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Human Genetics

, Volume 138, Issue 2, pp 151–166 | Cite as

LncRNA ZBTB40-IT1 modulated by osteoporosis GWAS risk SNPs suppresses osteogenesis

  • Bing Mei
  • Ya Wang
  • Weiyuan Ye
  • Han Huang
  • Qian Zhou
  • Yuanyuan Chen
  • Yajing Niu
  • Manling Zhang
  • Qingyang HuangEmail author
Original Investigation
  • 106 Downloads

Abstract

Previous genome-wide linkage and association studies have identified an osteoporosis-associated locus at 1p36 that harbors SNPs rs34920465 and rs6426749. The 1p36 locus also comprises the WNT4 gene with known role in bone metabolism and functionally unknown ZBTB40/lncRNA ZBTB40-IT1 genes. How these might interact to contribute to osteoporosis susceptibility is not known. In this study, we show that lncRNA ZBTB40-IT1 is able to suppress osteogenesis and promote osteoclastogenesis by regulating the expression of WNT4, RUNX2, OSX, ALP, COL1A1, OPG and RANKL in U-2OS and hFOB1.19 cell lines, whereas ZBTB40 plays an opposite role in bone metabolism. Treatment with parathyroid hormone significantly downregulates the expression of ZBTB40-IT1 in U-2OS cell lines. ZBTB40 can suppress ZBTB40-IT1 expression but has no response to parathyroid hormone treatment. Dual-luciferase assay and biotin pull-down assay demonstrate that osteoporosis GWAS lead SNPs rs34920465-G and rs6426749-C alleles can respectively bind transcription factors JUN::FOS and CREB1, and upregulate ZBTB40 and ZBTB40-IT1 expression. Our study discovers the critical role of ZBTB40 and lncRNA ZBTB40-IT1 in bone metabolism, and provides a mechanistic basis for osteoporosis GWAS lead SNPs rs34920465 and rs6426749.

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (nos. 31371275 and 30971635) and self-determined research fund of CCNU from the basic research and operation of MOE (CCNU18ZDPY05).

Supplementary material

439_2019_1969_MOESM1_ESM.tif (13 mb)
Supplementary material 1 Fig.S1 Genotyping of rs34920465 and rs6426749. Genotypes of rs34920465 (a) and rs6426749 (b) in U-2OS cells, Saos-2 cells, HEK293T cells and hFOB1.19 cells. Peak results of rs34920465 in hFOB1.19 cells are generated by reverse sequencing. Peak results of rs34920465 in U-2OS cells, Saos-2 cells and 293T cells are generated by forward sequencing. The peak results of rs6426749 in Saos-2 cells and hFOB1.19 cells are generated by reverse sequencing. Peak results of rs6426749 in U-2OS cells and 293T cells are generated by forward sequencing (TIF 13316 KB)
439_2019_1969_MOESM2_ESM.doc (92 kb)
Supplementary material 2 (DOC 92 KB)

