title: Quantitative trait loci for BMD in an SM/J by NZB/BlNJ intercross population and identification of Trps1 as a probable candidate gene.
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 F(2) 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.
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
authors.forename: Naoki
authors.initials: N
authors.lastname: Ishimori
authors.forename: Ioannis M
authors.initials: IM
authors.lastname: Stylianou
authors.forename: Ron
authors.initials: R
authors.lastname: Korstanje
authors.forename: Michael A
authors.initials: MA
authors.lastname: Marion
authors.forename: Renhua
authors.initials: R
authors.lastname: Li
authors.forename: Leah Rae
authors.initials: LR
authors.lastname: Donahue
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Rosen
authors.forename: Wesley G
authors.initials: WG
authors.lastname: Beamer
authors.forename: Beverly
authors.initials: B
authors.lastname: Paigen
authors.forename: Gary A
authors.initials: GA
authors.lastname: Churchill
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015519:Bone Density / Q000235:genetics*; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian / Q000235:genetics; D003433:Crosses, Genetic; D004843:Epistasis, Genetic; D005260:Female; D050980:GATA Transcription Factors / Q000737:chemistry / Q000235:genetics*; D016678:Genome / Q000235:genetics; D006239:Haplotypes; D040582:Inheritance Patterns / Q000235:genetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008957:Models, Genetic; D008969:Molecular Sequence Data; D040641:Quantitative Trait Loci / Q000235:genetics*; D012097:Repressor Proteins; D017386:Sequence Homology, Amino Acid; D012727:Sex Characteristics; D013131:Spine / Q000502:physiology
chemical_list: D050980:GATA Transcription Factors; D012097:Repressor Proteins; C525953:Trps1 protein, mouse