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Conference Paper: Genome-wide Haplotype Association Mapping (HAM) in Mice Leads to an Identification of a Genetic Variant in CER1 Associated with Bone Mineral Density in Premenopausal Women

TitleGenome-wide Haplotype Association Mapping (HAM) in Mice Leads to an Identification of a Genetic Variant in CER1 Associated with Bone Mineral Density in Premenopausal Women
Authors
Issue Date2007
Citation
The 29th Annual Meeting of the American Society for Bone and Mineral Research (ASBMR), Honolulu, HI, 16-19 September 2007. In Journal of Bone and Mineral Research, 2007, v. 22 n. S1, p. S283 How to Cite?
AbstractBone Mineral Density (BMD) is a complex trait likely determined by multiple genes. We attempted to identify the quantitative trait loci (QTL) for BMD in mouse genome and to replicate the findings in human. Information on single nucleotide polymorphisms (SNPs) (1) and whole body BMD of 18 weeks female mice (2) were gathered from 30 mouse strains. The Haplotype Association Mapping (HAM) program which utilized a sliding window of 3 SNPs in the grouping of a haplotype block was applied (1). A modified F-test was used to query for the existence of some haplotypes structure that can partition mice with high BMD and low BMD. The positional candidate gene was then replicated in 1,083 young southern Chinese women aged 20-40 years having extreme high (BMD Z score > +1 at either the spine or hip) and low BMD (Z score=< -1.28, equivalent to the lowest 10th percentile of the population). The association was examined using binary logistic regression with adjustment of age, height and weight. 22 blocks in the female mice genome were identified to contain genes for BMD variation. Chromosome 4, 82.2-87.9 Mb and Chromosome 12, 26.9-28.6 Mb had two peaks in close proximity. No genes can be found in the gap in Chromosome 12, 26.9-28.6 Mb. 27 genes were found in that of Chromosome 4, 82.2-87.9 Mb. Examination of the gene list identified Cer1 as a positional candidate gene in chromosome 4 QTL. Cer1 is a homolog of Cerberus in Xenopus, which belongs to a cystine knot superfamily containing a cystine knot motif in a C-terminal cysteine-rich region. Genotyping of 10 SNPs in human CER1 gene in 1,083 high and low BMD subjects revealed a non-synonymous SNP (rs3747532) was associated with an increased risk of low BMD in premenopausal women (odds ratio 2.2; 95% confidence interval: 1.0 - 4.6; p < 0.05). Our successful identification of an association of CER1 with BMD variation in both young mature female mice and humans suggested that CER1 is one of the genes associated with peak bone mass. Our study highlights the utility of publicly available databases for rapidly surveying the genome for QTL. References: 1. Pletcher, M. T., McClurg, P., Batalov, S., Su, A. I., Barnes, S. W., Lagler, E., et al. (2004). Use of a dense single nucleotide polymorphism map for in silico mapping in the mouse. PLoS Biol 2:e393 2. http://www.jax.org/phenome
Persistent Identifierhttp://hdl.handle.net/10722/96073
ISSN

 

