Abstract: We mapped a quantitative trait locus (QTL) for BMD to mid-distal chromosome (Chr) 6 in a cross between C57BL/6J (B6) and C3H/HeJ (C3H). The B6.C3H-6T (6T) congenic was developed to map candidate genes in this QTL. Recently, a 25 cM paracentric inversion was discovered on Chr 6 in C3H/HeJ; we found 6T also carries this inversion. Microarrays from the liver of B6 and 6T uncovered two narrow bands of decreased gene expression in close proximity to the predicted locations of the inversion breakpoints. Changes in specific gene expression in 6T were consistent with its phenotype of low trabecular bone volume and marrow adipogenesis. The BXH recombinant inbred (RI) strains do not carry the C3H/HeJ inversion. To test if the inversion, or allelic effects, were responsible for the 6T phenotype, we made a new congenic, B.H-6, developed by introgressing a 30 Mb region of C3H genomic sequence from BXH6 onto a B6 background. While genetically identical to 6T, this new congenic had a distinct metabolic and skeletal phenotype, with more body fat and greater trabecular BV/TV compared to B6 or 6T. We conclude that the phenotype of 6Tcannot be explained by simple allelic differences in one or more genes from C3H. Rather, 6T demonstrates that disordered regulation of gene expression by genomic rearrangement can have a profound effect on a complex trait, such as BMD, and that genomic rearrangement can supersede the effects of various alleles.