Genomics & Informatics

Korea Genome Organization (한국유전체학회)
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Identification of a Copy Number Variation on Chromosome 20q13.12 Associated with Osteoporotic Fractures in the Korean Population

  • Park, Tae-Joon (Division of Structural and Functional Genomics, Center for Genome Science, National Institute of Health, Osong Health Technology Administration Complex) ;
  • Hwang, Mi Yeong (Division of Structural and Functional Genomics, Center for Genome Science, National Institute of Health, Osong Health Technology Administration Complex) ;
  • Moon, Sanghoon (Division of Structural and Functional Genomics, Center for Genome Science, National Institute of Health, Osong Health Technology Administration Complex) ;
  • Hwang, Joo-Yeon (Division of Structural and Functional Genomics, Center for Genome Science, National Institute of Health, Osong Health Technology Administration Complex) ;
  • Go, Min Jin (Division of Structural and Functional Genomics, Center for Genome Science, National Institute of Health, Osong Health Technology Administration Complex) ;
  • Kim, Bong-Jo (Division of Structural and Functional Genomics, Center for Genome Science, National Institute of Health, Osong Health Technology Administration Complex)
  • Received : 2016.08.09
  • Accepted : 2016.11.14
  • Published : 2016.12.31
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Abstract

Osteoporotic fractures (OFs) are critical hard outcomes of osteoporosis and are characterized by decreased bone strength induced by low bone density and microarchitectural deterioration in bone tissue. Most OFs cause acute pain, hospitalization, immobilization, and slow recovery in patients and are associated with increased mortality. A variety of genetic studies have suggested associations of genetic variants with the risk of OF. Genome-wide association studies have reported various single-nucleotide polymorphisms and copy number variations (CNVs) in European and Asian populations. To identify CNV regions associated with OF risk, we conducted a genome-wide CNV study in a Korean population. We performed logistic regression analyses in 1,537 Korean subjects (299 OF cases and 1,238 healthy controls) and identified a total of 8 CNV regions significantly associated with OF (p < 0.05). Then, one CNV region located on chromosome 20q13.12 was selected for experimental validation. The selected CNV region was experimentally validated by quantitative polymerase chain reaction. The CNV region of chromosome 20q13.12 is positioned upstream of a family of long non-coding RNAs, LINC01260. Our findings could provide new information on the genetic factors associated with the risk of OF.

