/2J‐F2 mice combined with PheQTL and trait covariance analysis in GeneNetwork2 using legacy BXD‐RI trait datasets. We identified a QTL on Chromosome 18 influencing changes in body weight across days in females (log of the odds [LOD] = 6.3; 1.5‐LOD: 3–12 cM) that contains the candidate gene Zeb1. We also identified a sex‐combined QTL influencing initial palatable food intake on Chromosome 5 (LOD = 5.8; 1.5‐LOD: 21–28 cM) that contains the candidate gene Lcorl and a second QTL influencing escalated palatable food intake on Chromosome 6 in males (LOD = 5.4; 1.5‐LOD: 50–59 cM) that contains the candidate genes Adipor2 and Plxnd1. Finally, we identified a suggestive QTL in females for slope of BLE on distal Chromosome 18 (LOD = 4.1; p = 0.055; 1.5‐LOD: 23–35 cM). Future studies will use BXD‐RI strains to fine map loci and support candidate gene nomination for gene editing.