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Fine mapping of bone structure and strength QTLs in heterogeneous stock rat.

Authors: Alam, I  Koller, DL  Canete, T  Blazquez, G  Mont-Cardona, C  Lopez-Aumatell, R  Martinez-Membrives, E  Diaz-Moran, S  Tobena, A  Fernandez-Teruel, A  Stridh, P  Diez, M  Olsson, T  Johannesson, M  Baud, A  Econs, MJ  Foroud, T 
Citation: Alam I, etal., Bone. 2015 Dec;81:417-26. doi: 10.1016/j.bone.2015.08.013. Epub 2015 Aug 19.
Pubmed: (View Article at PubMed) PMID:26297441
DOI: Full-text: DOI:10.1016/j.bone.2015.08.013

We previously demonstrated that skeletal structure and strength phenotypes vary considerably in heterogeneous stock (HS) rats. These phenotypes were found to be strongly heritable, suggesting that the HS rat model represents a unique genetic resource for dissecting the complex genetic etiology underlying bone fragility. The purpose of this study was to identify and localize genes associated with bone structure and strength phenotypes using 1524 adult male and female HS rats between 17 to 20 weeks of age. Structure measures included femur length, neck width, head width; femur and lumbar spine (L3-5) areas obtained by DXA; and cross-sectional areas (CSA) at the midshaft, distal femur and femoral neck, and the 5th lumbar vertebra measured by CT. In addition, measures of strength of the whole femur and femoral neck were obtained. Approximately 70,000 polymorphic SNPs distributed throughout the rat genome were selected for genotyping, 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 at each locus from each of the 8 HS founder strains. The haplotypes were then tested for association with each structure and strength phenotype via a mixed model with covariate adjustment. We identified quantitative trait loci (QTLs) for structure phenotypes on chromosomes 3, 8, 10, 12, 17 and 20, and QTLs for strength phenotypes on chromosomes 5, 10 and 11 that met a conservative genome-wide empiric significance threshold (FDR=5%; P<3x10(-6)). Importantly, most QTLs were localized to very narrow genomic regions (as small as 0.3 Mb and up to 3 Mb), each harboring a small set of candidate genes, both novel and previously shown to have roles in skeletal development and homeostasis.

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CRRD Object Information
CRRD ID: 11528619
Created: 2016-08-17
Species: All species
Last Modified: 2016-08-17
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.