Genomics & Informatics

Korea Genome Organization (한국유전체학회)
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Genome-Wide Association Study of Bone Mineral Density in Korean Men

  • Bae, Ye Seul (Department of Family Medicine, Seoul National University Hospital, Seoul National University College of Medicine) ;
  • Im, Sun-Wha (Neuro-Immune Information Storage Network Research Center, Seoul National University College of Medicine) ;
  • Kang, Mi So (Department of Family Medicine, Seoul National University Hospital, Seoul National University College of Medicine) ;
  • Kim, Jin Hee (Department of Family Medicine, Seoul National University Hospital, Seoul National University College of Medicine) ;
  • Lee, Soon Hang (Department of Family Medicine, Seoul National University Hospital, Seoul National University College of Medicine) ;
  • Cho, Be Long (Department of Family Medicine, Seoul National University Hospital, Seoul National University College of Medicine) ;
  • Park, Jin Ho (Department of Family Medicine, Seoul National University Hospital, Seoul National University College of Medicine) ;
  • Nam, You-Seon (Department of Family Medicine, Seoul National University Hospital, Seoul National University College of Medicine) ;
  • Son, Ho-Young (Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine) ;
  • Yang, San Deok (Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine) ;
  • Sung, Joohon (Department of Epidemiology, Seoul National University School of Public Health/Institute of Health and Environment, Seoul National University) ;
  • Oh, Kwang Ho (Department of Family Medicine, Seoul National University Hospital, Seoul National University College of Medicine) ;
  • Yun, Jae Moon (Department of Family Medicine, Seoul National University Hospital, Seoul National University College of Medicine) ;
  • Kim, Jong Il (Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine)
  • Received : 2016.04.14
  • Accepted : 2016.05.08
  • Published : 2016.06.30
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Abstract

Osteoporosis is a medical condition of global concern, with increasing incidence in both sexes. Bone mineral density (BMD), a highly heritable trait, has been proven a useful diagnostic factor in predicting fracture. Because medical information is lacking about male osteoporotic genetics, we conducted a genome-wide association study of BMD in Korean men. With 1,176 participants, we analyzed 4,414,664 single nucleotide polymorphisms (SNPs) after genomic imputation, and identified five SNPs and three loci correlated with bone density and strength. Multivariate linear regression models were applied to adjust for age and body mass index interference. Rs17124500 ($p=6.42{\times}10^{-7}$), rs34594869 ($p=6.53{\times}10^{-7}$) and rs17124504 ($p=6.53{\times}10^{-7}$) in 14q31.3 and rs140155614 ($p=8.64{\times}10^{-7}$) in 15q25.1 were significantly associated with lumbar spine BMD (LS-BMD), while rs111822233 ($p=6.35{\times}10^{-7}$) was linked with the femur total BMD (FT-BMD). Additionally, we analyzed the relationship between BMD and five genes previously identified in Korean men. Rs61382873 (p = 0.0009) in LRP5, rs9567003 (p = 0.0033) in TNFSF11 and rs9935828 (p = 0.0248) in FOXL1 were observed for LS-BMD. Furthermore, rs33997547 (p = 0.0057) in ZBTB and rs1664496 (p = 0.0012) in MEF2C were found to influence FT-BMD and rs61769193 (p = 0.0114) in ZBTB to influence femur neck BMD. We identified five SNPs and three genomic regions, associated with BMD. The significance of our results lies in the discovery of new loci, while also affirming a previously significant locus, as potential osteoporotic factors in the Korean male population.

