Genome‐Wide Haplotype Association Mapping in Mice Identifies a Genetic Variant in CER1 Associated With BMD and Fracture in Southern Chinese Women

BMD is a heritable trait and risk indicator for osteoporosis. In this study, we used a genome‐wide haplotype association mapping (HAM) approach to identify a haplotype block within Cer1 that partitions inbred mice strains into high and low BMD groups. A cohort of 1083 high and low BMD human subjects were studied, and a nonsynonymous SNP (rs3747532) in human CER1 was identified to be associated with increased risk of both low BMD in premenopausal women (OR: 2.2; 95% CI: 1.0–4.6; p < 0.05) and increased risk of vertebral fractures (OR: 1.82, p = 0.025) in the postmenopausal cohort. We also showed that Cer1 is expressed in mouse bone and growth plate by RT‐PCR, immunohistochemistry, and in situ hybridization, consistent with polymorphisms potentially influencing BMD. Our successful identification of an association with CER1 in humans together with our mouse study suggests that CER1 may play a role in the development of bone or its metabolism. Our study highlights the use of publicly available databases for rapidly surveying the genome for quantitative trait loci.

[1]  V. Chan,et al.  A Differential Association of ALOX15 Polymorphisms with Bone Mineral Density in Pre- and Post-Menopausal Women , 2007, Human Heredity.

[2]  L. Rifas.  The role of noggin in human mesenchymal stem cell differentiation , 2007, Journal of cellular biochemistry.

[3]  K. Kwan,et al.  Surviving Endoplasmic Reticulum Stress Is Coupled to Altered Chondrocyte Differentiation and Function , 2007, PLoS biology.

[4]  S. Vukicevic,et al.  Systemically Administered Bone Morphogenetic Protein-6 Restores Bone in Aged Ovariectomized Rats by Increasing Bone Formation and Suppressing Bone Resorption* , 2006, Journal of Biological Chemistry.

[5]  H. Yoshikawa,et al.  Bone Morphogenetic Proteins in Bone Stimulate Osteoclasts and Osteoblasts During Bone Development , 2006, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[6]  E. Canalis,et al.  Notch 1 Overexpression Inhibits Osteoblastogenesis by Suppressing Wnt/β-Catenin but Not Bone Morphogenetic Protein Signaling* , 2006, Journal of Biological Chemistry.

[7]  Andrew I. Su,et al.  Comparative analysis of haplotype association mapping algorithms , 2006, BMC Bioinformatics.

[8]  A. Paterson,et al.  Effect of Environmental Factors and Gender on the Heritability of Bone Mineral Density and Bone Size , 2005, Annals of human genetics.

[9]  G. Churchill,et al.  Evidence of a Large-Scale Functional Organization of Mammalian Chromosomes , 2005, PLoS biology.

[10]  G. Peltz,et al.  Computational genetics: from mouse to human? , 2005, Trends in genetics : TIG.

[11]  A. Economides,et al.  Skeletal overexpression of gremlin impairs bone formation and causes osteopenia. , 2005, Endocrinology.

[12]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[13]  A. Uitterlinden,et al.  Polymorphisms in the sclerosteosis/van Buchem disease gene (SOST) region are associated with bone-mineral density in elderly whites. , 2004, American journal of human genetics.

[14]  John M. Shelton,et al.  Histone Deacetylase 4 Controls Chondrocyte Hypertrophy during Skeletogenesis , 2004, Cell.

[15]  Serge Batalov,et al.  Use of a Dense Single Nucleotide Polymorphism Map for In Silico Mapping in the Mouse , 2004, PLoS biology.

[16]  Gary Peltz,et al.  In Silico Genetics: Identification of a Functional Element Regulating H2-Eα Gene Expression , 2004, Science.

[17]  Sandrine Dudoit,et al.  Multiple Testing. Part II. Step-Down Procedures for Control of the Family-Wise Error Rate , 2004, Statistical applications in genetics and molecular biology.

[18]  M. Justice,et al.  A twist code determines the onset of osteoblast differentiation. , 2004, Developmental cell.

[19]  G. Peltz,et al.  Regulation of Bone Mass in Mice by the Lipoxygenase Gene Alox15 , 2004, Science.

[20]  Robert W. Williams,et al.  The nature and identification of quantitative trait loci: a community's view , 2003, Nature Reviews Genetics.

[21]  M. Zaidi,et al.  Impaired osteoblastic differentiation, reduced bone formation, and severe osteoporosis in noggin-overexpressing mice. , 2003, The Journal of clinical investigation.

[22]  A. Economides,et al.  Skeletal overexpression of noggin results in osteopenia and reduced bone formation. , 2003, Endocrinology.

[23]  S. Gabriel,et al.  The Structure of Haplotype Blocks in the Human Genome , 2002, Science.

[24]  E. Chesler,et al.  In Silico Mapping of Mouse Quantitative Trait Loci , 2001, Science.

[25]  E. Orwoll,et al.  Confirmation and Fine Mapping of Chromosomal Regions Influencing Peak Bone Mass in Mice , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[26]  E. Orwoll,et al.  Gender Specificity in the Genetic Determinants of Peak Bone Mass , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[27]  N. Ueno,et al.  Bone Morphogenetic Protein 2 Stimulates Osteoclast Differentiation and Survival Supported by Receptor Activator of Nuclear Factor-κB Ligand. , 2001, Endocrinology.

[28]  G. Peltz,et al.  In Silico Mapping of Complex Disease-Related Traits in Mice , 2001, Science.

[29]  A. McMahon,et al.  Indian hedgehog couples chondrogenesis to osteogenesis in endochondral bone development. , 2001, The Journal of clinical investigation.

[30]  Janan T. Eppig,et al.  A mouse phenome project , 2000, Mammalian Genome.

[31]  R. Jilka,et al.  Essential Requirement of BMPs‐2/4 for Both Osteoblast and Osteoclast Formation in Murine Bone Marrow Cultures from Adult Mice: Antagonism by Noggin , 2000, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[32]  J. Rossant,et al.  A mouse cerberus/Dan-related gene family. , 1999, Developmental biology.

[33]  T. Bouwmeester,et al.  The head inducer Cerberus is a multifunctional antagonist of Nodal, BMP and Wnt signals , 1999, Nature.

[34]  E. Orwoll,et al.  Quantitative Trait Loci Affecting Peak Bone Mineral Density in Mice , 1998, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[35]  R. Behringer,et al.  Expression of the mouse cerberus-related gene, Cerr1, suggests a role in anterior neural induction and somitogenesis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[36]  J. Kanis,et al.  Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: Synopsis of a WHO report , 1994, Osteoporosis International.

[37]  S. Ortolani,et al.  Genetics of osteoporosis , 1994, Calcified Tissue International.

[38]  M. Nevitt,et al.  Vertebral fracture assessment using a semiquantitative technique , 1993, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[39]  Josée Dupuis,et al.  Genome-wide association with bone mass and geometry in the Framingham Heart Study , 2007, BMC Medical Genetics.

[40]  Y. Ouchi,et al.  Association of a single nucleotide polymorphism in the lipoxygenase ALOX15 5′-flanking region (−5229G/A) with bone mineral density , 2004, Journal of Bone and Mineral Metabolism.

[41]  Pak Chung Sham,et al.  Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits , 2003, Bioinform..

[42]  Alex E. Lash,et al.  Gene Expression Omnibus: NCBI gene expression and hybridization array data repository , 2002, Nucleic Acids Res..