Osteoporosis International

, Volume 24, Issue 10, pp 2603–2610 | Cite as

Replication of Caucasian loci associated with bone mineral density in Koreans

Original Article



Most bone mineral density (BMD) loci were reported in Caucasian genome-wide association studies (GWAS). This study investigated the association between 59 known BMD loci (+200 suggestive SNPs) and DXA-derived BMD in East Asian population with respect to sex and site specificity. We also identified four novel BMD candidate loci from the suggestive SNPs.


Most GWAS have reported BMD-related variations in Caucasian populations. This study investigates whether the BMD loci discovered in Caucasian GWAS are also associated with BMD in East Asian ethnic samples.


A total of 2,729 unrelated Korean individuals from a population-based cohort were analyzed. We selected 747 single-nucleotide polymorphisms (SNPs). These markers included 547 SNPs from 59 loci with genome-wide significance (GWS, p value less than 5 × 10−8) levels and 200 suggestive SNPs that showed weaker BMD association with p value less than 5 × 10−5. After quality control, 535 GWS SNPs and 182 suggestive SNPs were included in the replication analysis.


Of the 535 GWS SNPs, 276 from 25 loci were replicated (p < 0.05) in the Korean population with 51.6 % replication rate. Of the 182 suggestive variants, 16 were replicated (p < 0.05, 8.8 % of replication rate), and five reached a significant combined p value (less than 7.0 × 10−5, 0.05/717 SNPs, corrected for multiple testing). Two markers (rs11711157, rs3732477) are for the same signal near the gene CPN2 (carboxypeptidase N, polypeptide 2). The other variants, rs6436440 and rs2291296, were located in the genes AP1S3 (adaptor-related protein complex 1, sigma 3 subunit) and RARB (retinoic acid receptor, beta).


Our results illustrate ethnic differences in BMD susceptibility genes and underscore the need for further genetic studies in each ethnic group. We were also able to replicate some SNPs with suggestive associations. These SNPs may be BMD-related genetic markers and should be further investigated.


Bone density Genetic loci Osteoporosis Replication SNP 



This work was supported by the National Genome Research Institute, Korean Center for Disease Control and Prevention (2001-2003-348-6111-221, 2004-347-6111-213, and 2005-347-2400-2440-215). We appreciate the critical review and consultation for Eun-Soon Shin and Jong Eun Lee from DNA Link, Inc.

Conflicts of interest


Supplementary material

198_2013_2354_MOESM1_ESM.xlsx (168 kb)
ESM 1 (XLSX 168 kb)


