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 Citations (Scopus)


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 (JAG]) gene was associated with high BMD (p = 5.27 x 10(-8) for lumbar spine [LS] and p = 4.15 x 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% Cl 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 (1) = 8.52 x 10(-9) for LS and 3.47 x 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 "N' 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 JAG I 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
Issue number2
Publication statusPublished - 12 Feb 2010


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