Genetic Determination of Bone Mineral Density: Evidence for a Major Gene

Nguyen, Tuan V.; Livshits, Gregory; Yakovenko, K.; Eisman, John A.

doi:10.1210/jc.2002-030026

Cited by 29 publications

(30 citation statements)

References 33 publications

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“…This study used data from three independent populations in Australia, the United States, and Chuvasha (Russian Autonomous Republic). Details of the study design of the studies have been described previously (6–8) . Characteristics of the study subjects are shown in Table 1.…”

Section: Methodsmentioning

confidence: 99%

Genetics of Bone Mineral Density: Evidence for a Major Pleiotropic Effect From an Intercontinental Study

Livshits

Deng

Nguyen

et al. 2004

Journal of Bone and Mineral Research

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BMD is a primary predictor of osteoporotic fracture, and its genetic determination is still unclear. This study showed that the correlation between BMD at different skeletal sites is caused by an underlying genetic structure of common genetic effects. In addition to possible shared (pleiotropic) genetic and environmental effects, each of the BMD variables may also be determined by site-specific genetic factors.Introduction: BMD is a primary predictor of osteoporotic fracture and a key phenotype for the genetic study of osteoporosis. The interindividual variation in BMD measured at a given skeletal site is largely regulated by genetic factors. A strong phenotypic covariation exists for BMD at different skeletal sites. This study tests the hypothesis that the covariation is in fact caused by an underlying genetic structure of common genetic effects and that, in addition to possible shared (pleiotropic) genetic effects, each of the BMD variables may also be determined by site-specific genetic factors Materials and Methods: A bivariate complex segregation analysis as implemented in statistical package PAP was conducted to explore various models of pleiotropic genetic and environmental transmission in lumbar spine and femoral neck BMD, as well as in compact and spongious segments of hand phalanges. The BMD was obtained in three ethnically, culturally, and socially heterogeneous samples of white pedigrees, with 2549 individuals between 18 and 100 years of age, from Australia, Europe, and North America. Results and Conclusions:The genetic correlation between BMD measures ranged between 0.50 Ϯ 0.09 and 0.79 Ϯ 0.04 in the three samples. In each sample, the model incorporated a major locus pleiotropic effect, and residual correlation was found to be the most parsimonious model. Estimated parameters from the model indicated a significant pleiotropic major gene effect on both lumbar spine and femoral neck BMD, with the existence of a significant residual correlation (0.51 Ϯ 0.07 to 0.66 Ϯ 0.04). These results suggest that the covariation in BMD at different skeletal sites, and between mostly compact versus mostly trabecular bone, was largely determined by common genetic factors that are pleiotropic or in close linkage and linkage disequilibirum, while at the same time, exhibiting considerable evidence of shared environmental effects. The results, for the first time, suggest that the possibility of pleiotropic genetic effect may be controlled by a major genetic locus. Identification of the major locus could open new opportunity to understanding the liability and pathogenic processes in which they are involved in the determination of fracture risk.

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Section: Methodsmentioning

confidence: 99%

Genetics of Bone Mineral Density: Evidence for a Major Pleiotropic Effect From an Intercontinental Study

Livshits

Deng

Nguyen

et al. 2004

Journal of Bone and Mineral Research

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“…In osteoporosis, perturbations in local cytokines, growth factors, systemic hormones and transcription factors cause imbalance between bone formation and resorption, resulting in net bone loss (Karsenty, 1999). Peak bone mass, the result of net bone accrual in early life and with a maximum in the second and third decade of life, is greatly influenced by genetic factors (50-85%) (Giguere and Rousseau, 2000;Ralston, 2002;Nguyen et al, 2003;Ralston and de Crombrugghe, 2006). BMD depends on peak bone mass, but also on the rate of bone loss in later life.…”

Section: Introductionmentioning

confidence: 99%

Osteopenia, decreased bone formation and impaired osteoblast development inSox4heterozygous mice

