Quantitative Trait Loci Analysis of Structural and Material Skeletal Phenotypes in C57BL/6J and DBA/2 Second-Generation and Recombinant Inbred Mice

Abstract

QTL analyses identified several chromosomal regions influencing skeletal phenotypes of the femur and tibia in BXD F 2 and BXD RI populations of mice. QTLs for skeletal traits co-located with each other and with correlated traits such as body weight and length, adipose mass, and serum alkaline phosphatase.Introduction: Past research has shown substantial genetic influence on bone quality, and the impact of reduced bone mass on our aging population has heightened the interest in skeletal genetic research. Materials and Methods: Quantitative trait loci (QTL) analyses were performed on morphologic measures and structural and material properties of the femur and tibia in 200-day-old C57BL/6J × DBA/2 (BXD) F 2 (second filial generation; n ‫ס‬ 400) and BXD recombinant inbred (RI; n ‫ס‬ 23 strains) populations of mice. Body weight, body length, adipose mass, and serum alkaline phosphatase were correlated phenotypes included in the analyses. Results: Skeletal QTLs for morphologic bone measures such as length, width, cortical thickness, and crosssectional area mapped to nearly every chromosome. QTLs for both structural properties (ultimate load, yield load, or stiffness) and material properties (stress and strain characteristics and elastic modulus) mapped to chromosomes 4, 6, 9, 12, 13, 15, and 18. QTLs that were specific to structural properties were identified on chromosomes 1, 2, 3, 7, 8, and 17, and QTLs that were specific to skeletal material properties were identified on chromosomes 5, 11, 16, and 19. QTLs for body size (body weight, body length, and adipose mass) often mapped to the same chromosomal regions as those identified for skeletal traits, suggesting that several QTLs identified as influencing bone could be mediated through body size. Conclusion: New QTLs, not previously reported in the literature, were identified for structural and material properties and morphological measures of the mouse femur and tibia. Body weight and length, adipose mass, and serum alkaline phosphatase were correlated phenotypes that mapped in close proximity of skeletal chromosomal loci. The more specific measures of bone quality included in this investigation enhance our understanding of the functional significance of previously identified QTLs.

Genetic Analysis of Craniofacial Traits in the Medaka

“…A number of studies have analyzed morphological phenotypes as quantitative traits in mice (Cheverud et al 1997;Dohmoto et al 2002;Nishimura et al 2003;Lang et al 2005). The LOD scores in our study of medaka are similar to those obtained in mice.…”

“…We analyzed 184 F 2 samples in this study, and mapped, at most, 5 genomic regions per trait (supplemental Table 4). The highest LOD score in our study was 6.2, just slightly lower than the LOD score of 7.3 obtained in the study of 200 F 2 mice (Lang et al 2005). Thus, the medaka can be an alternative animal model for the genetic analysis of morphological traits, which is less expensive and easier to prepare a large number of samples.…”

“…When craniofacial traits were analyzed in .100 mice, a few QTL were identified for each trait with highest LOD scores of 5 (Dohmoto et al 2002;Nishimura et al 2003). When skeletal morphology was analyzed in 200 F 2 mice, 7.3 was the highest LOD score and most traits were mapped to between 1 and 5 genomic regions (Lang et al 2005). The ability to identify QTL is affected by a sample size.…”

Proximal hip geometry is linked to several chromosomal regions: Genome-wide linkage results from the Framingham Osteoporosis Study

“…In other words, our analysis focuses on contribution of loci governing bone geometry per se, instead of general robustness of the skeleton due to overall body size and mass. There are also indications, in both humans [44,45] and mice [29] that common genetic factors contribute to femoral dimensions and cross-sectional traits, body weight and height. In future studies we plan to explore the presence of the genetic correlation between femoral geometric parameters, body size and body composition, in the same sample.…”

“…Therefore, to better understand the genetics underlying hip fractures, it is important to examine heritable determinants of bone geometry. The aim of this study was to determine heritability (h 2 ) of geometric indices of the proximal hip in men and women members of extended pedigrees from the community based Framingham Osteoporosis Study sample, and to perform whole-genome genetic linkage analyses Additionally, because there are known effects of body size on size and strength of the bones [29] we evaluated whether or not an adjustment for body size would influence the magnitude of heritability and linkage.…”