Quantitative trait loci for BMD in an SM/J by NZB/BlNJ intercross population and identification of Trps1 as a probable candidate gene

Naoki Ishimori, Ioannis M. Stylianou, Ron Korstanje, Michael A. Marion, Renhua Li, Leah Rae Donahue, Clifford J. Rosen, Wesley G. Beamer, Beverly Paigen, Gary A. Churchill

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Identification of genes that regulate BMD will enhance our understanding of osteoporosis and could provide novel molecular targets for treatment or prevention. We generated a mouse intercross population and carried out a quantitative trait locus (QTL) analysis of 143 female and 124 male F2 progeny from progenitor strains SM/J and NZB/BlNJ using whole body and vertebral areal BMD (aBMD) as measured by DXA. We found that both whole body and vertebral aBMD was affected by two loci on chromosome 9: one with a significant epistatic interaction on distal chromosome 8 and the other with a sex-specific effect. Two additional significant QTLs were identified on chromosome 12, and several suggestive ones were identified on chromosomes 5, 8, 15, and 19. The chromosome 9, 12, and 15 loci have been previously identified in other crosses. SNP-based haplotype analysis of the progenitor strains identified blocks within the QTL region that distinguish the low allele strains from the high allele strains, significantly narrowing the QTL region and reducing the possible candidate genes to 98 for chromosome 9, 31 for chromosome 12, and only 2 for chromosome 15. Trps1 is the most probable candidate gene for the chromosome 15 QTL. The sex-specific effects may help to elucidate the BMD differences between males and females. This study shows the power of statistical modeling to resolve linked QTLs and the use of haplotype analysis in narrowing the list of candidates.

Original languageEnglish
Pages (from-to)1529-1537
Number of pages9
JournalJournal of Bone and Mineral Research
Volume23
Issue number9
DOIs
StatePublished - Sep 2008
Externally publishedYes

Keywords

  • Haplotype analysis
  • High-fat diet
  • Peripheral DXA
  • Quantitative trait gene

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