References

  1. Aizawa R, Yamada A, Suzuki D, Iimura T, Kassai H, Harada T, Tsukasaki M, Yamamoto G, Tachikawa T, Nakao K, Yamamoto M, Yamaguchi A, Aiba A, Kamijo R (2012) Cdc42 is required for chondrogenesis and inter-digital programmed cell death during limb development. Mech Dev 129:38–50.  https://doi.org/10.1016/j.mod.2012.02.002 Google Scholar
  2. Bergenstock MK, Partridge NC (2007) Parathyroid hormone stimulation of noncanonical Wnt signaling in bone. Ann N Y Acad Sci 1116:354–359.  https://doi.org/10.1196/annals.1402.047 Google Scholar
  3. Bergenstock MK, Partridge NC (2008) Parathyroid hormone (PTH) regulation of non-canonical Wnt-4: a stimulator of differentiation in osteoblasts and bone marrow stromal stem cells. Faseb J 22: 646–649.  https://doi.org/10.1096/fasebj.22.1_supplement.646.9 Google Scholar
  4. Chang J, Sonoyama W, Wang Z, Jin Q, Zhang C, Krebsbach PH, Giannobile W, Shi S, Wang CY (2007) Noncanonical Wnt-4 signaling enhances bone regeneration of mesenchymal stem cells in craniofacial defects through activation of p38 MAPK. J Biol Chem 282: 30938–30948.  https://doi.org/10.1074/jbc.M702391200 Google Scholar
  5. Chen XF, Zhu DL, Yang M, Hu WX, Duan YY, Lu BJ, Rong Y, Dong SS, Hao RH, Chen JB, Chen YX, Yao S, Thynn HN, Guo Y, Yang TL (2018) An osteoporosis risk SNP at 1p36.12 acts as an allele-specific enhancer to modulate LINC00339 expression via long-range loop formation. Am J Hum Genet 102:776–793.  https://doi.org/10.1016/j.ajhg.2018.03.001 Google Scholar
  6. Dempster DW, Cosman F, Kurland ES, Zhou H, Nieves J, Woelfert L, Shane E, Plavetić K, Müller R, Bilezikian J, Lindsay R (2001) Effects of daily treatment with parathyroid hormone on bone microarchitecture and turnover in patients with osteoporosis: a paired biopsy study. J Bone Miner Res 16:1846–1853.  https://doi.org/10.1359/jbmr.2001.16.10.1846 Google Scholar
  7. Devoto M, Shimoya K, Caminis J, Ott J, Tenenhouse A, Whyte MP, Sereda L, Hall S, Considine E, Williams CJ, Tromp G, Kuivaniemi H, Ala-Kokko L, Prockop DJ, Spotila LD (1998) First-stage autosomal genome screen in extended pedigrees suggests genes predisposing to low bone mineral density on chromosomes 1p, 2p and 4q. Eur J Hum Genet 6:151–157.  https://doi.org/10.1038/sj.ejhg.5200169 Google Scholar
  8. Devoto M, Specchia C, Li HH, Caminis J, Tenenhouse A, Rodriguez H, Spotila LD (2001) Variance component linkage analysis indicates a QTL for femoral neck bone mineral density on chromosomes 1p36. Hum Mol Genet 10:2447–2452.  https://doi.org/10.1093/hmg/10.21.2447 Google Scholar
  9. Estrada K, Styrkarsdottir U, Evangelou E, Hsu YH, Duncan EL, Ntzani EE, Oei L, Albagha OM, Amin N, Kemp JP, Koller DL, Li G, Liu CT, Minster RL, Moayyeri A, Vandenput L, Willner D, Xiao SM, Yerges-Armstrong LM,Zheng HF, Alonso N, Eriksson J, Kammerer CM, Kaptoge SK, Leo PJ, Thorleifsson G, Wilson SG, Wilson JF, Aalto V, Alen M, Aragaki AK, Aspelund T, Center JR, Dailiana Z, Duggan DJ, Garcia M, Garcia-Giralt N, Giroux S, Hallmans G, Hocking LJ, Husted LB, Jameson KA, Khusainova R, Kim GS, Kooperberg C, Koromila T, Kruk M, Laaksonen M, Lacroix AZ,Lee SH, Leung PC, Lewis JR, Masi L, Mencej-Bedrac S, Nguyen TV, Nogues X, Patel MS,Prezelj J, Rose L.M, Scollen S, Siggeirsdottir K, Smith AV, Svensson O, Trompet S,Trummer O, van Schoor NM, Woo J, Zhu K, Balcells S, Brandi ML, Buckley BM, Cheng S,Christiansen C, Cooper C, Dedoussis G, Ford I, Frost M, Goltzman D, González-Macías J, Kähönen M, Karlsson M, Khusnutdinova E, Koh JM, Kollia P, Langdahl BL, Leslie WD,Lips P, Ljunggren Ö, Lorenc RS, Marc J, Mellström D, Obermayer-Pietsch B, Olmos JM, Pettersson-Kymmer