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High‐Resolution Genome Screen for Bone Mineral Density in Heterogeneous Stock Rat
Author(s) -
Alam Imranul,
Koller Daniel L,
Cañete Toni,
Blázquez Gloria,
LópezAumatell Regina,
MartínezMembrives Esther,
DíazMorán Sira,
Tobeña Adolf,
FernándezTeruel Alberto,
Stridh Pernilla,
Diez Margarita,
Olsson Tomas,
Johannesson Martina,
Baud Amelie,
Econs Michael J,
Foroud Tatiana
Publication year - 2014
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.2195
Subject(s) - single nucleotide polymorphism , bone mineral , biology , linkage disequilibrium , haplotype , quantitative trait locus , genetics , bone density , femur , lumbar vertebrae , heritability , population , osteoporosis , locus (genetics) , genome wide association study , anatomy , genotype , gene , lumbar , medicine , endocrinology , paleontology , environmental health
We previously demonstrated that skeletal mass, structure, and biomechanical properties vary considerably in heterogeneous stock (HS) rat strains. In addition, we observed strong heritability for several of these skeletal phenotypes in the HS rat model, suggesting that it represents a unique genetic resource for dissecting the complex genetics underlying bone fragility. The purpose of this study was to identify and localize genes associated with bone mineral density in HS rats. We measured bone phenotypes from 1524 adult male and female HS rats between 17 and 20 weeks of age. Phenotypes included dual‐energy X‐ray absorptiometry (DXA) measurements for bone mineral content and areal bone mineral density (aBMD) for femur and lumbar spine (L 3 –L 5 ), and volumetric BMD measurements by CT for the midshaft and distal femur, femur neck, and fifth lumbar vertebra (L 5 ). A total of 70,000 polymorphic single‐nucleotide polymorphisms (SNPs) distributed throughout the genome were selected from genotypes obtained from the Affymetrix rat custom SNPs array for the HS rat population. These SNPs spanned the HS rat genome 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 for each genotyped locus from each of the eight founder HS strains. The haplotypes were tested for association with each bone density phenotype via a mixed model with covariate adjustment. We identified quantitative trait loci (QTLs) for BMD phenotypes on chromosomes 2, 9, 10, and 13 meeting a conservative genomewide empiric significance threshold (false discovery rate [FDR] = 5%; p < 3 × 10 −6 ). Importantly, most QTLs were localized to very small genomic regions (1–3 megabases [Mb]), allowing us to identify a narrow set of potential candidate genes including both novel genes and genes previously shown to have roles in skeletal development and homeostasis. © 2014 American Society for Bone and Mineral Research.