Identification of quantitative trait loci influencing skeletal architecture in mice: emergence of Cdh11 as a primary candidate gene regulating femoral morphology.

Bone strength is influenced by many properties intrinsic to bone, including its mass, geometry, and mineralization. To further advance our understanding of the genetic basis of bone-strength-related traits, we used a large (n = 815), moderately (G(4) ) advanced intercross line (AIL) of mice derived from a high-runner selection line (HR) and the C57BL/6J inbred strain. In total, 16 quantitative trait loci (QTLs) were identified that affected areal bone mineral density (aBMD) and femoral length and width. Four significant (p < .05) and one suggestive (p < .10) QTLs were identified for three aBMD measurements: total body, vertebral, and femoral. A QTL on chromosome (Chr.) 3 influenced all three aBMD measures, whereas the other four QTLs were unique to a single measure. A total of 10 significant and one suggestive QTLs were identified for femoral length (FL) and two measures of femoral width, anteroposterior (AP) and mediolateral (ML). FL QTLs were distinct from loci affecting AP and ML width, and of the 7 AP QTLs, only three affected ML. A QTL on Chr. 8 that explained 7.1% and 4.0% of the variance in AP and ML, respectively, was mapped to a 6-Mb region harboring 12 protein-coding genes. The pattern of haplotype diversity across the QTL region and expression profiles of QTL genes suggested that of the 12, cadherin 11 (Cdh11) was most likely the causal gene. These findings, when combined with existing data from gene knockouts, identify Cdh11 as a strong candidate gene within which genetic variation may affect bone morphology.