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A Second-Stage Genome Scan for QTLs Influencing BMD Variation

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Abstract

Low bone mineral density (BMD) is a major risk factor for osteoporotic fracture. To identify genomic regions harboring quantitative trait loci (QTLs) contributing to BMD variation, we performed a two-stage genome screen. The first stage involved genotyping of a sample of 53 pedigrees with 630 individuals using 400 microsatellite markers spaced at approximately 10-cM intervals throughout the genome. Ten genomic regions with multi- and/or two-point LOD scores greater than 1.5 were observed. In the present second-stage study, 60 microsatellite markers, with a mean spacing of about 5 cM, were genotyped in these regions in an expanded sample of 79 pedigrees that contained 1816 subjects. Each pedigree was ascertained through a proband with extreme BMD at the hip or spine. BMD at the spine (L1–4), hip (the femoral neck, trochanter, and intertrochanteric region), and wrist (the ultradistal region) was measured by dual-energy X-ray absorptiometry (DXA) and was adjusted for age, sex, height, and weight. Two-point and multipoint linkage analyses were performed for each BMD site using statistical genetic methods that are implemented in the computer package SOLAR. Several regions (7q11, 10q26, 12q13, and 12q24) achieved LOD scores in excess of 1 in the second-stage followup study. The current results replicate some of our previous linkage findings and also highlight some of the difficulties facing microsatellite linkage mapping for complex human diseases.

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Acknowledgments

Investigators of this work were partially supported by grants from Health Future Foundation, NIH grants (K01 AR02170-01, R01 AR45349-01, R01 GM60402-01A1, P01 DC01813-07), grants from State of Nebraska Cancer and Smoking Related Disease Research Program (LB595) and the Nebraska Tobacco Settlement Fund (LB692), U.S. Department of Energy grant DE-FG03 00ER63000/A00, Creighton University, grants (30025025, 30170504, 30230210) from National Science Foundation of China, and a grant from Hunan Normal University. DNA extraction effort by the technicians from the Creighton Osteoporosis Research Center is appreciated.

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Authors and Affiliations

  1. Osteoporosis Research Center, Creighton University, Omaha, Nebraska, 68131, USA

    Q. -Y. Huang, F. -H. Xu, H. Shen, L. -J. Zhao, H. -Y. Deng, Y. -J. Liu, V. Dvomyk, T. Conway, K. M. Davies, Y. -Z. Liu, R. R. Recker & H. -W. Deng

  2. Department of Biomedical Sciences, Creighton University, Omaha, Nebraska, 68131, USA

    Q. -Y. Huang, F. -H. Xu, H. Shen, L. -J. Zhao, Y. -J. Liu, Y. -Z. Liu & H. -W. Deng

  3. College of Life Sciences, Central China Normal University, 430079, Wuhan, Hubei, Peoples Republic of China

    Q. -Y. Huang

  4. Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, 410081, ChangSha, Hunan, Peoples Republic of China

    H. -W. Deng

  5. Center for Medical Informatics, School of Medicine, Yale University, New Haven, Connecticut, 06520-8009, USA

    J. -L. Li

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  1. Q. -Y. Huang
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Huang, Q.Y., Xu, F.H., Shen, H. et al. A Second-Stage Genome Scan for QTLs Influencing BMD Variation. Calcif Tissue Int 75, 138–143 (2004). https://doi.org/10.1007/s00223-004-0088-y

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