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Human Molecular Genetics Advance Access published online on September 23, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi346
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received June 4, 2005
Revised September 7, 2005
Accepted September 7, 2005

Article

Interspecies synteny mapping identifies a quantitative trait locus for bone mineral density on human chromosome Xp22

Claire A Parsons 1, H. Joel Mroczkowski 2, Fiona E.A. McGuigan 1, Omar M E Albagha 3, Stavros Manolagas 4, David M. Reid 1, Stuart H. Ralston 3*, and Robert J Shmookler Reis 5

1 Bone Research Group, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK
2 Department of Geriatrics, and Dept. of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205
3 Rheumatic Diseases Unit, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH 2XU, UK
4 Department of Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Health Care System, Little Rock, AR 72205
5 Department of Geriatrics, and Dept. of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205; Department of Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Health Care System, Little Rock, AR 72205

* To whom correspondence should be addressed.
Stuart H. Ralston, E-mail: stuart.ralston{at}ed.ac.uk


  Abstract

Bone mineral density (BMD) is a complex trait with a strong genetic component and an important predictor of osteoporotic fracture risk. Here we report the use of a cross-species strategy to identify genes that regulate BMD, proceeding from quantitative trait mapping in mice to association mapping of the syntenic region in the human genome. We identified a quantitative trait locus (QTL) on the mouse X chromosome for post-maturity change in spine BMD in a cross of SAMP6 and AKR/J mice, and conducted association mapping of the syntenic region on human chromosome Xp22. We studied 76 single nucleotide polymorphisms (SNP) from the human region in two sets of DNA pools prepared from individuals with lumbar spine BMD (LS-BMD) values falling into the top and bottom 13th percentiles of a population-based study of 3100 postmenopausal women. This procedure identified a region of significant association for two adjacent SNP (rs234494 and rs234495) within the Xp22 locus (p < 0.001). Individual genotyping for rs234494 in the BMD pools confirmed the presence of an association for alleles (p = 0.018) and genotypes (p = 0.008). Analysis of rs234494 and rs234495 in 1053 women derived from the same population who were unselected for BMD values showed an association with LS-BMD for rs234495 (p = 0.01) and for haplotypes defined by both SNP (p = 0.002). Our study illustrates that interspecies synteny can be used to identify and refine QTL for complex traits and represents the first example where a human QTL for BMD regulation has been mapped using this approach.

Keywords: linkage; genetics; synteny; association studies; osteoporosis; bone mineral density.
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