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

Fiona E. A. McGuigan, C A Parsons, Omar M. E. Albagha, H. J. Mroczkowski, S. Manolagas, David M Reid, S. H. Ralston, R. J. Shmookler Reis

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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 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.
Original languageEnglish
Pages (from-to)3141-3148
Number of pages8
JournalHuman Molecular Genetics
Volume14
DOIs
Publication statusPublished - 1 Nov 2005

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Synteny
Quantitative Trait Loci
Human Chromosomes
Bone Density
Single Nucleotide Polymorphism
Spine
Inbred AKR Mouse
Osteoporotic Fractures
X Chromosome
Human Genome
Haplotypes
Population
Alleles
Genotype
DNA

Cite this

McGuigan, F. E. A., Parsons, C. A., Albagha, O. M. E., Mroczkowski, H. J., Manolagas, S., Reid, D. M., ... Shmookler Reis, R. J. (2005). Interspecies synteny mapping identifies a quantitative trait locus for bone mineral density on human chromosome Xp22. Human Molecular Genetics, 14, 3141-3148. https://doi.org/10.1093/hmg/ddi346

Interspecies synteny mapping identifies a quantitative trait locus for bone mineral density on human chromosome Xp22. / McGuigan, Fiona E. A.; Parsons, C A; Albagha, Omar M. E.; Mroczkowski, H. J.; Manolagas, S.; Reid, David M; Ralston, S. H.; Shmookler Reis, R. J.

In: Human Molecular Genetics, Vol. 14, 01.11.2005, p. 3141-3148.

Research output: Contribution to journalArticle

McGuigan, FEA, Parsons, CA, Albagha, OME, Mroczkowski, HJ, Manolagas, S, Reid, DM, Ralston, SH & Shmookler Reis, RJ 2005, 'Interspecies synteny mapping identifies a quantitative trait locus for bone mineral density on human chromosome Xp22' Human Molecular Genetics, vol. 14, pp. 3141-3148. https://doi.org/10.1093/hmg/ddi346
McGuigan, Fiona E. A. ; Parsons, C A ; Albagha, Omar M. E. ; Mroczkowski, H. J. ; Manolagas, S. ; Reid, David M ; Ralston, S. H. ; Shmookler Reis, R. J. / Interspecies synteny mapping identifies a quantitative trait locus for bone mineral density on human chromosome Xp22. In: Human Molecular Genetics. 2005 ; Vol. 14. pp. 3141-3148.
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