Association of JAG1 with Bone Mineral Density and Osteoporotic Fractures: A Genome-wide Association Study and Follow-up Replication Studies

Annie W.C. Kung, Su Mei Xiao, Stacey Cherny, Gloria H.Y. Li, Yi Gao, Gloria Tso, Kam S. Lau, Keith D.K. Luk, Jian min Liu, Bin Cui, Min Jia Zhang, Zhen lin Zhang, Jin wei He, Hua Yue, Wia bo Xia, Lian mei Luo, Shu li He, Douglas P. Kiel, David Karasik, Yi Hsiang HsuL. Adrienne Cupples, Serkalem Demissie, Unnur Styrkarsdottir, Bjarni V. Halldorsson, Gunnar Sigurdsson, Unnur Thorsteinsdottir, Kari Stefansson, J. Brent Richards, Guangju Zhai, Nicole Soranzo, Ana Valdes, Tim D. Spector, Pak C. Sham

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153 Scopus citations

Abstract

Bone mineral density (BMD), a diagnostic parameter for osteoporosis and a clinical predictor of fracture, is a polygenic trait with high heritability. To identify genetic variants that influence BMD in different ethnic groups, we performed a genome-wide association study (GWAS) on 800 unrelated Southern Chinese women with extreme BMD and carried out follow-up replication studies in six independent study populations of European descent and Asian populations including 18,098 subjects. In the meta-analysis, rs2273061 of the Jagged1 (JAG1) gene was associated with high BMD (p = 5.27 × 10-8 for lumbar spine [LS] and p = 4.15 × 10-5 for femoral neck [FN], n = 18,898). This SNP was further found to be associated with the low risk of osteoporotic fracture (p = 0.009, OR = 0.7, 95% CI 0.57-0.93, n = 1881). Region-wide and haplotype analysis showed that the strongest association evidence was from the linkage disequilibrium block 5, which included rs2273061 of the JAG1 gene (p = 8.52 × 10-9 for LS and 3.47 × 10-5 at FN). To assess the function of identified variants, an electrophoretic mobility shift assay demonstrated the binding of c-Myc to the "G" but not "A" allele of rs2273061. A mRNA expression study in both human bone-derived cells and peripheral blood mononuclear cells confirmed association of the high BMD-related allele G of rs2273061 with higher JAG1 expression. Our results identify the JAG1 gene as a candidate for BMD regulation in different ethnic groups, and it is a potential key factor for fracture pathogenesis.

Original languageEnglish
Pages (from-to)229-239
Number of pages11
JournalAmerican Journal of Human Genetics
Volume86
Issue number2
DOIs
StatePublished - 12 Feb 2010
Externally publishedYes

Bibliographical note

Funding Information:
This project is supported by Hong Kong Research Grant Council; The Bone Health Fund of HKU Foundation; and Matching Grant, CRCG Grant, and The Osteoporosis Research Fund of The University of Hong Kong. The Twins UK study was funded by the Wellcome Trust, European Community's Sixth and Seventh Framework Programmes (FP7/2007-2013), ENGAGE project HEALTH-F4-2007-201413, and the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254). The study also receives support from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London. T.D.S. is an NIHR senior Investigator. The project also received support from a Biotechnology and Biological Sciences Research Council (BBSRC) project grant (G20234). The authors acknowledge the funding and support of the National Eye Institute via an NIH/CIDR genotyping project (PI, Terri Young). For genotyping of the Twins UK study, we thank the staff from the Genotyping Facilities at the Wellcome Trust Sanger Institute for sample preparation, Quality Control and Genotyping led by Leena Peltonen and Panos Deloukas; Le Centre National de Genotypage, France, led by Mark Lathrop; Duke University, North Carolina, USA, led by David Goldstein; and the Finnish Institute of Molecular Medicine, Finnish Genome Center, University of Helsinki, led by Aarno Palotie. The Framingham Osteoporosis Study (FOS) study was funded by grants from the US National Institute for Arthritis, Musculoskeletal and Skin Diseases and National Institute on Aging (R01 AR/AG 41398 to D.P.K. and R01 AR 050066 to D.K.). The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted with the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. The following are employees of deCODE Company, Iceland, and own stock or stock options of deCODE Company: U.S., B.V.H., U.T., and K.S.

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