DC FieldValueLanguage
dc.contributor.authorCheung, CLen_HK
dc.contributor.authorTang, LFen_HK
dc.contributor.authorSham, PCen_HK
dc.contributor.authorMcClug, Pen_HK
dc.contributor.authorChan, SYen_HK
dc.contributor.authorSmith, DKen_HK
dc.contributor.authorSu, AIen_HK
dc.contributor.authorCheah, KSEen_HK
dc.contributor.authorKung, AWCen_HK
dc.contributor.authorSong, Yen_HK
dc.date.accessioned2010-09-25T16:22:32Z-
dc.date.available2010-09-25T16:22:32Z-
dc.date.issued2007en_HK
dc.identifier.citationThe 29th Annual Meeting of the American Society for Bone and Mineral Research (ASBMR), Honolulu, HI, 16-19 September 2007. In Journal of Bone and Mineral Research, 2007, v. 22 n. S1, p. S283-
dc.identifier.issn1523-4681-
dc.identifier.urihttp://hdl.handle.net/10722/96073-
dc.description.abstractBone Mineral Density (BMD) is a complex trait likely determined by multiple genes. We attempted to identify the quantitative trait loci (QTL) for BMD in mouse genome and to replicate the findings in human. Information on single nucleotide polymorphisms (SNPs) (1) and whole body BMD of 18 weeks female mice (2) were gathered from 30 mouse strains. The Haplotype Association Mapping (HAM) program which utilized a sliding window of 3 SNPs in the grouping of a haplotype block was applied (1). A modified F-test was used to query for the existence of some haplotypes structure that can partition mice with high BMD and low BMD. The positional candidate gene was then replicated in 1,083 young southern Chinese women aged 20-40 years having extreme high (BMD Z score > +1 at either the spine or hip) and low BMD (Z score=< -1.28, equivalent to the lowest 10th percentile of the population). The association was examined using binary logistic regression with adjustment of age, height and weight. 22 blocks in the female mice genome were identified to contain genes for BMD variation. Chromosome 4, 82.2-87.9 Mb and Chromosome 12, 26.9-28.6 Mb had two peaks in close proximity. No genes can be found in the gap in Chromosome 12, 26.9-28.6 Mb. 27 genes were found in that of Chromosome 4, 82.2-87.9 Mb. Examination of the gene list identified Cer1 as a positional candidate gene in chromosome 4 QTL. Cer1 is a homolog of Cerberus in Xenopus, which belongs to a cystine knot superfamily containing a cystine knot motif in a C-terminal cysteine-rich region. Genotyping of 10 SNPs in human CER1 gene in 1,083 high and low BMD subjects revealed a non-synonymous SNP (rs3747532) was associated with an increased risk of low BMD in premenopausal women (odds ratio 2.2; 95% confidence interval: 1.0 - 4.6; p < 0.05). Our successful identification of an association of CER1 with BMD variation in both young mature female mice and humans suggested that CER1 is one of the genes associated with peak bone mass. Our study highlights the utility of publicly available databases for rapidly surveying the genome for QTL. References: 1. Pletcher, M. T., McClurg, P., Batalov, S., Su, A. I., Barnes, S. W., Lagler, E., et al. (2004). Use of a dense single nucleotide polymorphism map for in silico mapping in the mouse. PLoS Biol 2:e393 2. http://www.jax.org/phenome-
dc.languageengen_HK
dc.relation.ispartofJournal of Bone and Mineral Researchen_HK
dc.titleGenome-wide Haplotype Association Mapping (HAM) in Mice Leads to an Identification of a Genetic Variant in CER1 Associated with Bone Mineral Density in Premenopausal Womenen_HK
dc.typeConference_Paperen_HK
dc.identifier.emailCheung, CL: sunlunarstar@yahoo.com.hken_HK
dc.identifier.emailTang, LF: lftang@cs.hku.hken_HK
dc.identifier.emailSham, PC: pcsham@HKUCC.hku.hken_HK
dc.identifier.emailChan, SY: matfz@yahoo.comen_HK
dc.identifier.emailSmith, DK: dsmith@hkucc.hku.hken_HK
dc.identifier.emailCheah, KSE: hrmbdkc@hkusua.hku.hken_HK
dc.identifier.emailKung, AWC: awckung@hku.hken_HK
dc.identifier.emailSong, Y: songy@hkucc.hku.hken_HK
dc.identifier.authoritySham, PC=rp00459en_HK
dc.identifier.authorityCheah, KSE=rp00342en_HK
dc.identifier.authorityKung, AWC=rp00368en_HK
dc.identifier.authoritySong, Y=rp00488en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/jbmr.5650221407-
dc.identifier.hkuros152417en_HK

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