Nissen‐Meyer

Jemtland

Gautvik

et al. 2007

Journal of Cell Science

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The transcription factor Sox4 is vital for fetal development, as Sox4–/– homozygotes die in utero. Sox4 mRNA is expressed in the early embryonic growth plate and is regulated by parathyroid hormone, but its function in bone modeling/remodeling is unknown. We report that Sox4+/– mice exhibit significantly lower bone mass (by dual-energy X-ray absorptiometry) from an early age, and fail to obtain the peak bone mass of wild-type (WT) animals. Microcomputed tomography (μCT), histomorphometry and biomechanical testing of Sox4+/– bones show reduced trabecular and cortical thickness, growth plate width, ultimate force and stiffness compared with WT. Bone formation rate (BFR) in 3-month-old Sox4+/– mice is 64% lower than in WT. Primary calvarial osteoblasts from Sox4+/– mice demonstrate markedly inhibited proliferation, differentiation and mineralization. In these cultures, osterix (Osx) and osteocalcin (OCN) mRNA expression was reduced, whereas Runx2 mRNA was unaffected. No functional defects were found in osteoclasts. Silencing of Sox4 by siRNA in WT osteoblasts replicated the defects observed in Sox4+/– cells. We demonstrate inhibited formation and altered microarchitecture of bone in Sox4+/– mice versus WT, without apparent defects in bone resorption. Our results implicate the transcription factor Sox4 in regulation of bone formation, by acting upstream of Osx and independent of Runx2.

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“…(3)(4)(5)(6)(7) Architectural properties of whole bone, as well as trabecular bone, typically display continuous distributions within the population and are considered to be complex, quantitative traits. Complex traits can be influenced by many different genes functioning in concert.…”

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QTL Analysis of Trabecular Bone in BXD F2 and RI Mice

Bower

Lang

Vogler

et al. 2006

Journal of Bone and Mineral Research

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A sample of 693 mice was used to identify regions of the mouse genome associated with trabecular bone architecture as measured using µCT. QTLs for bone in the proximal tibial metaphysis were identified on several chromosomes indicating regions containing genes that regulate properties of trabecular bone.Introduction: Age-related osteoporosis is a condition of major concern because of the morbidity and mortality associated with osteoporotic fractures in humans. Osteoporosis is characterized by reduced bone density, strength, and altered trabecular architecture, all of which are quantitative traits resulting from the actions of many genes working in concert with each other and the environment over the lifespan. CT gives accurate measures of trabecular bone architecture providing phenotypic data related to bone volume and trabecular morphology. The primary objective of this research was to identify chromosomal regions called quantitative trait loci (QTLs) that contain genes influencing trabecular architecture as measured by CT. Materials and Methods:The study used crosses between C57BL/6J (B6) and DBA/2J (D2) as progenitor strains of a second filial (F 2 ) generation (n ‫ס‬ 141 males and 148 females) and 23 BXD recombinant inbred (RI) strains (n ≈ 9 of each sex per strain). The proximal tibial metaphyses of the 200-day-old mice were analyzed by CT to assess phenotypic traits characterizing trabecular bone, including bone volume fraction, trabecular connectivity, and quantitative measures of trabecular orientation and anisotropy. Heritabilities were calculated and QTLs were identified using composite interval mapping. Results: A number of phenotypes were found to be highly heritable. Heritability values for measured phenotypes using RI strains ranged from 0.15 for degree of anisotropy in females to 0.51 for connectivity density in females and total volume in males. Significant and confirmed QTLs, with LOD scores ജ4.3 in the F 2 cohort and ജ1.5 in the corresponding RI cohort were found on chromosomes 1 (43 cM), 5 (44 cM), 6 (20 cM), and 8 (49 cM). Other QTLs with LOD scores ranging from 2.8 to 6.9 in the F 2 analyses were found on chromosomes 1, 5, 6, 8, 9, and 12. QTLs were identified using data sets comprised of both male and female quantitative traits, suggesting similar genetic action in both sexes, whereas others seemed to be associated exclusively with one sex or the other, suggesting the possibility of sex-dependent effects. Conclusions: Identification of the genes underlying these QTLs may lead to improvements in recognizing individuals most at risk for developing osteoporosis and in the design of new therapeutic interventions.

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Genetic Determination of Bone Mineral Density: Evidence for a Major Gene

Cited by 29 publications

References 33 publications

Genetics of Bone Mineral Density: Evidence for a Major Pleiotropic Effect From an Intercontinental Study

Genetics of Bone Mineral Density: Evidence for a Major Pleiotropic Effect From an Intercontinental Study

Osteopenia, decreased bone formation and impaired osteoblast development inSox4heterozygous mice

QTL Analysis of Trabecular Bone in BXD F2 and RI Mice

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