Whole-Genome Scan for Linkage to Bone Strength and Structure in Inbred Fischer 344 and Lewis Rats

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

doi:10.1359/jbmr.050512

Cited by 30 publications

(36 citation statements)

References 51 publications

(77 reference statements)

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“…Interestingly, however, we did not observe evidence of linkage to this region in the large sample of female F344/LEW F 2 rats previously studied for any vBMD or aBMD phenotype. (5) A novel pleiotropic QTL was detected on proximal rat chromosome 6 in the COP/DA F 2 animals. This QTL im- (12,26) Distal femur vBMD 11.2 (9) 6.5 (8) 4.7 (10) 7p21, Spine BMD (20) 14q21, Spine BMD (14) 14q31-32, Spine and trochanter BMD (14,15) (13) Mid-femur vBMD 5.9 (35) 13q21, Hip BMD (13) 14q11, Hip bone size (27) pacts variability in both femur aBMD (LOD ‫ס‬ 11.7) and distal femur vBMD (LOD ‫ס‬ 11.2).…”

Section: Figmentioning

confidence: 96%

Linkage Screen for BMD Phenotypes in Male and Female COP and DA Rat Strains

Koller

Liu

Alam

et al. 2008

Journal of Bone and Mineral Research

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ABSTRACT:Because particular inbred strains of experimental animals are informative for only a subset of the genes underlying variability in BMD, we undertook a genome screen to identify quantitative trait loci (QTLs) in 828 F 2 progeny (405 males and 423 females) derived from the Copenhagen 2331 (COP) and dark agouti (DA) strains of rats. This screen was performed to complement our study in female Fischer 344 (F344) and Lewis (LEW) rats and to further delineate the factors underlying the complex genetic architecture of BMD in the rat model. Microsatellite genotyping was performed using markers at an average density of 20 cM. BMD was measured by pQCT and DXA. These data were analyzed in the R/qtl software to detect QTLs acting in both sexes as well as those having sex-specific effects. A QTL was detected in both sexes on chromosome 18 for midfemur volumetric BMD (vBMD; genome-wide, p < 0.01). On distal chromosome 1, a QTL was found for femur and vertebral aBMD as well as distal femur vBMD, and this QTL appears distinct from the proximal chromosome 1 QTL impacting BMD in our F344/LEW cross. Additional aBMD and vBMD QTLs and several sex-specific QTLs were also detected. These included a male-specific QTL (p < 0.01) on chromosome 8 and a female-specific QTL on chromosomes 7 and 14 (p < 0.01). Few of the QTLs identified showed overlap with the significant QTLs from the F344/LEW cross. These results confirm that the genetic influence on BMD in the rat model is quite complex and would seem to be influenced by a number of different genes, some of which have sex-specific effects.

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Section: Figmentioning

confidence: 96%

Linkage Screen for BMD Phenotypes in Male and Female COP and DA Rat Strains

Koller

Liu

Alam

et al. 2008

Journal of Bone and Mineral Research

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“…A total of 93 markers spanning the entire genome (Chromosomes 1-20 and X) were selected for genotyping and yielded an average intermarker distance of 20 cM. Out of these 93 markers, 82 markers are different from those selected for the F344-LEW cross in previous study [2]. The PCR primer sequences were designed for multiplexing using the fluorescent dyes.…”

Section: Dna Isolation and Microsatellite Marker Genotypingmentioning

confidence: 99%

“…We previously reported results from a genome screen for bone strength and structure phenotypes in a second filial (F2) population of offspring from inbred Fischer 344 (F344) and Lewis (LEW) progenitor strains [2]. Significant quantitative trait loci (QTL) for femoral structure were detected on chromosomes (Chrs) 2, 4, 5, 7 and 15.…”

Section: Introductionmentioning

confidence: 99%

Genetic loci affecting bone structure and strength in inbred COP and DA rats

Sun

Alam

Liu

et al. 2008

Bone

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Previous studies have shown that the Copenhagen 2331 (COP) and Dark Agouti (DA) rats have significant differences in bone structure and strength despite their similar body mass. Thus, these inbred rat strains may provide a unique resource to identify the genetics underlying the phenotypic variation in bone fragility. A sample of 828 (405 males and 423 females) COP × DA F2 progeny had extensive phenotyping for bone structure measures including cortical bone area and polar moment of inertia at the femur midshaft and total, cortical and trabecular bone areas, for the lumbar vertebra 5 (L5). Bone strength phenotypes included ultimate force, stiffness and work to failure of femur and L5. These skeletal phenotypes were measured using peripheral quantitative computed tomography (pQCT) and mechanical testing. A whole-genome screen was conducted in the F2 rats, using microsatellite markers spaced at approximately 20 cM intervals. Genetic marker maps were generated from the F2 data and used for genome-wide linkage analyses to detect linkage to the bone structure and strength phenotypes. Permutation testing was employed to obtain the thresholds for genomewide significance (p<0.01). Significant QTL for femur structure and strength were identified on chromosome (Chr) 1 with a maximum LOD score of 33.5; evidence of linkage was found in both the male and female rats. In addition, Chrs 6, 7, 10, 13, 15 and 18 were linked to femur midshaft structure. QTL linked to femur strength were identified on Chrs 5 and 10. For L5 vertebrae, Chrs 2, 16, and 18 harbored QTL for cortical structure and trabecular structure for L5 was linked to Chrs 1, 7, 12, and 18. One female-specific QTL for femur ultimate force was identified on Chr 5, and two male-specific QTL for L5 cortical area were found on Chrs 2 and 18. Our study demonstrates strong evidence of linkage for bone structure and strength to multiple rat chromosomes.

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“…In experimental crosses, F344 has been shown to carry alleles that cause overall skeletal fragility [6,[11][12][13]. The GK strain displays hyperglycemia and impaired insulin secretion and is a well characterised genetic model for type-2 diabetes [14,15].…”

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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Whole-Genome Scan for Linkage to Bone Strength and Structure in Inbred Fischer 344 and Lewis Rats

Cited by 30 publications

References 51 publications

Linkage Screen for BMD Phenotypes in Male and Female COP and DA Rat Strains

Linkage Screen for BMD Phenotypes in Male and Female COP and DA Rat Strains

Genetic loci affecting bone structure and strength in inbred COP and DA rats

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

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