  1. 1.
    Pocock NA, Eisman JA, Hopper JL, Yeates MG, Sambrook PN, Eberl S (1987) Genetic determinants of bone mass in adults. A twin study. J Clin Invest 80(3):706PubMedCrossRefGoogle Scholar
  2. 2.
    Ferrari S, Rizzoli R, Slosman D, Bonjour JP (1998) Familial resemblance for bone mineral mass is expressed before puberty. J Clin Endocrinol Metab 83(2):358–361PubMedCrossRefGoogle Scholar
  3. 3.
    Deng HW, Xu FH, Huang QY, Shen H, Deng H, Conway T, Liu YJ, Liu YZ, Li JL, Zhang HT (2002) A whole-genome linkage scan suggests several genomic regions potentially containing quantitative trait loci for osteoporosis. J Clin Endocrinol Metab 87(11):5151–5159PubMedCrossRefGoogle Scholar
  4. 4.
    Richards JB, Kavvoura FK, Rivadeneira F, Styrkársdóttir U, Estrada K, Halldórsson BV, Hsu YH, Zillikens MC, Wilson SG, Mullin BH (2009) Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture. Ann Intern Med 151(8):528PubMedCrossRefGoogle Scholar
  5. 5.
    Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL, Gibbs RA, Belmont JW, Boudreau A, Hardenbol P, Leal SM (2007) A second generation human haplotype map of over 3.1 million SNPs. Nature 449(7164):851–861PubMedCrossRefGoogle Scholar
  6. 6.
    Rivadeneira F, Styrkársdottir U, Estrada K, Halldórsson BV, Hsu YH, Richards JB, Zillikens MC, Kavvoura FK, Amin N, Aulchenko YS (2009) Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet 41(11):1199–1206PubMedCrossRefGoogle Scholar
  7. 7.
    Styrkarsdottir U, Halldorsson BV, Gretarsdottir S, Gudbjartsson DF, Walters GB, Ingvarsson T, Jonsdottir T, Saemundsdottir J, Snorradóttir S, Center JR (2009) New sequence variants associated with bone mineral density. Nat Genet 41(1):15–17PubMedCrossRefGoogle Scholar
  8. 8.
    Styrkarsdottir U, Halldorsson BV, Gretarsdottir S, Gudbjartsson DF, Walters GB, Ingvarsson T, Jonsdottir T, Saemundsdottir J, Center JR, Nguyen TV (2008) Multiple genetic loci for bone mineral density and fractures. N Engl J Med 358(22):2355–2365PubMedCrossRefGoogle Scholar
  9. 9.
    Xiong DH, Liu XG, Guo YF, Tan LJ, Wang L, Sha BY, Tang ZH, Pan F, Yang TL, Chen XD (2009) Genome-wide association and follow-up replication studies identified ADAMTS18 and TGFBR3 as bone mass candidate genes in different ethnic groups. Am J Hum Genet 84(3):388PubMedCrossRefGoogle Scholar
  10. 10.
    Kung AWC, Xiao SM, Cherny S, Li GHY, Gao Y, Tso G, Lau KS, Luk KDK, Liu J, Cui B (2010) Association of JAG1 with bone mineral density and osteoporotic fractures: a genome-wide association study and follow-up replication studies. Am J Hum Genet 86(2):229PubMedCrossRefGoogle Scholar
  11. 11.
    Duncan EL, Brown MA (2010) Genetic determinants of bone density and fracture risk—state of the art and future directions. J Clin Endocrinol Metab 95(6):2576–2587PubMedCrossRefGoogle Scholar
  12. 12.
    Estrada K, Styrkarsdottir U, Evangelou E, Hsu YH, Duncan EL, Ntzani EE, Oei L, Albagha OME, Amin N, Kemp JP (2012) Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet 44(5):491–501PubMedCrossRefGoogle Scholar
  13. 13.
    Richards J, Rivadeneira F, Inouye M, Pastinen T, Soranzo N, Wilson S, Andrew T, Falchi M, Gwilliam R, Ahmadi K (2008) Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet 371(9623):1505–1512PubMedCrossRefGoogle Scholar
  14. 14.
    Zhang YP, Deng FY, Chen Y, Pei YF, Fang Y, Guo YF, Guo X, Liu XG, Zhou Q, Liu YJ (2010) Replication study of candidate genes/loci associated with osteoporosis based on genome-wide screening. Osteoporos Int 21(5):785–795PubMedCrossRefGoogle Scholar
  15. 15.
    Gullberg B, Johnell O, Kanis J (1997) World-wide projections for hip fracture. Osteoporos Int 7(5):407–413PubMedCrossRefGoogle Scholar
  16. 16.
    Fu J, Festen EAM, Wijmenga C (2011) Multi-ethnic studies in complex traits. Hum Mol Genet 20(R2):R206–R213PubMedCrossRefGoogle Scholar
  17. 17.
    Cho YS, Go MJ, Kim YJ, Heo JY, Oh JH, Ban HJ, Yoon D, Lee MH, Kim DJ, Park M (2009) A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat Genet 41(5):527–534PubMedCrossRefGoogle Scholar
  18. 18.
    Shin CS, Choi HJ, Kim MJ, Kim JT, Yu SH, Koo BK, Cho HY, Cho SW, Kim SW, Park YJ (2010) Prevalence and risk factors of osteoporosis in Korea: a community-based cohort study with lumbar spine and hip bone mineral density. Bone 47(2):378–387PubMedCrossRefGoogle Scholar
  19. 19.
