Sex-Specific Genetic Loci for Femoral Neck Bone Mass and Strength Identified in Inbred COP and DA Rats

Alam, Imranul; Sun, Qiwei; Liu, Lixiang; Koller, Daniel L.; Carr, Lucinda G.; Econs, Michael J.; Foroud, Tatiana; Turner, Charles H.

doi:10.1359/jbmr.080221

Cited by 14 publications

(22 citation statements)

References 39 publications

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“…Using progeny derived from inbred Fisher 344 and Lewis rats, Alam et al detected significant quantitative trait loci (QTLs) for variation in midshaft femur ultimate force, energy to break, and stiffness [8]; fifth lumbar vertebra ultimate force [8]; and femoral neck ultimate force and energy to break [9]. Studies in another rat model (progeny of Copenhagen 233 and Dark Agouti rats) also revealed QTLs for femoral neck biomechanical properties[10] and femoral midshaft and fifth lumbar vertebra ultimate force [11]. In a study of femurs of HcB/8 and HcB/23 recombinant congenic mice, Saless [12] identified QTLs for total displacement, post yield deflection, and stiffness.…”

Section: Introductionmentioning

confidence: 99%

Heritability of lumbar trabecular bone mechanical properties in baboons

Havill

Allen

Bredbenner

et al. 2010

Bone

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Genetic effects on mechanical properties have been demonstrated in rodents, but not confirmed in primates. Our aim was to quantify the proportion of variation in vertebral trabecular bone mechanical properties that is due to the effects of genes. L3 vertebrae were collected from 110 females and 46 male baboons (6-32 years old) from a single extended pedigree. Cranio-caudally oriented trabecular bone cores were scanned with microCT then tested in monotonic compression to determine apparent ultimate stress, modulus, and toughness. Age and sex effects and heritability (h 2 ) were assessed using maximum likelihood-based variance components methods. Additive effects of genes on residual trait variance were significant for ultimate stress (h 2 =0.58), toughness (h 2 =0.64), and BV/TV (h 2 =0.55). When BV/TV was accounted for, the residual variance in ultimate stress accounted for by the additive effects of genes was no longer significant. Toughness, however, showed evidence of a non-BV/TV-related genetic effect. Overall, maximum stress and modulus show strong genetic effects that are nearly entirely due to bone volume. Toughness shows strong genetic effects related to bone volume and shows additional genetic effects (accounting for 10% of the total trait variance) that are independent of bone volume. These results support continued use of bone volume as a focal trait to identify genes related to skeletal fragility, but also show that other focal traits related to toughness and variation in the organic component of bone matrix will enhance our ability to find additional genes that are particularly relevant to fatigue-related fractures.

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Section: Introductionmentioning

confidence: 99%

Heritability of lumbar trabecular bone mechanical properties in baboons

Havill

Allen

Bredbenner

et al. 2010

Bone

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“…The majority of this literature is devoted to bone mineral density as the phenotype of interest, although an increasing fraction now also addresses bone size as well. Biomechanical performance has been studied as a phenotypic endpoint in only a small number of rodent genetic mapping experiments [7–17]. The relative dearth of biomechanical genetic investigations reflects the very real barriers to their successful completion: greater technical difficulty, lesser robustness of the phenotypes, and ultimately lesser statistical power to find quantitative trait loci (QTLs).…”

Section: Introductionmentioning

confidence: 99%

Linkage mapping of femoral material properties in a reciprocal intercross of HcB-8 and HcB-23 recombinant mouse strains

