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 Hsu; L. 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

doi:10.1016/j.ajhg.2009.12.014

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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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 (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 language	English
Pages (from-to)	229 - 239
Number of pages	11
Journal	American Journal of Human Genetics
Volume	86
Issue number	2
DOIs	https://doi.org/10.1016/j.ajhg.2009.12.014
Publication status	Published - 12 Feb 2010

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Kung, A. W. C., Xiao, S.-M., Cherny, S., Li, G. H. Y., Gao, Y., Tso, G., Lau, K. S., Luk, K. D. K., Liu, J., Cui, B., Zhang, M.-J., Zhang, Z., He, J., Yue, H., Xia, W., Luo, L., He, S., Kiel, D. P., Karasik, D., ... Sham, P. C. (2010). Association of JAG1 with Bone Mineral Density and Osteoporotic Fractures: A Genome-wide Association Study and Follow-up Replication Studies. American Journal of Human Genetics, 86(2), 229 - 239. https://doi.org/10.1016/j.ajhg.2009.12.014

@article{2d1ff154d26d43f8bbace3c101b77983,

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 (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.",

author = "Kung, {Annie W. C.} and Su-Mei Xiao and Stacey Cherny and Li, {Gloria H. Y.} and Yi Gao and Gloria Tso and Lau, {Kam S.} and Luk, {Keith D. K.} and Jian-min Liu and Bin Cui and Min-Jia Zhang and Zhen-lin Zhang and Jin-wei He and Hua Yue and Wia-bo Xia and Lian-mei Luo and Shu-li He and Kiel, {Douglas P.} and David Karasik and Yi-Hsiang Hsu and Cupples, {L. Adrienne} and Serkalem Demissie and Unnur Styrkarsdottir and Halldorsson, {Bjarni V.} and Gunnar Sigurdsson and Unnur Thorsteinsdottir and Kari Stefansson and Richards, {J. Brent} and Guangju Zhai and Nicole Soranzo and Ana Valdes and Spector, {Tim D.} and Sham, {Pak C.}",

year = "2010",

month = feb,

day = "12",

doi = "10.1016/j.ajhg.2009.12.014",

language = "English",

volume = "86",

pages = "229 -- 239",

journal = "American Journal of Human Genetics",

issn = "1537-6605",

publisher = "Elsevier",

number = "2",

}

Kung, AWC, Xiao, S-M, Cherny, S, Li, GHY, Gao, Y, Tso, G, Lau, KS, Luk, KDK, Liu, J, Cui, B, Zhang, M-J, Zhang, Z, He, J, Yue, H, Xia, W, Luo, L, He, S, Kiel, DP, Karasik, D, Hsu, Y-H, Cupples, LA, Demissie, S, Styrkarsdottir, U, Halldorsson, BV, Sigurdsson, G, Thorsteinsdottir, U, Stefansson, K, Richards, JB, Zhai, G, Soranzo, N, Valdes, A , Spector, TD & Sham, PC 2010, 'Association of JAG1 with Bone Mineral Density and Osteoporotic Fractures: A Genome-wide Association Study and Follow-up Replication Studies', American Journal of Human Genetics, vol. 86, no. 2, pp. 229 - 239. https://doi.org/10.1016/j.ajhg.2009.12.014

TY - JOUR

T1 - Association of JAG1 with Bone Mineral Density and Osteoporotic Fractures: A Genome-wide Association Study and Follow-up Replication Studies

AU - Kung, Annie W. C.

AU - Xiao, Su-Mei

AU - Cherny, Stacey

AU - Li, Gloria H. Y.

AU - Gao, Yi

AU - Tso, Gloria

AU - Lau, Kam S.

AU - Luk, Keith D. K.

AU - Liu, Jian-min

AU - Cui, Bin

AU - Zhang, Min-Jia

AU - Zhang, Zhen-lin

AU - He, Jin-wei

AU - Yue, Hua

AU - Xia, Wia-bo

AU - Luo, Lian-mei

AU - He, Shu-li

AU - Kiel, Douglas P.

AU - Karasik, David

AU - Hsu, Yi-Hsiang

AU - Cupples, L. Adrienne

AU - Demissie, Serkalem

AU - Styrkarsdottir, Unnur

AU - Halldorsson, Bjarni V.

AU - Sigurdsson, Gunnar

AU - Thorsteinsdottir, Unnur

AU - Stefansson, Kari

AU - Richards, J. Brent

AU - Zhai, Guangju

AU - Soranzo, Nicole

AU - Valdes, Ana

AU - Spector, Tim D.

AU - Sham, Pak C.

PY - 2010/2/12

Y1 - 2010/2/12

N2 - 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.

AB - 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.

U2 - 10.1016/j.ajhg.2009.12.014

DO - 10.1016/j.ajhg.2009.12.014

M3 - Article

SN - 1537-6605

VL - 86

SP - 229

EP - 239

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 2

ER -

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

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