Identification of a quantitative trait locus on rat chromosome 4 that is strongly linked to femoral neck structure and strength

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

doi:10.1016/j.bone.2005.12.009

Cited by 23 publications

(31 citation statements)

References 30 publications

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“…(33) However, in this study, we found only a couple of QTLs influencing ultimate force on Chr 4 in COP and DA rats, suggesting that COP and DA rats harbor different genetic variants that influence the femoral neck. Additionally, we found several chromosomal locations in both of Fischer 344 × Lewis and COP × DA inbred models overlapped for femoral neck phenotypes.…”

Section: Discussioncontrasting

confidence: 58%

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

Alam

Sun

Liu

et al. 2008

Journal of Bone and Mineral Research

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ABSTRACT:Introduction: Hip fracture is the most devastating osteoporotic fracture type with significant morbidity and mortality. Several studies in humans identified chromosomal regions linked to hip size and bone mass. Animal models, particularly the inbred rat, serve as complementary approaches for studying the genetic influence on hip fragility. The purpose of this study is to identify sex-independent and sex-specific quantitative trait loci (QTLs) for femoral neck density, structure, and strength in inbred Copenhagen 2331 (COP) and Dark Agouti (DA) rats. Materials and Methods: A total of 828 (405 males and 423 females) F 2 progeny derived from the inbred COP and DA strains of rats were phenotyped for femoral neck volumetric BMD (vBMD), cross-sectional area, polar moment of inertia (Ip), neck width, ultimate force, and energy to break. A whole genome screen was performed using 93 microsatellite markers with an average intermarker distance of 20 cM. Recombinationbased marker maps were generated using MAPMAKER/EXP from the COP × DA F 2 data and compared with published Rat Genome Database (RGD) maps. These maps were used for genome-wide linkage analyses to detect sex-independent and sex-specific QTLs. Results: Significant evidence of linkage (p < 0.01) for sex-independent QTLs were detected for (1) femoral neck vBMD on chromosomes (Chrs) 1, 6, 10, and 12, (2) femoral neck structure on Chrs 5, 7, 10, and 18, and (3) biomechanical properties on Chrs 1 and 4. Male-specific QTLs were discovered on Chrs 2, 9, and 18 for total vBMD, on Chr 17 for trabecular vBMD, on Chr 9 for total bone area, and on Chr 15 for ultimate force. A female-specific QTL was discovered on Chr 2 for ultimate force. The effect size of the individual QTL varied between 1% and 4%. Conclusions: We detected evidence that sex-independent and sex-specific QTLs contribute to hip fragility in the inbred rat. Several QTLs regions identified in this study are homologous to human chromosomal regions previously linked to QTLs contributing to femoral neck and related phenotypes.

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Section: Discussioncontrasting

confidence: 58%

“…The accuracy and repeatability of the pQCT measurements was confirmed using a method described previously. (33) …”

Section: Pqctmentioning

confidence: 99%

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

Alam

Sun

Liu

et al. 2008

Journal of Bone and Mineral Research

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“…The same region also overlaps QTLs for fasting glucose [15,20], establishing this region as a candidate region for genetic fine mapping to elucidate possible mechanisms between type-2 diabetes and bone size. Adding to the evidence that this is an important region in bone regulation, it also overlaps with QTLs linked to areal BMD and cortical area of femur identified in a (F344×LEW)F2 rat cross [6,13]. Of note, this chr 1 locus harbours the osteoporosis candidate genes transforming growth factor beta 1 (TGFB1) and estrogen receptor alfa (ESR1) [36,37].…”

Section: Discussionmentioning

confidence: 69%

“…Since linkage was only detected in rats with GK mtDNA, it is interesting to note that three nuclear genes encoding mitochondrial proteins are located within this QTL: region overlaps a previously identified QTL strongly linked to femoral neck structure phenotypes in (F344×LEW)F2 rats [13]; and a gene expression study identified several candidate genes within this QTL, which are involved in bone metabolism (IGF2, FGF2, VEGF, TNF) and correlated with the investigated phenotypes [38]. This chromosome region is also homologous to a region in the human genome where linkage to femoral neck related phenotypes has been identified [39][40][41][42].…”

Section: Discussionmentioning

confidence: 84%

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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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High-Resolution Genome Screen for Bone Mineral Density in Heterogeneous Stock Rat

Alam

Koller

Cañete

et al. 2014

Journal of Bone and Mineral Research

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We previously demonstrated that skeletal mass, structure and biomechanical properties vary considerably in heterogeneous stock (HS) rat strains. In addition, we observed strong heritability for several of these skeletal phenotypes in the HS rat model, suggesting that it represents a unique genetic resource for dissecting the complex genetics underlying bone fragility. The purpose of this study was to identify and localize genes associated with bone mineral density in HS rats. We measured bone phenotypes from 1524 adult male and female HS rats between 17 to 20 weeks of age. Phenotypes included DXA measurements for bone mineral content and areal bone mineral density for femur and lumbar spine (L3-5), and volumetric BMD measurements by CT for the midshaft and distal femur, femur neck and 5th lumbar vertebra. A total of 70,000 polymorphic SNPs distributed throughout the genome were selected from genotypes obtained from the Affymetrix rat custom SNPs array for the HS rat population. These SNPs spanned the HS rat genome with a mean linkage disequilibrium coefficient between neighboring SNPs of 0.95. Haplotypes were estimated across the entire genome for each rat using a multipoint haplotype reconstruction method, which calculates the probability of descent for each genotyped locus from each of the 8 founder HS strains. The haplotypes were tested for association with each bone density phenotype via a mixed model with covariate adjustment. We identified quantitative trait loci (QTLs) for bone mineral density phenotypes on chromosomes 2, 9, 10 and 13 meeting a conservative genome-wide empiric significance threshold (FDR=5%; P<3 × 10−6). Importantly, most QTLs were localized to very small genomic regions (1-3 Mb), allowing us to identify a narrow set of potential candidate genes including both novel genes and genes previously shown to have roles in skeletal development and homeostasis.

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Identification of a quantitative trait locus on rat chromosome 4 that is strongly linked to femoral neck structure and strength

Cited by 23 publications

References 30 publications

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

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

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

High-Resolution Genome Screen for Bone Mineral Density in Heterogeneous Stock Rat

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