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

Parsons, Claire A; Mroczkowski, H Joel; McGuigan, Fiona E A LU ; Albagha, Omar M E; Manolagas, Stavros; Reid, David M; Ralston, Stuart H and Shmookler Reis, Robert J (2005) In Human Molecular Genetics 14(21). p.8-3141
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... (More)

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.

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publishing date
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Contribution to journal
publication status
published
keywords
Absorptiometry, Photon, Animals, Bone Density, Chromosome Mapping, Chromosomes, Human, X, Crosses, Genetic, Female, Femur, Haplotypes, Humans, Linear Models, Lumbar Vertebrae, Mice, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Species Specificity, Synteny, Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.
in
Human Molecular Genetics
volume
14
issue
21
pages
8 pages
publisher
Oxford University Press
external identifiers
  • scopus:27744526420
ISSN
0964-6906
DOI
10.1093/hmg/ddi346
language
English
LU publication?
no
id
58186283-5a4d-4cc0-85f7-a9caf161e22c
date added to LUP
2018-01-02 11:10:17
date last changed
2018-05-29 11:47:08
@article{58186283-5a4d-4cc0-85f7-a9caf161e22c,
  abstract     = {<p>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&lt;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.</p>},
  author       = {Parsons, Claire A and Mroczkowski, H Joel and McGuigan, Fiona E A and Albagha, Omar M E and Manolagas, Stavros and Reid, David M and Ralston, Stuart H and Shmookler Reis, Robert J},
  issn         = {0964-6906},
  keyword      = {Absorptiometry, Photon,Animals,Bone Density,Chromosome Mapping,Chromosomes, Human, X,Crosses, Genetic,Female,Femur,Haplotypes,Humans,Linear Models,Lumbar Vertebrae,Mice,Middle Aged,Polymorphism, Single Nucleotide,Quantitative Trait Loci,Species Specificity,Synteny,Comparative Study,Journal Article,Research Support, N.I.H., Extramural,Research Support, Non-U.S. Gov't,Research Support, U.S. Gov't, Non-P.H.S.},
  language     = {eng},
  month        = {11},
  number       = {21},
  pages        = {8--3141},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {Interspecies synteny mapping identifies a quantitative trait locus for bone mineral density on human chromosome Xp22},
  url          = {http://dx.doi.org/10.1093/hmg/ddi346},
  volume       = {14},
  year         = {2005},
}