title: 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.
authors.affiliation: Department of Medicine, Research Centre of Heart, Brain, Hormone & Healthy Aging, Faculty of Medicine, The University of Hong Kong, Hong Kong, China. awckung@hkucc.hku.hk
authors.forename: Annie W C
authors.initials: AW
authors.lastname: Kung
authors.forename: Su-Mei
authors.initials: SM
authors.lastname: Xiao
authors.forename: Stacey
authors.initials: S
authors.lastname: Cherny
authors.forename: Gloria H Y
authors.initials: GH
authors.lastname: Li
authors.forename: Yi
authors.initials: Y
authors.lastname: Gao
authors.forename: Gloria
authors.initials: G
authors.lastname: Tso
authors.forename: Kam S
authors.initials: KS
authors.lastname: Lau
authors.forename: Keith D K
authors.initials: KD
authors.lastname: Luk
authors.forename: Jian-min
authors.initials: JM
authors.lastname: Liu
authors.forename: Bin
authors.initials: B
authors.lastname: Cui
authors.forename: Min-Jia
authors.initials: MJ
authors.lastname: Zhang
authors.forename: Zhen-lin
authors.initials: ZL
authors.lastname: Zhang
authors.forename: Jin-wei
authors.initials: JW
authors.lastname: He
authors.forename: Hua
authors.initials: H
authors.lastname: Yue
authors.forename: Wia-bo
authors.initials: WB
authors.lastname: Xia
authors.forename: Lian-mei
authors.initials: LM
authors.lastname: Luo
authors.forename: Shu-li
authors.initials: SL
authors.lastname: He
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Kiel
authors.forename: David
authors.initials: D
authors.lastname: Karasik
authors.forename: Yi-Hsiang
authors.initials: YH
authors.lastname: Hsu
authors.forename: L Adrienne
authors.initials: LA
authors.lastname: Cupples
authors.forename: Serkalem
authors.initials: S
authors.lastname: Demissie
authors.forename: Unnur
authors.initials: U
authors.lastname: Styrkarsdottir
authors.forename: Bjarni V
authors.initials: BV
authors.lastname: Halldorsson
authors.forename: Gunnar
authors.initials: G
authors.lastname: Sigurdsson
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.forename: J Brent
authors.initials: JB
authors.lastname: Richards
authors.forename: Guangju
authors.initials: G
authors.lastname: Zhai
authors.forename: Nicole
authors.initials: N
authors.lastname: Soranzo
authors.forename: Ana
authors.initials: A
authors.lastname: Valdes
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.forename: Pak C
authors.initials: PC
authors.lastname: Sham
mesh_terms: D000368:Aged; D000483:Alleles; D015519:Bone Density / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D015331:Cohort Studies; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005500:Follow-Up Studies; D050723:Fractures, Bone / Q000150:complications* / Q000235:genetics / Q000503:physiopathology; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D010024:Osteoporosis / Q000150:complications* / Q000235:genetics* / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015203:Reproducibility of Results; D000072099:Serrate-Jagged Proteins
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D000072099:Serrate-Jagged Proteins