Mapping Quantitative Trait Loci for Vertebral Trabecular Bone Volume Fraction and Microarchitecture in Mice

• Published in: Journal of bone and mineral research 2004-04, Vol.19 (4), p.587-599
• Main Authors: Bouxsein, Mary L, Uchiyama, Toru, Rosen, Clifford J, Shultz, Kathryn L, Donahue, Leah R, Turner, Charles H, Sen, Saunak, Churchill, Gary A, Müller, Ralph, Beamer, Wesley G
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Bone Density - genetics; Bone Density - physiology; Female; Femur - anatomy & histology; Femur - physiology; Fundamental and applied biological sciences. Psychology; Genetic Markers; genetics; Lod Score; Lumbar Vertebrae - anatomy & histology; Lumbar Vertebrae - physiology; Mice; Mice, Inbred C3H; mouse; Quantitative Trait Loci - genetics; quantitative trait locus; Quantitative Trait, Heritable; Skeleton and joints; trabecular bone; vertebra; Vertebrates: osteoarticular system, musculoskeletal system
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1359/JBMR.0301255

BMD, which reflects both cortical and cancellous bone, has been shown to be highly heritable; however, little is known about the specific genetic factors regulating trabecular bone. Genome‐wide linkage analysis of vertebral trabecular bone traits in 914 adult female mice from the F2 intercross of C57BL/6J and C3H/HeJ inbred strains revealed a pattern of genetic regulation derived from 13 autosomes, with 5–13 QTLs associated with each of the traits. Ultimately, identification of genes that regulate trabecular bone traits may yield important information regarding mechanisms that regulate mechanical integrity of the skeleton. Introduction: Both cortical and cancellous bone influence the mechanical integrity of the skeleton, with the relative contribution of each varying with skeletal site. Whereas areal BMD, which reflects both cortical and cancellous bone, has been shown to be highly heritable, little is known about the genetic determinants of trabecular bone density and architecture. Materials and Methods: To identify heritable determinants of vertebral trabecular bone traits, we evaluated the fifth lumbar vertebra from 914 adult female mice from the F2 intercross of C57BL/6J (B6) and C3H/HeJ (C3H) progenitor strains. High‐resolution μCT was used to assess total volume (TV), bone volume (BV), bone volume fraction (BV/TV), trabecular thickness (Tb.Th), separation (Tb.Sp), and number (Tb.N) of the trabecular bone in the vertebral body in the progenitors (n = 8/strain) and female B6C3H‐F2 progeny (n = 914). Genomic DNA from F2 progeny was screened for 118 PCR‐based markers discriminating B6 and C3H alleles on all 19 autosomes. Results and Conclusions: Despite having a slightly larger trabecular bone compartment, C3H progenitors had dramatically lower vertebral trabecular BV/TV (−53%) and Tb.N (−40%) and higher Tb.Sp (71%) compared with B6 progenitors (p < 0.001 for all). Genome‐wide quantitative trait analysis revealed a pattern of genetic regulation derived from 13 autosomes, with 5–13 quantitative trait loci (QTLs) associated with each of the vertebral trabecular bone traits, exhibiting adjusted LOD scores ranging from 3.1 to 14.4. The variance explained in the F2 population by each of the individual QTL after adjusting for contributions from other QTLs ranged from 0.8% to 5.9%. Taken together, the QTLs explained 22–33% of the variance of the vertebral traits in the F2 population. In conclusion, we observed a complex pattern of genetic regulation for vertebr