Heritability of fat distributions in male mice from the founder strains of the Diversity Outbred mouse population

Abstract

Specific fat distributions are risk factors for complex diseases, including coronary heart disease and obstructive sleep apnea. To demonstrate the utility of high-diversity mouse models for elucidating genetic associations, we describe the phenotyping and heritability of fat distributions within the five classical inbred and three wild-derived founder mouse strains of the Collaborative Cross and Diversity Outbred mice. Measurements of subcutaneous and internal fat volumes in the abdomen, thorax and neck, and fat volumes in the tongue and pericardium were obtained using magnetic resonance imaging in male mice from the A/J (n = 12), C57BL/6J (n = 17), 129S1/SvlmJ (n = 12), NOD/LtJ (n = 14), NZO/HILtJ (n = 12), CAST/EiJ (n = 14), PWK/PhJ (n = 12), and WSB/EiJ (n = 15) strains. Phenotypes were compared across strains using analysis of variance and heritability estimated as the proportion of phenotypic variability attributable to strain. Heritability ranged from 44% to 91% across traits, including >70% heritability of tongue fat. A majority of heritability estimates remained significant controlling for body weight, suggesting genetic influences independent of general obesity. Principal components analysis supports genetic influences on overall obesity and specific to increased pericardial and intra-neck fat. Thus, among the founder strains of the Collaborative Cross and Diversity Outbred mice we observed significant heritability of subcutaneous and internal fat volumes in the neck, thorax and abdomen, pericardial fat volume and tongue fat volume, consistent with genetic architecture playing an important role in explaining trait variability. Findings pave the way for studies utilizing high-diversity mouse models to identify genes affecting fat distributions and, in turn, influencing risk for associated complex disorders.

Prediction performance of linear models and gradient boosting machine on complex phenotypes in outbred mice

“…Results from these analyzes are presented as Supplementary Table 1 . Among all phenotypes available, we chose 10 traits based on their distinct assumed genetic architectures from previous results with the same dataset ( Li and Churchill 2010 ; Churchill et al 2012 ; Zhang et al 2012 ; Tyler et al 2016 , 2017; Keller et al 2019 ; Keenan et al 2021) and other populations ( Chitre et al 2020) . The analyzed traits were bone mineral density at 12 weeks (BMD), body weight at 10, 15, and 20 weeks (BW10, BW15, and BW20, respectively), circulating cholesterol at 19 weeks (CHOL), adjusted body fat percentage at 12 weeks (FATP), circulating glucose at 19 weeks (GLUC), circulating triglycerides at 19 weeks (TRGL), circulating insulin at 8 weeks (INSUL), and urine creatinine at 20 weeks (UCRT).…”