Saless

Franco

Litscher

et al. 2010

Bone

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Skeletal fragility is an important health problem with a large genetic component. We performed a 603 animal F2 reciprocal intercross of the recombinant congenic strains HcB-8 and HcB-23 to genetically map quantitative trait loci (QTLs) for tissue-level femoral biomechanical performance. These included elastic and post-yield strain, Young’s modulus, stress and maximum strain, and toughness and were calculated from 3-point bend testing of femora by the application of standard beam equations. We mapped these with R/qtl and QTL Cartographer and established significance levels empirically by permutation testing. Significant QTLs for at least one trait are present on chromosomes 1, 6, and 10 in the full F2 population, with additional QTLs evident in subpopulations defined by sex and cross direction. On chromosome 10, we find a QTL for post-yield strain and toughness, phenotypes that have not been mapped previously. Notably, the HcB-8 allele at this QTL increases post-yield strain and toughness, but decreases bone mineral density (BMD), while the material property QTLs on chromosomes 1, 6, and at a second chromosome 10 QTL are independent of BMD. We found significant sex × QTL and cross-direction × QTL interactions. A robust, pleiotropic chromosome 4 QTL that we previously reported at the whole bone level showed no evidence of linkage at the tissue level, supporting our interpretation that modeling capacity is its primary phenotype. . Our data demonstrate an inverse relationship between femoral perimeter and Young’s modulus, with R2 = 0.27, supporting the view that geometric and material bone properties are subject to an integrated set of regulatory mechanisms. Mapping QTLs for tissue-level biomechanical performance advances understanding of the genetic basis of bone quality.

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“…The use of animal models as a complement to studies in human populations permit identification of candidate genes for additional phenotypes related to bone structure and strength. Inbred rodent strains have been established as valuable models for dissecting the genetic regulation of bone, and several chromosomal regions linked to bone geometry, biomechanics and bone density in distinct trabecular or cortical bone compartments have been identified [3,[5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Genetic loci for bone architecture determined by three-dimensional CT in crosses with the diabetic GK rat

Lagerholm

Park²,

Luthman³

et al. 2010

Bone

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The F344 rat carries alleles contributing to bone fragility while the GK rat spontaneously develops type-2 diabetes. These characteristics make F344 x GK crosses well suited for the identification of genes related to bone size and allow for future investigation on the association with type-2 diabetes. The aim of this study was to identify quantitative trait loci (QTLs) for bone size phenotypes measured by a new application of three-dimensional computed tomography (3DCT) and to investigate the effects of sex-and reciprocal cross.Tibia from male and female GK and F344 rats, representing the parental, F1 and F2 generations, were examined with 3DCT and analyzed for: total and cortical volumetric BMD, straight and curved length, peri-and endosteal area at mid-shaft. F2 progeny (108 male and 98 female) were genotyped with 192 genome-wide microsatellite markers (average distance 10 cM). Sex-and reciprocal cross-separated QTL analyses were performed for the identification of QTLs linked to 3DCT phenotypes and true interactions were confirmed by likelihood ratio analysis in all F2 animals.Several genome-wide significant QTLs were found in the sex-and reciprocal cross-separated progeny on chromosomes (chr) 1, 3, 4, 9, 10, 14, and 17. Overlapping QTLs for both males and females in the (GK×F344)F2 progeny were located on chr 1 (39-67 cM). This region confirms previously reported pQCT QTLs and overlaps loci for fasting glucose. Sex separated linkage analysis confirmed a male specific QTL on chr 9 (67-82 cM) for endosteal area at the fibula site. Analyses separating the F2 population both by sex and reciprocal cross identified cross specific QTLs on chr 14 (males) and chr 3 and 4 (females). Two loci, chr 4 and 6, are unique to 3DCT and separate from pQCT generated loci.The 3DCT method was highly reproducible and provided high precision measurements of bone size in the rat enabling identification of new sex-and cross-specific loci. The QTLs on chr 1 indicate potential genetic association between bone-related phenotypes and traits affecting type-2 diabetes. The results illustrate the complexity of the genetic architecture of bone size phenotypes, and demonstrate the importance of complementary methods for bone analysis.

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Sex-Specific Genetic Loci for Femoral Neck Bone Mass and Strength Identified in Inbred COP and DA Rats

Cited by 14 publications

References 39 publications

Heritability of lumbar trabecular bone mechanical properties in baboons

Heritability of lumbar trabecular bone mechanical properties in baboons

Linkage mapping of femoral material properties in a reciprocal intercross of HcB-8 and HcB-23 recombinant mouse strains

Genetic loci for bone architecture determined by three-dimensional CT in crosses with the diabetic GK rat

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