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

Lagerholm, Sofia LU ; Park, Hee-Bok LU ; Luthman, Holger LU ; Nilsson, Mats A LU ; McGuigan, Fiona LU ; Swanberg, Maria LU and Åkesson, Kristina LU (2010) In Bone 47. p.1039-1047
Abstract
The F344 rat carries alleles contributing to bone fragility while the GK rat spontaneously develops type-2 diabetes. These characteristics make F344xGK 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... (More)
The F344 rat carries alleles contributing to bone fragility while the GK rat spontaneously develops type-2 diabetes. These characteristics make F344xGK 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 10cM). 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 (GKxF344)F2 progeny were located on chr 1 (39-67cM). 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 (67-82cM) 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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Bone
volume
47
pages
1039 - 1047
publisher
Elsevier
external identifiers
  • WOS:000285278100006
  • PMID:20699128
  • Scopus:78049432444
ISSN
1873-2763
DOI
10.1016/j.bone.2010.08.003
language
English
LU publication?
yes
id
e6a0e2df-7f5c-44a6-afcc-f7c8566ce20d (old id 1665382)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/20699128?dopt=Abstract
date added to LUP
2010-09-03 10:05:02
date last changed
2016-10-13 04:26:04
@misc{e6a0e2df-7f5c-44a6-afcc-f7c8566ce20d,
  abstract     = {The F344 rat carries alleles contributing to bone fragility while the GK rat spontaneously develops type-2 diabetes. These characteristics make F344xGK 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 10cM). 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 (GKxF344)F2 progeny were located on chr 1 (39-67cM). 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 (67-82cM) 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.},
  author       = {Lagerholm, Sofia and Park, Hee-Bok and Luthman, Holger and Nilsson, Mats A and McGuigan, Fiona and Swanberg, Maria and Åkesson, Kristina},
  issn         = {1873-2763},
  language     = {eng},
  pages        = {1039--1047},
  publisher    = {ARRAY(0x80bbba8)},
  series       = {Bone},
  title        = {Genetic loci for bone architecture determined by three-dimensional CT in crosses with the diabetic GK rat.},
  url          = {http://dx.doi.org/10.1016/j.bone.2010.08.003},
  volume       = {47},
  year         = {2010},
}