In silico QTL mapping of basal liver iron levels in inbred mouse strains

Abstract

Both iron deficiency and iron excess are detrimental in many organisms, and previous studies in both mice and humans suggest that genetic variation may influence iron status in mammals. However, these genetic factors are not well defined. To address this issue, we measured basal liver iron levels in 18 inbred strains of mice of both sexes on a defined iron diet and found ∼4-fold variation in liver iron in males (lowest 153 μg/g, highest 661 μg/g) and ∼3-fold variation in females (lowest 222 μg/g, highest 658 μg/g). We carried out a genome-wide association mapping to identify haplotypes underlying differences in liver iron and three other related traits (copper and zinc liver levels, and plasma diferric transferrin levels) in a subset of 14 inbred strains for which genotype information was available. We identified two putative quantitative trait loci (QTL) that contain genes with a known role in iron metabolism: Eif2ak1 and Igf2r. We also identified four putative QTL that reside in previously identified iron-related QTL and 22 novel putative QTL. The most promising putative QTL include a 0.22 Mb region on Chromosome 7 and a 0.32 Mb region on Chromosome 11 that both contain only one candidate gene, Adam12 and Gria1, respectively. Identified putative QTL are good candidates for further refinement and subsequent functional studies.

Fig. 1.

Distribution of liver iron (A), plasma diferric transferrin levels (B), liver copper (C), and liver zinc levels (D) in male and female animals of 18 inbred strains. For the NZW/LacJ strain there were no male animals available. All data are expressed as means (± SD) and ordered by decreasing values of the mean in males.

Fig. 2.

Heritability of liver iron, plasma diferric transferrin, liver copper, and liver zinc in male and female animals (17 and 18 strains, respectively). Heritability was calculated and expressed as ratios of between strain variance and total variance, estimated by ANOVA. Fe₂TF, diferric transferrin level.

Fig. 3.

Results of genome-wide haplotype association mapping in male (13 strains) and female (14 strains) animals of inbred mice for liver iron, diferric transferrin, copper and zinc. The association score threshold of 5th percentile is marked red, as well as all the results exceeding it.