Age and diet shape the genetic architecture of body weight in Diversity Outbred mice

Abstract

AO_SCPLOWBSTRACTC_SCPLOWUnderstanding how genetic variation shapes an age-dependent complex trait relies on accurate quantification of both the additive genetic effects and genotype-environment interaction effects in an age-dependent manner. We used a generalization of the linear mixed model to quantify diet-dependent genetic contributions to body weight and growth rate measured from early development through adulthood of 960 Diversity Outbred female mice subjected to five dietary interventions. We observed that heritability of body weight remained substantially high (h2 {approx} 0.8) throughout adulthood under the 40% calorie restriction diet, while heritability, although still appreciably high, declined with age under all other dietary regimes. We identified 14 loci significantly associated with body weight in an age-dependent manner and 19 loci that contribute to body weight in an age- and diet-dependent manner. We found the effect of body weight alleles to be dynamic with respect to genomic background, age, and diet, identifying the scope of pleiotropy and several instances of allelic heterogeneity. In many cases, we fine-mapped these loci to narrow genomic intervals containing a few genes and impute putative functional variants from the genome sequence of the DO founders. Of the loci associated with body weight in a diet-dependent manner, many have been previously linked to neurological function and behavior in mice or humans. These results enable us to more fully understand the dynamics of the genetic architecture of body weight with age and in response to different dietary interventions, and to predict the effectiveness of dietary intervention on overall health in distinct genetic backgrounds.