Genetic influences account for the majority of the population variance in bone mineral density and bone fragility. Considering that hip fracture is the most expensive of osteoporotic fractures, both in terms of health care cost and in human costs (i.e., morbidity and mortality), there should be considerable interest in an animal model for studying genetic influences on hip fragility. We recently identified two strains of rats, Copenhagen 2331 (COP) and DA, which have considerable variation in the biomechanical properties of their femoral necks. We propose to use these rat strains to identify genes responsible for the variation in hip fragility. We will test three hypotheses: (1) COP and DA rats reach peak femoral neck strength and bone mass at six months of age. Our goal is to determine genetic influences on the biomechanical properties and bone structure at an age when femoral neck strength is at its peak. Sprague-Dawley rats achieve peak bone mass and strength within a window of 5-9 months of age. Presumably, COP and DA strains follow similar skeletal growth curves. We will measure femoral biomechanical properties, geometry and microstructure in rats ranging from 2 to 10 months of age to determine the age associated with peak values; (2) chromosomal regions harboring genes that regulate femoral neck strength and microstructure can be determined for rats. COP and DA progenitor rats will be mated and their F1 hybrid offspring intercrossed to create an F2 population containing 500-600 individuals. These rats will be phenotyped based upon femoral neck biomechanical, geometrical and microstructural measurements. Quantitative trait loci (QTL) analyses will be performed to identify the genetic loci influencing variation phenotypes. We anticipate that these analyses will identify several QTLs containing genes that influence femoral neck fragility; and (3) femoral shaft and neck fragility are regulated, at least in part, by different genetic loci. The COP x DA F2 population will be further characterized for bone fragility at the femoral midshaft QTL analyses will be performed to identify the genetic loci contributing to the variation in the phenotypes. We anticipate that these analyses will identify some QTLs previously linked to femoral neck fragility in Aim 2, as well as novel QTLs specifically influencing femoral shaft phenotypes.
| Alam, Imranul; Koller, Daniel L; Cañete, Toni et al. (2015) Fine mapping of bone structure and strength QTLs in heterogeneous stock rat. Bone 81:417-426 |
| Alam, Imranul; Koller, Daniel L; Cañete, Toni et al. (2014) High-resolution genome screen for bone mineral density in heterogeneous stock rat. J Bone Miner Res 29:1619-26 |
| Rat Genome Sequencing and Mapping Consortium; Baud, Amelie; Hermsen, Roel et al. (2013) Combined sequence-based and genetic mapping analysis of complex traits in outbred rats. Nat Genet 45:767-75 |
| Swaminathan, Shanker; Shen, Li; Risacher, Shannon L et al. (2012) Amyloid pathway-based candidate gene analysis of [(11)C]PiB-PET in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Brain Imaging Behav 6:1-15 |
| Alam, Imranul; Koller, Daniel L; Sun, Qiwei et al. (2011) Heterogeneous stock rat: a unique animal model for mapping genes influencing bone fragility. Bone 48:1169-77 |
| Alam, Imranul; Carr, Lucinda G; Liang, Tiebing et al. (2010) Identification of genes influencing skeletal phenotypes in congenic P/NP rats. J Bone Miner Res 25:1314-25 |
| Alam, Imranul; Sun, Qiwei; Koller, Daniel L et al. (2010) Genes influencing spinal bone mineral density in inbred F344, LEW, COP, and DA rats. Funct Integr Genomics 10:63-72 |
| Koller, Daniel L; Liu, Lixiang; Alam, Imranul et al. (2009) Epistasis between QTLs for bone density variation in Copenhagen x dark agouti F2 rats. Mamm Genome 20:180-6 |
| Alam, Imranul; Sun, Qiwei; Koller, Daniel L et al. (2009) Differentially expressed genes strongly correlated with femur strength in rats. Genomics 94:257-62 |
| Koller, Daniel L; Liu, Lixiang; Alam, Imranul et al. (2008) Linkage screen for BMD phenotypes in male and female COP and DA rat strains. J Bone Miner Res 23:1382-8 |
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