Diet-dependent genetic and genomic imprinting effects on obesity in mice

Abstract

Although the current obesity epidemic is of environmental origin, there is substantial genetic variation in individual response to an obesogenic environment. In this study, we perform a genome-wide scan for quantitative trait loci (QTLs) affecting obesity per se, or an obese response to a high-fat diet in mice from the LG/J by SM/J Advanced Intercross (AI) Line (Wustl:LG,SM-G16). A total of 1,002 animals from 78 F₁₆ full sibships were weaned at 3 weeks of age and half of each litter placed on high- and low-fat diets. Animals remained on the diet until 20 weeks of age when they were necropsied and the weights of the reproductive, kidney, mesenteric, and inguinal fat depots were recorded. Effects on these phenotypes, along with total fat depot weight and carcass weight at necropsy, were mapped across the genome using 1,402 autosomal single-nucleotide polymorphism (SNP) markers. Haplotypes were reconstructed and additive, dominance, and imprinting genotype scores were derived every 1 cM along the F₁₆ map. Analysis was performed using a mixed model with additive, dominance, and imprinting genotype scores, their interactions with sex, diet, and with sex-by-diet as fixed effects and with family and its interaction with sex, diet, and sex-by-diet as random effects. We discovered 95 trait-specific QTLs mapping to 40 locations. Most QTLs had additive effects with dominance and imprinting effects occurring at two-thirds of the loci. Nearly every locus interacted with sex and/or diet in important ways demonstrating that gene effects are primarily context dependent, changing depending on sex and/or diet.

Figure 1

Genotypic values of total fat depot weight in high-fat fed males (HM) and females (HF) with contrasting imprinting genotypic values at locus Dob17e. In the females there are negative additive and negative imprinting genotypic values, whereas in males both values are positive. Error bars indicate ± 1.0 s.e.

Figure 2

Genotypic values of reproductive fat depot weights in the high-fat (HF) and low-fat (LF) fed females at QTL Dob6c, where the genetic effects in the cohorts are distinct. Low-fat fed females have a significant positive additive effect and a significant negative imprinting effect, producing a pattern consistent with maternal expression, while high-fat fed females have no additive effect, a significant positive dominance effect and a significant positive imprinting effect. Error bars indicate ± 1.0 s.e.

Figure 3

Genotypic values of reproductive fat depot weights in the four sex–diet-specific cohorts and in the full population, pooled across the cohorts (FULL), at QTL Dob1a. This locus has an effect only evident in the HF. There are no significant differences among the genotypes in the LM, HM, LF, or FULL population cohorts but there is a significant negative additive effect, with the S allele leading to a heavier weight, and a positive imprinting effect with maternal expression in the HF cohort. Error bars indicate ± 1.0 s.e. LF, low-fat fed females; LM, low-fat fed males; HF, high-fat fed females; HM, high-fat fed males; QTL, quantitative trait locus.