U, Reid DM, Riancho JA, Ridker PM, Rousseau F, Slagboom PE, Tang NL, Urreizti R, Van Hul W, Viikari J, Zarrabeitia MT, Aulchenko YS, Castano-Betancourt M, Grundberg E, Herrera L, Ingvarsson T, Johannsdottir H, Kwan T, Li R, Luben R, Medina-Gómez C, Palsson, ST, Reppe S, Rotter JI, Sigurdsson G, van Meurs JB, Verlaan D, Williams FM, Wood AR, Zhou Y, Gautvik KM,Pastinen T, Raychaudhuri S, Cauley JA, Chasman DI, Clark GR, Cummings SR, Danoy P,Dennison EM, Eastell R, Eisman, JA, Gudnason V, Hofman A, Jackson RD, Jones G, Jukema JW, Khaw KT, Lehtimäki T, Liu Y, Lorentzon M, McCloskey E, Mitchell BD, Nandakumar K, Nicholson GC, Oostra BA, Peacock M, Pols HA, Prince RL, Raitakari O, Reid IR, Robbins J, Sambrook PN, Sham PC, Shuldiner AR,Tylavsky FA, van Duijn CM, Wareham NJ, Cupples LA, Econs MJ, Evans DM, Harris TB,Kung AW, Psaty BM, Reeve J, Spector TD, Streeten EA, Zillikens MC, Thorsteinsdottir U, Ohlsson C, Karasik D, Richards JB, Brown MA, Stefansson K, Uitterlinden AG, Ralston SH, Ioannidis JP, Kiel DP, Rivadeneira F (2012) Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet 44: 491–501.  https://doi.org/10.1038/ng.2249
  10. Greenblatt MB, Shim JH, Glimcher LH (2013) Mitogen-activated protein kinase pathways in osteoblasts. Annu Rev Cell Dev Biol 29:63–79.  https://doi.org/10.1146/annurev-cellbio-101512-122347 Google Scholar
  11. GTEx Consortium Human Genomics (2015) The genotype-tissue expression (GTEx) pilot analysis: multi-tissue gene regulation in humans. Science 348: 648–660.  https://doi.org/10.1126/science.1262110 Google Scholar
  12. Guo H, Ahmed M, Zhang F, Yao CQ, Li S, Liang Y, Hua J, Soares F, Sun Y, Langstein J, Li Y, Poon C, Bailey SD, Desai K, Fei T, Li Q, Sendorek DH, Fraser M, Prensner JR, Pugh TJ, Pomerantz M, Bristow RG, Lupien M, Feng FY, Boutros PC, Freedman ML, Walsh MJ, He HH (2016) Modulation of long noncoding RNAs by risk SNPs underlying genetic predispositions to prostate cancer. Nat Genet 48:1142–1150.  https://doi.org/10.1038/ng.3637 Google Scholar
  13. Hon CC, Ramilowski JA, Harshbarger J, Bertin N, Rackham OJ, Gough J, Denisenko E, Schmeier S, Poulsen TM, Severin J, Lizio M, Kawaji H, Kasukawa T, Itoh M, Burroughs AM, Noma S, Djebali S, Alam T, Medvedeva YA, Testa AC, Lipovich L, Yip CW, Abugessaisa I, Mendez M, Hasegawa A, Tang D, Lassmann T, Heutink P, Babina M, Wells CA, Kojima S, Nakamura Y, Suzuki H, Daub CO, de Hoon MJ, Arner E, Hayashizaki Y, Carninci P, Forrest AR (2017) An atlas of human long non-coding RNAs with accurate 5′ ends. Nature 543:199–204.  https://doi.org/10.1038/nature21374 Google Scholar
  14. Hua JT, Ahmed M, Guo H, Zhang Y, Chen S, Soares F, Lu J, Zhou S, Wang M, Li H, Larson NB, McDonnell SK, Patel PS, Liang Y, Yao CQ, van der Kwast T, Lupien M, Feng FY, Zoubeidi A, Tsao MS, Thibodeau SN, Boutros PC, He HH (2018) Risk SNP-mediated promoter-enhancer switching drives prostate cancer through lncRNA PCAT19. Cell 174: 564–575.  https://doi.org/10.1016/j.cell.2018.06.014 Google Scholar
  15. Huang Y, Zheng Y, Jia L, Li W (2015) Long noncoding RNA H19 promotes osteoblast differentiation via TGF-β1/Smad3/HDAC signaling pathway by deriving miR-675. Stem Cells 33:3481–3492.  https://doi.org/10.1002/stem.2225 Google Scholar
  16. Ikeda F, Nishimura R, Matsubara T, Tanaka S, Inoue J, Reddy SV, Hata K, Yamashita K, Hiraga T, Watanabe T, Kukita T, Yoshioka K, Rao A, Yoneda T (2004) Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation. J Clin Investig 114:475–584.  https://doi.org/10.1172/JCI19657 Google Scholar
