Linkage screen for BMD phenotypes in male and female COP and DA rat strains.

Because particular inbred strains of experimental animals are informative for only a subset of the genes underlying variability in BMD, we undertook a genome screen to identify quantitative trait loci (QTLs) in 828 F(2) progeny (405 males and 423 females) derived from the Copenhagen 2331 (COP) and dark agouti (DA) strains of rats. This screen was performed to complement our study in female Fischer 344 (F344) and Lewis (LEW) rats and to further delineate the factors underlying the complex genetic architecture of BMD in the rat model. Microsatellite genotyping was performed using markers at an average density of 20 cM. BMD was measured by pQCT and DXA. These data were analyzed in the R/qtl software to detect QTLs acting in both sexes as well as those having sex-specific effects. A QTL was detected in both sexes on chromosome 18 for midfemur volumetric BMD (vBMD; genome-wide, p < 0.01). On distal chromosome 1, a QTL was found for femur and vertebral aBMD as well as distal femur vBMD, and this QTL appears distinct from the proximal chromosome 1 QTL impacting BMD in our F344/LEW cross. Additional aBMD and vBMD QTLs and several sex-specific QTLs were also detected. These included a male-specific QTL (p < 0.01) on chromosome 8 and a female-specific QTL on chromosomes 7 and 14 (p < 0.01). Few of the QTLs identified showed overlap with the significant QTLs from the F344/LEW cross. These results confirm that the genetic influence on BMD in the rat model is quite complex and would seem to be influenced by a number of different genes, some of which have sex-specific effects.