Chromosomal Mapping of Osteopenia-Associated Quantitative Trait Loci Using Closely Related Mouse Strains

Authors

  • Helen Beneš,

    1. Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, U.S.A.
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  • Robert S. Weinstein,

    1. Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, U.S.A.
    2. Division of Endocrinology and Center for Osteoporosis and Metabolic Diseases, University of Arkansas for Medical Sciences, Little Rock, Arkansas, U.S.A.
    3. Central Arkansas Veterans Health Care System, Research-151, Little Rock, Arkansas, U.S.A.
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  • Wenhui Zheng,

    1. Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, U.S.A.
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  • John J. Thaden,

    1. Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, U.S.A.
    2. Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, U.S.A.
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  • Robert L. Jilka,

    1. Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, U.S.A.
    2. Division of Endocrinology and Center for Osteoporosis and Metabolic Diseases, University of Arkansas for Medical Sciences, Little Rock, Arkansas, U.S.A.
    3. Central Arkansas Veterans Health Care System, Research-151, Little Rock, Arkansas, U.S.A.
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  • Stavros C. Manolagas,

    1. Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, U.S.A.
    2. Division of Endocrinology and Center for Osteoporosis and Metabolic Diseases, University of Arkansas for Medical Sciences, Little Rock, Arkansas, U.S.A.
    3. Central Arkansas Veterans Health Care System, Research-151, Little Rock, Arkansas, U.S.A.
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  • Robert J. Shmookler Reis

    Corresponding author
    1. Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, U.S.A.
    2. Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, U.S.A.
    3. Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, U.S.A.
    4. Central Arkansas Veterans Health Care System, Research-151, Little Rock, Arkansas, U.S.A.
    • Reis J. L. McClellan Veterans Medical Center 4300 West Seventh Street, Research-151 Little Rock, Arkansas 72205 U.S.A.
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Abstract

Peak bone mineral density (BMD) is a highly heritable trait in humans and is currently the best predictor of skeletal fragility underlying osteoporosis. The SAMP6 mouse strain displays unusually low BMD at maturity, and age-dependent osteopenia associated with defective osteoblastogenesis. To identify quantitative trait loci (QTLs) influencing bone density, we constructed crosses between SAMP6 and either AKR/J or SAMP6, two related mouse strains of higher peak BMD. Due to common ancestry of these strains, intercross parents differed at only 39–40% of 227 highly-polymorphic genotyping markers, thus restricting our search to this informative portion of the genome and reducing the number of mice required for QTL significance. Using dual energy X-ray absorptiometry (DEXA), we measured spinal BMD in F2 cross progeny at 4 months of age, and selectively genotyped those in the highest and lowest quartiles for BMD. Based on linear regression of bone density on genotype, including Composite Interval Mapping to enhance mapping precision while adjusting for effects of distal markers, we identified multiple QTLs significantly affecting spinal BMD; these were mapped to regions of chromosomes 2 (two sites, one confirmed in both crosses), 7, 11, 13 and 16. One of these loci had been previously identified as a significant bone-density QTL, while 3 substantiate QTLs suggested by a low-power study of 24 recombinant-inbred mouse lines. Such recurrent appearance of QTLs, especially in crosses involving distantly-related strains, implies that polymorphism at these loci may be favored by evolution and might underlie variation in peak bone density among humans.

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