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

• Published in: American journal of human genetics Vol. 86; no. 2; pp. 229 - 239
• Main Authors: Kung, Annie W.C., Xiao, Su-Mei, Cherny, Stacey, Li, Gloria H.Y., Gao, Yi, Tso, Gloria, Lau, Kam S., Luk, Keith D.K., Liu, Jian-min, Cui, Bin, Zhang, Min-Jia, Zhang, Zhen-lin, He, Jin-wei, Yue, Hua, Xia, Wia-bo, Luo, Lian-mei, He, Shu-li, Kiel, Douglas P., Karasik, David, Hsu, Yi-Hsiang, Cupples, L. Adrienne, Demissie, Serkalem, Styrkarsdottir, Unnur, Halldorsson, Bjarni V., Sigurdsson, Gunnar, Thorsteinsdottir, Unnur, Stefansson, Kari, Richards, J. Brent, Zhai, Guangju, Soranzo, Nicole, Valdes, Ana, Spector, Tim D., Sham, Pak C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.02.2010; Cell Press; Elsevier
• Subjects: Aged; Alleles; Asian people; Bone density; Bone Density - genetics; Calcium-Binding Proteins - genetics; Cohort Studies; Electrophoretic Mobility Shift Assay; Female; Follow-Up Studies; Fractures; Fractures, Bone - complications; Fractures, Bone - genetics; Fractures, Bone - physiopathology; Gene Expression Regulation; Genetic Predisposition to Disease; Genetics; Genome-Wide Association Study; Genomics; Humans; Intercellular Signaling Peptides and Proteins - genetics; Jagged-1 Protein; Membrane Proteins - genetics; Middle Aged; Osteoporosis; Osteoporosis - complications; Osteoporosis - genetics; Osteoporosis - physiopathology; Polymorphism, Single Nucleotide - genetics; Reproducibility of Results; Ribonucleic acid; RNA; Serrate-Jagged Proteins
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2009.12.014

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.