UNLABELLED: To further delineate the factors underlying the complex genetic architecture of BMD in the rat model, a genome screen for epistatic interactions was conducted. Several significant interactions were identified, involving both previously identified and novel QTLs. INTRODUCTION: The variation in several of the risk factors for osteoporotic fracture, including BMD, has been shown to be caused largely by genetic differences. However, the genetic architecture of BMD is complex in both humans and in model organisms. We have previously reported quantitative trait locus (QTL) results for BMD from a genome screen of 595 female F(2) progeny of Fischer 344 and Lewis rats. These progeny also provide an excellent opportunity to search for epistatic effects, or interaction between genetic loci, that contribute to fracture risk. MATERIALS AND METHODS: Microsatellite marker data from a 20-cM genome screen was analyzed along with weight-adjusted BMD (DXA and pQCT) phenotypic data using the R/qtl software package. Genotype and phenotype data were permuted to determine a genome-wide significance threshold for the epistasis or interaction LOD score corresponding to an alpha level of 0.01. RESULTS AND CONCLUSIONS: Novel loci on chromosomes 12 and 15 showed a strong epistatic effect on total BMD at the femoral midshaft by pQCT (LOD = 5.4). A previously reported QTL on chromosome 7 was found to interact with a novel locus on chromosome 20 to affect whole lumbar BMD by pQCT (LOD = 6.2). These results provide new information regarding the mode of action of previously identified rat QTLs, as well as identifying novel loci that act in combination with known QTLs or with other novel loci to contribute to the risk factors for osteoporotic fracture.
UNLABELLED: To further delineate the factors underlying the complex genetic architecture of BMD in the rat model, a genome screen for epistatic interactions was conducted. Several significant interactions were identified, involving both previously identified and novel QTLs. INTRODUCTION: The variation in several of the risk factors for osteoporotic fracture, including BMD, has been shown to be caused largely by genetic differences. However, the genetic architecture of BMD is complex in both humans and in model organisms. We have previously reported quantitative trait locus (QTL) results for BMD from a genome screen of 595 female F(2) progeny of Fischer 344 and Lewis rats. These progeny also provide an excellent opportunity to search for epistatic effects, or interaction between genetic loci, that contribute to fracture risk. MATERIALS AND METHODS: Microsatellite marker data from a 20-cM genome screen was analyzed along with weight-adjusted BMD (DXA and pQCT) phenotypic data using the R/qtl software package. Genotype and phenotype data were permuted to determine a genome-wide significance threshold for the epistasis or interaction LOD score corresponding to an alpha level of 0.01. RESULTS AND CONCLUSIONS: Novel loci on chromosomes 12 and 15 showed a strong epistatic effect on total BMD at the femoral midshaft by pQCT (LOD = 5.4). A previously reported QTL on chromosome 7 was found to interact with a novel locus on chromosome 20 to affect whole lumbar BMD by pQCT (LOD = 6.2). These results provide new information regarding the mode of action of previously identified rat QTLs, as well as identifying novel loci that act in combination with known QTLs or with other novel loci to contribute to the risk factors for osteoporotic fracture.
Authors: D L Koller; M J Econs; P A Morin; J C Christian; S L Hui; P Parry; M E Curran; L A Rodriguez; P M Conneally; G Joslyn; M Peacock; C C Johnston; T Foroud Journal: J Clin Endocrinol Metab Date: 2000-09 Impact factor: 5.958
Authors: S G Wilson; P W Reed; A Bansal; M Chiano; M Lindersson; M Langdown; R L Prince; D Thompson; E Thompson; M Bailey; P W Kleyn; P Sambrook; M M Shi; T D Spector Journal: Am J Hum Genet Date: 2002-12-11 Impact factor: 11.025
Authors: Munro Peacock; Daniel L Koller; Siu Hui; C Conrad Johnston; Tatiana Foroud; Michael J Econs Journal: Osteoporos Int Date: 2004-03-16 Impact factor: 4.507
Authors: W G Beamer; K L Shultz; G A Churchill; W N Frankel; D J Baylink; C J Rosen; L R Donahue Journal: Mamm Genome Date: 1999-11 Impact factor: 2.957
Authors: C H Turner; Q Sun; J Schriefer; N Pitner; R Price; M L Bouxsein; C J Rosen; L R Donahue; K L Shultz; W G Beamer Journal: Calcif Tissue Int Date: 2003-09 Impact factor: 4.333
Authors: Daniel L Koller; Lixiang Liu; Imranul Alam; Qiwei Sun; Michael J Econs; Tatiana Foroud; Charles H Turner Journal: J Bone Miner Res Date: 2008-09 Impact factor: 6.741
Authors: Heather L Hansen; Todd L Bredbenner; Daniel P Nicolella; Michael C Mahaney; Lorena M Havill Journal: Bone Date: 2009-06-10 Impact factor: 4.398