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

Abstract

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.

Cocaine-Induced Locomotor Activation Differs Across Inbred Mouse Substrains

“…Additionally, a recently developed genotyping array captures polymorphisms between inbred mouse substrains, facilitating rapid and reliable genotyping of RCCs (33). RCCs have been used successfully to identify genetic polymorphisms that impact psychostimulant response, binge eating, binge alcohol consumption, thermal nociception and brain weight (34)(35)(36)(37)(38).…”

Assessment of Binge-Like Eating of Unsweetened vs. Sweetened Chow Pellets in BALB/c Substrains

“…Mice remain the premier mammalian model organism for understanding the genetic and molecular mechanisms of complex traits that model aspects of complex diseases and disorders, permitting control over environmental variance, diet composition, and access to diet than in human studies and providing the molecular tools for validation. We previously described genetic elements mediating differences between the C57BL/6J and DBA/2J strains and mapped quantitative trait loci on chromosomes 5 and 11 responsible for initial palatable food intake and the escalation of palatable food consumption respectively (Babbs et al, 2018;Yao et al, 2021). Large phenotypic differences between closely related substrains, such as with C57BL/6 substrains (Kirkpatrick et al, 2017), can greatly facilitate genetic mapping and gene identification in an F2 reduced complexity cross (the generation and testing of a filial generation 2 population, produced by intercrossing of substrains) by reducing the density of genetic polymorphisms, reducing the chance of gene × gene interactions, and increasing the likelihood of identifying a single causal locus (Bryant et al, 2018(Bryant et al, , 2020.…”