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References

  1. Johnell O, Kanis JA, Oden A, Johansson H, De Laet C, Delmas P, et al. Predictive value of BMD for hip and other fractures. J Bone Miner Res 2005;20:1185-1194. https://doi.org/10.1359/JBMR.050304
  2. Kanis JA, Oden A, Johnell O, Johansson H, De Laet C, Brown J, et al. The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women. Osteoporos Int 2007;18:1033-1046. https://doi.org/10.1007/s00198-007-0343-y
  3. Siddiqui NA, Shetty KR, Duthie EH Jr. Osteoporosis in older men: discovering when and how to treat it. Geriatrics 1999;54:20-22, 27-28, 30.
  4. Choi YJ, Oh HJ, Kim DJ, Lee Y, Chung YS. The prevalence of osteoporosis in Korean adults aged 50 years or older and the higher diagnosis rates in women who were beneficiaries of a national screening program: the Korea National Health and Nutrition Examination Survey 2008-2009. J Bone Miner Res 2012;27:1879-1886. https://doi.org/10.1002/jbmr.1635
  5. Orwoll ES, Klein RF. Osteoporosis in men. Endocr Rev 1995;16:87-116. https://doi.org/10.1210/edrv-16-1-87
  6. Drake MT, Murad MH, Mauck KF, Lane MA, Undavalli C, Elraiyah T, et al. Clinical review. Risk factors for low bone mass-related fractures in men: a systematic review and meta-analysis. J Clin Endocrinol Metab 2012;97:1861-1870. https://doi.org/10.1210/jc.2011-3058
  7. Jutberger H, Lorentzon M, Barrett-Connor E, Johansson H, Kanis JA, Ljunggren O, et al. Smoking predicts incident fractures in elderly men: Mr OS Sweden. J Bone Miner Res 2010;25:1010-1016.
  8. Peacock M, Turner CH, Econs MJ, Foroud T. Genetics of osteoporosis. Endocr Rev 2002;23:303-326. https://doi.org/10.1210/edrv.23.3.0464
  9. Arden NK, Baker J, Hogg C, Baan K, Spector TD. The heritability of bone mineral density, ultrasound of the calcaneus and hip axis length: a study of postmenopausal twins. J Bone Miner Res 1996;11:530-534.
  10. Mo XB, Lu X, Zhang YH, Zhang ZL, Deng FY, Lei SF. Gene-based association analysis identified novel genes associated with bone mineral density. PLoS One 2015;10:e0121811. https://doi.org/10.1371/journal.pone.0121811
  11. Urano T, Inoue S. Recent genetic discoveries in osteoporosis, sarcopenia and obesity. Endocr J 2015;62:475-484. https://doi.org/10.1507/endocrj.EJ15-0154
  12. Estrada K, Styrkarsdottir U, Evangelou E, Hsu YH, Duncan EL, Ntzani EE, et al. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet 2012;44:491-501. https://doi.org/10.1038/ng.2249
  13. Kim YA, Choi HJ, Lee JY, Han BG, Shin CS, Cho NH. Replication of Caucasian loci associated with bone mineral density in Koreans. Osteoporos Int 2013;24:2603-2610. https://doi.org/10.1007/s00198-013-2354-1
  14. Park SE, Oh KW, Lee WY, Baek KH, Yoon KH, Son HY, et al. Association of osteoporosis susceptibility genes with bone mineral density and bone metabolism related markers in Koreans: the Chungju Metabolic Disease Cohort (CMC) study. Endocr J 2014;61:1069-1078. https://doi.org/10.1507/endocrj.EJ14-0119
  15. Roshandel D, Thomson W, Pye SR, Boonen S, Borghs H, Vanderschueren D, et al. A validation of the first genome-wide association study of calcaneus ultrasound parameters in the European Male Ageing Study. BMC Med Genet 2011;12:19.
  16. Styrkarsdottir U, Halldorsson BV, Gudbjartsson DF, Tang NL, Koh JM, Xiao SM, et al. European bone mineral density loci are also associated with BMD in East-Asian populations. PLoS One 2010;5:e13217. https://doi.org/10.1371/journal.pone.0013217
  17. Cho YS, Go MJ, Kim YJ, Heo JY, Oh JH, Ban HJ, et al. A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat Genet 2009;41:527-534. https://doi.org/10.1038/ng.357
  18. Kim HJ, Park JH, Lee S, Son HY, Hwang J, Chae J, et al. A common variant of NGEF is associated with abdominal visceral fat in Korean men. PLoS One 2015;10:e0137564. https://doi.org/10.1371/journal.pone.0137564
  19. Son KY, Son HY, Chae J, Hwang J, Jang S, Yun JM, et al. Genetic association of APOA5 and APOE with metabolic syndrome and their interaction with health-related behavior in Korean men. Lipids Health Dis 2015;14:105. https://doi.org/10.1186/s12944-015-0111-5
  20. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007;81:559-575. https://doi.org/10.1086/519795
  21. Delaneau O, Marchini J; 1000 Genomes Project Consortium. Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel. Nat Commun 2014;5:3934. https://doi.org/10.1038/ncomms4934
  22. Howie B, Fuchsberger C, Stephens M, Marchini J, Abecasis GR. Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat Genet 2012;44:955-959. https://doi.org/10.1038/ng.2354
  23. Felson DT, Zhang Y, Hannan MT, Anderson JJ. Effects of weight and body mass index on bone mineral density in men and women: the Framingham study. J Bone Miner Res 1993;8:567-573.
  24. Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP, et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 2010;26:2336-2337. https://doi.org/10.1093/bioinformatics/btq419
  25. Bushinsky DA. Acidosis and bone. Miner Electrolyte Metab 1994;20:40-52.
  26. Ralston SH, Galwey N, MacKay I, Albagha OM, Cardon L, Compston JE, et al. Loci for regulation of bone mineral density in men and women identified by genome wide linkage scan: the FAMOS study. Hum Mol Genet 2005;14:943-951. https://doi.org/10.1093/hmg/ddi088
  27. Amos CI, Wu X, Broderick P, Gorlov IP, Gu J, Eisen T, et al. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet 2008;40:616-622. https://doi.org/10.1038/ng.109
  28. Takeda AN, Pinon GM, Bens M, Fagart J, Rafestin-Oblin ME, Vandewalle A. The synthetic androgen methyltrienolone (r1881) acts as a potent antagonist of the mineralocorticoid receptor. Mol Pharmacol 2007;71:473-482.
  29. Falahati-Nini A, Riggs BL, Atkinson EJ, O'Fallon WM, Eastell R, Khosla S. Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men. J Clin Invest 2000;106:1553-1560. https://doi.org/10.1172/JCI10942
  30. Fink HA, Ewing SK, Ensrud KE, Barrett-Connor E, Taylor BC, Cauley JA, et al. Association of testosterone and estradiol deficiency with osteoporosis and rapid bone loss in older men. J Clin Endocrinol Metab 2006;91:3908-3915. https://doi.org/10.1210/jc.2006-0173
  31. Thakker RV, Whyte MP, Eisman JA, Igarashi T. Genetics of Bone Biology and Skeletal Disease. San Diego: Academic Press, 2012.

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