Association of JAG1 with bone mineral density and osteoporotic fractures: a genome-wide association study and follow-up replication studies.
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.
Kung
Annie W C
AW
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
Xiao
Su-Mei
SM
Cherny
Stacey
S
Li
Gloria H Y
GH
Gao
Yi
Y
Tso
Gloria
G
Lau
Kam S
KS
Luk
Keith D K
KD
Liu
Jian-min
JM
Cui
Bin
B
Zhang
Min-Jia
MJ
Zhang
Zhen-lin
ZL
He
Jin-wei
JW
Yue
Hua
H
Xia
Wia-bo
WB
Luo
Lian-mei
LM
He
Shu-li
SL
Kiel
Douglas P
DP
Karasik
David
D
Hsu
Yi-Hsiang
YH
Cupples
L Adrienne
LA
Demissie
Serkalem
S
Styrkarsdottir
Unnur
U
Halldorsson
Bjarni V
BV
Sigurdsson
Gunnar
G
Thorsteinsdottir
Unnur
U
Stefansson
Kari
K
Richards
J Brent
JB
Zhai
Guangju
G
Soranzo
Nicole
N
Valdes
Ana
A
Spector
Tim D
TD
Sham
Pak C
PC
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
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