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Human Molecular Genetics Advance Access originally published online on September 23, 2005
Human Molecular Genetics 2005 14(21):3141-3148; doi:10.1093/hmg/ddi346
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Claire A. Parsons1,{dagger}, H. Joel Mroczkowski2,{dagger}, Fiona E.A. McGuigan1,{dagger}, Omar M.E. Albagha4, Stavros Manolagas3, David M. Reid1, Stuart H. Ralston4,* and Robert J. Shmookler Reis2,3

1Bone Research Group, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK, 2Department of Geriatrics, and Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences and 3Department of Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Health Care System, Little Rock, AR 72205, USA and 4Rheumatic Diseases Unit, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK

* To whom correspondence should be addressed. Tel: +44 131-651-1035; Fax: +44 131-651-1085; Email: stuart.ralston{at}ed.ac.uk

Received June 4, 2005; Accepted September 7, 2005

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 post-menopausal 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 not selected 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.

{dagger} The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.


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