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Association of JAG1 with Bone Mineral Density and Osteoporotic Fractures: A Genome-wide Association Study and Follow-up Replication Studies |
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| Authors: | Annie W.C. Kung Su-Mei Xiao Stacey Cherny Yi Gao Kam S. Lau Jian-min Liu Min-Jia Zhang Jin-wei He Wia-bo Xia Shu-li He David Karasik L. Adrienne Cupples Serkalem Demissie Unnur Styrkarsdottir Gunnar Sigurdsson Unnur Thorsteinsdottir Kari Stefansson J. Brent Richards Guangju Zhai Ana Valdes Pak C. Sham |
| Affiliation: | 1 Department of Medicine, The University of Hong Kong, Hong Kong, China 2 Research Centre of Heart, Brain, Hormone & Healthy Aging, Faculty of Medicine, The University of Hong Kong, Hong Kong, China 3 Department of Psychiatry, The University of Hong Kong, Hong Kong, China 4 Department of Orthopaedics & Traumatology, The University of Hong Kong, Hong Kong, China 5 Department of Endocrine and Metabolic Diseases, Rui-jin Hospital, Shanghai Jiao-tong University School of Medicine, Shanghai 200025, China 6 The Center for Preventing and Treating Osteoporosis, Osteoporosis Research Unit, The Sixth People's Hospital, Shanghai Jiao-tong University, Shanghai 200233, China 7 Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China 8 Hebrew SeniorLife Institute for Aging Research and Harvard Medical School, Boston, MA 02131, USA 9 Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA 10 NHLBI Framingham Heart Study, Framingham, MA 01702-5827, USA 11 deCODE Genetics, Sturlugata 8, IS-101 Reykjavik, Iceland 12 Reykjavik University, Kringlan 1, IS-103 Reykjavik, Iceland 13 Department of Endocrinology and Metabolism, University Hospital, IS-108 Reykjavik, Iceland 14 Faculty of Medicine, University of Iceland, IS-101 Reykjavík, Iceland 15 Departments of Medicine and Human Genetics, McGill University, Montreal, Quebec H3T 1E2, Canada 16 Department of Twin Research and Genetic Epidemiology, King's College London, London WC2R 2LS, UK 17 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK |
| 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. |
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