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References

  1. Kanis JA, McCloskey EV, Johansson H, Cooper C, Rizzoli R, Reginster JY, et al. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int 2013;24:23-57. https://doi.org/10.1007/s00198-012-2074-y
  2. Hernlund E, Svedbom A, Ivergard M, Compston J, Cooper C, Stenmark J, et al. Osteoporosis in the European Union: medical management, epidemiology and economic burden. A report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA). Arch Osteoporos 2013;8:136. https://doi.org/10.1007/s11657-013-0136-1
  3. Cooper C, Harvey NC. Osteoporosis risk assessment. BMJ 2012;344:e4191. https://doi.org/10.1136/bmj.e4191
  4. Harvey N, Dennison E, Cooper C. Osteoporosis: impact on health and economics. Nat Rev Rheumatol 2010;6:99-105. https://doi.org/10.1038/nrrheum.2009.260
  5. van Meurs JB, Trikalinos TA, Ralston SH, Balcells S, Brandi ML, Brixen K, et al. Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis. JAMA 2008; 299:1277-1290. https://doi.org/10.1001/jama.299.11.1277
  6. Duncan EL, Danoy P, Kemp JP, Leo PJ, McCloskey E, Nicholson GC, et al. Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk. PLoS Genet 2011;7:e1001372. https://doi.org/10.1371/journal.pgen.1001372
  7. Hsu YH, Zillikens MC, Wilson SG, Farber CR, Demissie S, Soranzo N, et al. An integration of genome-wide association study and gene expression profiling to prioritize the discovery of novel susceptibility loci for osteoporosis-related traits. PLoS Genet 2010;6:e1000977. https://doi.org/10.1371/journal.pgen.1000977
  8. Kung AW, Xiao SM, Cherny S, Li GH, Gao Y, Tso G, et al. Association of JAG1 with bone mineral density and osteoporotic fractures: a genome-wide association study and follow-up replication studies. Am J Hum Genet 2010;86:229-239. https://doi.org/10.1016/j.ajhg.2009.12.014
  9. Richards JB, Rivadeneira F, Inouye M, Pastinen TM, Soranzo N, Wilson SG, et al. Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet 2008;371:1505-1512. https://doi.org/10.1016/S0140-6736(08)60599-1
  10. Rivadeneira F, Styrkarsdottir U, Estrada K, Halldorsson BV, Hsu YH, Richards JB, et al. Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet 2009;41:1199-1206. https://doi.org/10.1038/ng.446
  11. Styrkarsdottir U, Halldorsson BV, Gretarsdottir S, Gudbjartsson DF, Walters GB, Ingvarsson T, et al. Multiple genetic loci for bone mineral density and fractures. N Engl J Med 2008;358: 2355-2365. https://doi.org/10.1056/NEJMoa0801197
  12. Styrkarsdottir U, Halldorsson BV, Gretarsdottir S, Gudbjartsson DF, Walters GB, Ingvarsson T, et al. New sequence variants associated with bone mineral density. Nat Genet 2009;41:15-17. https://doi.org/10.1038/ng.284
  13. 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
  14. Yang TL, Chen XD, Guo Y, Lei SF, Wang JT, Zhou Q, et al. Genome-wide copy-number-variation study identified a susceptibility gene, UGT2B17, for osteoporosis. Am J Hum Genet 2008;83:663-674. https://doi.org/10.1016/j.ajhg.2008.10.006
  15. Chew S, Mullin BH, Lewis JR, Spector TD, Prince RL, Wilson SG. Homozygous deletion of the UGT2B17 gene is not associated with osteoporosis risk in elderly Caucasian women. Osteoporos Int 2011;22:1981-1986. https://doi.org/10.1007/s00198-010-1405-0
  16. Oei L, Hsu YH, Styrkarsdottir U, Eussen BH, de Klein A, Peters MJ, et al. A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus. J Med Genet 2014;51:122-131. https://doi.org/10.1136/jmedgenet-2013-102064
  17. Akan P, Sahlen M, Deloukas P. A histone map of human chromosome 20q13.12. PLoS One 2009;4:e4479. https://doi.org/10.1371/journal.pone.0004479
  18. Rojas A, Aguilar R, Henriquez B, Lian JB, Stein JL, Stein GS, et al. Epigenetic control of the bone-master Runx2 gene during osteoblast-lineage commitment by the histone demethylase JARID1B/KDM5B. J Biol Chem 2015;290:28329-28342. https://doi.org/10.1074/jbc.M115.657825
  19. Kiel DP, Demissie S, Dupuis J, Lunetta KL, Murabito JM, Karasik D. Genome-wide association with bone mass and geometry in the Framingham Heart Study. BMC Med Genet 2007;8 Suppl 1:S14. https://doi.org/10.1186/1471-2350-8-S1-S14
  20. Pique-Regi R, Caceres A, Gonzalez JR. R-Gada: a fast and flexible pipeline for copy number analysis in association studies. BMC Bioinformatics 2010;11:380. https://doi.org/10.1186/1471-2105-11-380
