A high-resolution association mapping panel for the dissection of complex traits in mice

Abstract

Systems genetics relies on common genetic variants to elucidate biologic networks contributing to complex disease-related phenotypes. Mice are ideal model organisms for such approaches, but linkage analysis has been only modestly successful due to low mapping resolution. Association analysis in mice has the potential of much better resolution, but it is confounded by population structure and inadequate power to map traits that explain less than 10% of the variance, typical of mouse quantitative trait loci (QTL). We report a novel strategy for association mapping that combines classic inbred strains for mapping resolution and recombinant inbred strains for mapping power. Using a mixed model algorithm to correct for population structure, we validate the approach by mapping over 2500 cis-expression QTL with a resolution an order of magnitude narrower than traditional QTL analysis. We also report the fine mapping of metabolic traits such as plasma lipids. This resource, termed the Hybrid Mouse Diversity Panel, makes possible the integration of multiple data sets and should prove useful for systems-based approaches to complex traits and studies of gene-by-environment interactions.

Genome-wide association mapping including phenotypes from relatives without genotypes

“…Similarly, GWAS has been applied to animals for the discovery of genes that are associated with disease and production traits (Karlsson et al, 2007;Bennett et al, 2010 ;Bolormaa et al, 2010 ;Orr et al, 2010 ;Pryce et al, 2010). In animal breeding, a closely related procedure that makes use of the same SNP chips, but for an entirely different purpose, is the genomic estimation of breeding values (GEBVs) for genomic selection (GWMAS), a form of marker-assisted selection.…”

The need for mouse models in osteoporosis genetics research

“…Second, alleles from wildderived strains of mice are under represented and as such the HMDP will not be able identify wild-allele-driven loci and may fail to map loci in regions where the classical strains are nearly all identical by decent. 23,39 As with the CC and the DO, the mapping resolution of the HMDP is superior to that obtained with traditional two-strain-intercross mapping populations. 23 Using a combined phenotype QTL and expression QTL approach, the Asxl2 gene was identified as underlying a BMD locus on mouse chromosome 12 in the HMDP.…”

“…23,39 As with the CC and the DO, the mapping resolution of the HMDP is superior to that obtained with traditional two-strain-intercross mapping populations. 23 Using a combined phenotype QTL and expression QTL approach, the Asxl2 gene was identified as underlying a BMD locus on mouse chromosome 12 in the HMDP. Furthermore, a role for this gene in osteoclast differentiation has been established, solidifying this gene as a true genetic regulator of bone mass, 38 however, it has not yet been ascertained if genetic variation in this gene is associated with BMD in human subjects.…”

“…22 This method has been prolifically applied to the phenotype of BMD and ~ 85 unique QTL have been reported. 20 These types of mapping studies have suffered from poor mapping resolution 23 and other issues, and only five candidate genes for BMD have been identified: Alox15 , Darc, Trps1, Pparg and Sfrp4. 24 -28 Although two strain intercross and interval mapping is no longer the workhorse of mouse genetics that they once were, gene-mapping efforts have not ceased.…”

“…This is a ' use as is ' panel of mice, in that all of the strains are ' completed ' and can be readily purchased. Furthermore, high-density genotyping for all lines is available 23 and gene expression data are available from femoral cortical bone from Figure 1 Periosteal circumference measured in the pre-CC. Periosteal circumference of the mid-diaphysis of the femur, as measured by peripheral quantitative computed tomography, is presented for 224 female ( a ) and 225 male ( b ) pre-CC mice.…”