    Willer CJ, Li Y, Abecasis GR (2010) METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26(17):2190–2191PubMedCrossRefGoogle Scholar
  20. 20.
    Styrkarsdottir U, Halldorsson BV, Gudbjartsson DF, Tang NLS, Koh JM, Xiao S, Kwok TCY, Kim GS, Chan JCN, Cherny S (2010) European bone mineral density loci are also associated with BMD in East-Asian populations. PLoS One 5(10):e13217PubMedCrossRefGoogle Scholar
  21. 21.
    Lefebvre V, Behringer R, De Crombrugghe B (2001) L-Sox5, Sox6 and Sox9 control essential steps of the chondrocyte differentiation pathway. Osteoarthr Cartil/OARS, Osteoarthr Res Soc 9:S69CrossRefGoogle Scholar
  22. 22.
    Arnold MA, Kim Y, Czubryt MP, Phan D, McAnally J, Qi X, Shelton JM, Richardson JA, Bassel-Duby R, Olson EN (2007) MEF2C transcription factor controls chondrocyte hypertrophy and bone development. Dev Cell 12(3):377–389PubMedCrossRefGoogle Scholar
  23. 23.
    Looker AC, Melton L, Harris T, Borrud L, Shepherd J, McGowan J (2009) Age, gender, and race/ethnic differences in total body and subregional bone density. Osteoporos Int 20(7):1141–1149PubMedCrossRefGoogle Scholar
  24. 24.
    Chantler S, Dickie K, Goedecke J, Levitt N, Lambert E, Evans J, Joffe Y, Micklesfield L (2012) Site-specific differences in bone mineral density in black and white premenopausal South African women. Osteoporos Int 23(2):533–542PubMedCrossRefGoogle Scholar
  25. 25.
    Puntus T, Schneider B, Meran J, Peterlik M, Kudlacek S (2011) Influence of age and gender on associations of body mass index with bone mineral density, bone turnover markers and circulating calcium-regulating and bone-active sex hormones. Bone 49(4):824–829PubMedCrossRefGoogle Scholar
  26. 26.
    Fu J, Jiang M, Mirando AJ, Yu HMI, Hsu W (2009) Reciprocal regulation of Wnt and Gpr177/mouse Wntless is required for embryonic axis formation. Proc Natl Acad Sci 106(44):18598–18603PubMedCrossRefGoogle Scholar
  27. 27.
    Peacock M, Koller DL, Fishburn T, Krishnan S, Lai D, Hui S, Johnston CC, Foroud T, Econs MJ (2005) Sex-specific and non-sex-specific quantitative trait loci contribute to normal variation in bone mineral density in men. J Clin Endocrinol Metab 90(5):3060–3066PubMedCrossRefGoogle Scholar
  28. 28.
    Liu CT, Estrada K, Yerges–Armstrong LM, Amin N, Evangelou E, Li G, Minster RL, Carless MA, Kammerer CM, Oei L (2012) Assessment of gene–by–sex interaction effect on bone mineral density. J Bone Miner Res 27(10):2051–2064PubMedCrossRefGoogle Scholar
  29. 29.
    Robinson MS, Bonifacino JS (2001) Adaptor-related proteins. Curr Opin Cell Biol 13(4):444–453PubMedCrossRefGoogle Scholar
  30. 30.
    Boehm M, Bonifacino JS (2001) Adaptins: the final recount. Mol Biol Cell 12(10):2907–2920PubMedCrossRefGoogle Scholar
  31. 31.
    Sheng N, Xie Z, Wang C, Bai G, Zhang K, Zhu Q, Song J, Guillemot F, Chen YG, Lin A (2010) Retinoic acid regulates bone morphogenic protein signal duration by promoting the degradation of phosphorylated Smad1. Proc Natl Acad Sci 107(44):18886–18891PubMedCrossRefGoogle Scholar
  32. 32.
    Liu L, Suzuki K, Nakagata N, Mihara K, Matsumaru D, Ogino Y, Yashiro K, Hamada H, Liu Z, Evans SM (2011) Retinoic acid signaling regulates Sonic hedgehog and bone morphogenetic protein signalings during genital tubercle development. Birth Defects Res Part B: Dev Reprod Toxicol 95(1):79–88Google Scholar
  33. 33.
    Cowan CM, Aalami OO, Shi YY, Chou YF, Mari C, Thomas R, Quarto N, Nacamuli RP, Contag CH, Wu B (2005) Bone morphogenetic protein 2 and retinoic acid accelerate in vivo bone formation, osteoclast recruitment, and bone turnover. Tissue Eng 11(3–4):645–658PubMedCrossRefGoogle Scholar
  34. 34.
    Liu J, Zhang M, Zhao L, Cui B, Li Z, Zhao H, Sun L, Tao B, Li M, Ning G (2010) Analysis of recently identified osteoporosis susceptibility genes in Han Chinese women. J Clin Endocrinol Metab 95(9):E112–E120PubMedCrossRefGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2013

Authors and Affiliations

  1. 1.Department of Internal MedicineSeoul National University College of MedicineSeoulKorea
  2. 2.Department of Internal MedicineChungbuk National University HospitalCheongjuKorea
  3. 3.Center for Genome Science, Korean National Institute of HealthCheongwon-gunKorea
  4. 4.Department of Preventive MedicineAjou University School of MedicineSuwonKorea

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