  21. Pique-Regi R, Monso-Varona J, Ortega A, Seeger RC, Triche TJ, Asgharzadeh S. Sparse representation and Bayesian detection of genome copy number alterations from microarray data. Bioinformatics 2008;24:309-318. https://doi.org/10.1093/bioinformatics/btm601
  22. Moon S, Keam B, Hwang MY, Lee Y, Park S, Oh JH, et al. A genome-wide association study of copy-number variation identifies putative loci associated with osteoarthritis in Koreans. BMC Musculoskelet Disord 2015;16:76. https://doi.org/10.1186/s12891-015-0531-4
  23. Barnes C, Plagnol V, Fitzgerald T, Redon R, Marchini J, Clayton D, et al. A robust statistical method for case-control association testing with copy number variation. Nat Genet 2008; 40:1245-1252. https://doi.org/10.1038/ng.206
  24. Wellcome Trust Case Control Consortium, Craddock N, Hurles ME, Cardin N, Pearson RD, Plagnol V, et al. Genomewide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature 2010;464: 713-720. https://doi.org/10.1038/nature08979
  25. Kim YK, Moon S, Hwang MY, Kim DJ, Oh JH, Kim YJ, et al. Gene-based copy number variation study reveals a microdeletion at 12q24 that influences height in the Korean population. Genomics 2013;101:134-138. https://doi.org/10.1016/j.ygeno.2012.11.002
  26. Frith MC, Bailey TL, Kasukawa T, Mignone F, Kummerfeld SK, Madera M, et al. Discrimination of non-protein-coding transcripts from protein-coding mRNA. RNA Biol 2006;3:40-48. https://doi.org/10.4161/rna.3.1.2789
  27. van Bakel H, Nislow C, Blencowe BJ, Hughes TR. Most "dark matter" transcripts are associated with known genes. PLoS Biol 2010;8:e1000371. https://doi.org/10.1371/journal.pbio.1000371
  28. Mercer TR, Qureshi IA, Gokhan S, Dinger ME, Li G, Mattick JS, et al. Long noncoding RNAs in neuronal-glial fate specification and oligodendrocyte lineage maturation. BMC Neurosci 2010;11:14. https://doi.org/10.1186/1471-2202-11-14
  29. Chen LL, Carmichael GG. Decoding the function of nuclear long non-coding RNAs. Curr Opin Cell Biol 2010;22:357-364. https://doi.org/10.1016/j.ceb.2010.03.003
  30. Dinger ME, Amaral PP, Mercer TR, Pang KC, Bruce SJ, Gardiner BB, et al. Long noncoding RNAs in mouse embryonic stem cell pluripotency and differentiation. Genome Res 2008; 18:1433-1445. https://doi.org/10.1101/gr.078378.108
  31. Loewer S, Cabili MN, Guttman M, Loh YH, Thomas K, Park IH, et al. Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells. Nat Genet 2010;42:1113-1117. https://doi.org/10.1038/ng.710
  32. Cao J. The functional role of long non-coding RNAs and epigenetics. Biol Proced Online 2014;16:11. https://doi.org/10.1186/1480-9222-16-11
  33. Yang TL, Guo Y, Zhang JG, Xu C, Tian Q, Deng HW. Genome-wide survey of runs of homozygosity identifies recessive loci for bone mineral density in Caucasian and Chinese populations. J Bone Miner Res 2015;30:2119-2126. https://doi.org/10.1002/jbmr.2558
  34. Tanaka I, Morikawa M, Okuse T, Shirakawa M, Imai K. Expression and regulation of WISP2 in rheumatoid arthritic synovium. Biochem Biophys Res Commun 2005;334:973-978. https://doi.org/10.1016/j.bbrc.2005.06.196
  35. Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 2001;107: 513-523. https://doi.org/10.1016/S0092-8674(01)00571-2
  36. Kumar S, Hand AT, Connor JR, Dodds RA, Ryan PJ, Trill JJ, et al. Identification and cloning of a connective tissue growth factor-like cDNA from human osteoblasts encoding a novel regulator of osteoblast functions. J Biol Chem 1999;274:17123-17131. https://doi.org/10.1074/jbc.274.24.17123
  37. Yerges LM, Klei L, Cauley JA, Roeder K, Kammerer CM, Moffett SP, et al. High-density association study of 383 candidate genes for volumetric BMD at the femoral neck and lumbar spine among older men. J Bone Miner Res 2009;24: 2039-2049. https://doi.org/10.1359/jbmr.090524
  38. Robinson JA, Chatterjee-Kishore M, Yaworsky PJ, Cullen DM, Zhao W, Li C, et al. Wnt/beta-catenin signaling is a normal physiological response to mechanical loading in bone. J Biol Chem 2006;281:31720-31728. https://doi.org/10.1074/jbc.M602308200
  39. Hammarstedt A, Hedjazifar S, Jenndahl L, Gogg S, Grunberg J, Gustafson B, et al. WISP2 regulates preadipocyte commitment and PPARgamma activation by BMP4. Proc Natl Acad Sci U S A 2013;110:2563-2568. https://doi.org/10.1073/pnas.1211255110

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