Mouse BMD quantitative trait loci show improved concordance with human genome-wide association loci when recalculated on a new, common mouse genetic map

Abstract

Bone mineral density (BMD) is a heritable trait, and in mice, over 100 quantitative trait loci (QTLs) have been reported, but candidate genes have been identified for only a small percentage. Persistent errors in the mouse genetic map have negatively affected QTL localization, spurring the development of a new, corrected map. In this study, QTLs for BMD were remapped in 11 archival mouse data sets using this new genetic map. Since these QTLs all were mapped in a comparable way, direct comparisons of QTLs for concordance would be valid. We then compared human genome-wide association study (GWAS) BMD loci with the mouse QTLs. We found that 26 of the 28 human GWAS loci examined were located within the confidence interval of a mouse QTL. Furthermore, 14 of the GWAS loci mapped to within 3 cM of a mouse QTL peak. Lastly, we demonstrated that these newly remapped mouse QTLs can substantiate a candidate gene for a human GWAS locus, for which the peak single-nucleotide polymorphism (SNP) fell in an intergenic region. Specifically, we suggest that MEF2C (human chromosome 5, mouse chromosome 13) should be considered a candidate gene for the genetic regulation of BMD. In conclusion, use of the new mouse genetic map has improved the localization of mouse BMD QTLs, and these remapped QTLs show high concordance with human GWAS loci. We believe that this is an opportune time for a renewed effort by the genetics community to identify the causal variants regulating BMD using a synergistic mouse-human approach.

Fig. 1

Mouse BMD QTLs compared with human GWAS loci. BMD QTLs for femoral (purple), whole-body (blue), and vertebral (green) BMD are presented to scale on the left side of each chromosome. Each white space along the chromosomal axis represents 10 cM. Each QTL is presented such that the vertical bar representing the QTL starts at the upper limit of the 95% confidence interval (CI) and extends to the lower end of the CI. The peak for the QTL is denoted by a black bar within the CI span. The human GWAS loci, as lifted over to the mouse genome coordinates, are represented as red triangles to the right of each chromosome.

Fig. 2

Confirmation of Mef2c as candidate gene for BMD on mouse chromosome 13. A GWS locus was identified on human chromosome 7 with a peak at rs1524058. The GWS locus is found in close proximity to two BMD QTLs in the mouse that were identified in MRL × SJL and B6 × CASA. The confidence intervals (CI) for these two mouse QTLs overlap for the interval from 38 to 55.9 cM (72.1 to 104 Mb). A total of 338 Refseq genes are located within the MRL × SJL CI, 186 genes within the B6 × CASA CI, and 153 genes are located where the CI for these two QTLs overlap. Using block haplotyping, we were able to eliminate all but six of these genes as candidates for this QTL. The gene Mef2c (black box) is the gene closest to the human GWS locus, and it remained a candidate after haplotyping.