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

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 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% 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 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 "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.

Bivariate association analysis in selected samples: application to a GWAS of two bone mineral density phenotypes in males with high or low BMD

“…Our study used a design, with extreme truncate selection of unrelated males, aiming to improve power. The approach of studying samples drawn from the extremes of the population distribution of BMD has been used in several linkage studies of BMD variation, 25,27 but rarely in association studies, 28 and to our knowledge, never in samples drawn from the population of males. Owing to our relatively small GWA sample size, no SNP showed evidence of association to either one or both BMD phenotypes at genome-wide significance threshold of 1.7Â10 À7 (0.05/298 783 SNPs).…”

Identification of homogeneous genetic architecture of multiple genetically correlated traits by block clustering of genome-wide associations

“…A number of candidate genes have been identified for traits associated with fracture, such as bone mineral density (BMD), (1)(2)(3) bone geometry, (4,5) and lean mass. (6) Although this is a powerful approach for disease gene discovery, many GWAS focus only on identification of candidate genes and provide no clues on gene networks that may underlie the trait variations.…”

Quantitative trait loci that modulate trabecular bone's risk of failure during unloading and reloading

“…Moreover, Bmp2 is down-regulated in bone cells during mechanical unloading [56] and up-regulated with mechanical loading [57], suggesting that Bmp2 is well integrated into the signaling cascades that modulate changes in mechanical demand. Perhaps of equal importance, Jag1 is a gene known to regulate bone mineral density, reduces susceptibility to fracture, and sensitizes bone cells for the anabolic effects of PTH hormone [58,59]. Jag-1 is down-regulated in bone cells during mechanical loading in vitro, perhaps increasing cell proliferation [60].…”