  17. Ito Y, Teitelbaum SL, Zou W, Zheng Y, Johnson JF, Chappel J, Ross FP, Zhao H (2010) Cdc42 regulates bone modeling and remodeling in mice by modulating RANKL/M-CSF signaling and osteoclast polarization. J Clin Investig 120:1981–1993.  https://doi.org/10.1172/JCI39650 Google Scholar
  18. Kemp JP, Medina-Gomez C, Estrada K, St Pourcain B, Heppe DH, Warrington NM, Oei L, Ring SM, Kruithof CJ, Timpson NJ, Wolber LE, Reppe S, Gautvik K, Grundberg E, Ge B, van der Eerden B, van de Peppel J, Hibbs MA, Ackert-Bicknell CL, Choi K, Koller DL, Econs MJ, Williams FM, Foroud T, Zillikens MC, Ohlsson C, Hofman A, Uitterlinden AG, Davey Smith G, Jaddoe VW, Tobias JH, Rivadeneira F, Evans DM (2014) Phenotypic dissection of bone mineral density reveals skeletal site specificity and facilitates the identification of novel loci in the genetic regulation of bone mass attainment. PLoS Genet 10:e1004423.  https://doi.org/10.1371/journal.pgen.1004423 Google Scholar
  19. Kemp JP, Morris JA, Medina-Gomez C, Forgetta V, Warrington NM, Youlten SE, Zheng J, Gregson CL, Grundberg E, Trajanoska K, Logan JG, Pollard AS, Sparkes PC, Ghirardello EJ, Allen R, Leitch VD, Butterfield NC, Komla-Ebri D, Adoum AT, Curry KF, White JK, Kussy F, Greenlaw KM, Xu C, Harvey NC, Cooper C, Adams DJ, Greenwood CMT, Maurano MT, Kaptoge S, Rivadeneira F, Tobias JH, Croucher PI, Ackert-Bicknell CL, Bassett JHD, Williams GR, Richards JB, Evans DM (2017) Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis. Nat Genet 49: 1468–1475.  https://doi.org/10.1038/ng.3949 Google Scholar
  20. Kim BJ, Ahn SH, Kim HM, Ikegawa S, Yang TL, Guo Y, Deng HW, Koh JM, Lee SH (2016) Replication of caucasian loci associated with osteoporosis-related traits in East Asians. J Bone Metab 23: 233–242.  https://doi.org/10.11005/jbm.2016.23.4.233 Google Scholar
  21. Kurihara M, Shiraishi A, Satake H, Kimura AP (2014) A conserved noncoding sequence can function as a spermatocyte-specific enhancer and a bidirectional promoter for a ubiquitously expressed gene and a testis-specific long noncoding RNA. J Mol Biol 426: 3069–3093.  https://doi.org/10.1016/j.jmb.2014.06.018 Google Scholar
  22. Liang WC, Fu WM, Wang YB, Sun YX, Xu LL, Wong CW, Chan KM, Li G, Waye MM, Zhang JF (2016) H19 activates Wnt signaling and promotes osteoblast differentiation by functioning as a competing endogenous RNA. Sci Rep 6:20121.  https://doi.org/10.1038/srep20121 Google Scholar
  23. Liu X, Yang W, Li Y, Li S, Zhou X, Zhao Q, Fan Y, Lin M, Chen R (2016) The intergenic region of the maize defensin-like protein genes Def1 and Def2 functions as an embryo-specific asymmetric bidirectional promoter. J Exp Bot 67:4403–4413.  https://doi.org/10.1093/jxb/erw226 Google Scholar
  24. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH (2001) Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 344: 1434–1441.  https://doi.org/10.1056/NEJM200105103441904 Google Scholar
  25. Park SE, Oh KW, Lee WY, Baek KH, Yoon KH, Son HY, Lee WC, Kang MI (2014) 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 61:1069–1078.  https://doi.org/10.1507/endocrj.EJ14-0119 Google Scholar
  26. Powell JE, Fung JN, Shakhbazov K, Sapkota Y, Cloonan N, Hemani G, Hillman KM, Kaufmann S, Luong HT, Bowdler L, Painter JN, Holdsworth-Carson SJ, Visscher PM, Dinger ME, Healey M, Nyholt DR, French JD, Edwards SL, Rogers PA, Montgomery GW (2016) Endometriosis risk alleles at 1p36.12 act through inverse regulation of CDC42 and LINC00339. Hum Mol Genet 25:5046–5058.  https://doi.org/10.1093/hmg/ddw320 Google Scholar
  27. Qin L, Liu Y, Wang Y, Wu G, Chen J, Ye W, Huang Q (2016) Computational characterization of osteoporosis associated SNPs and genes identified by genome-wide association studies. PLoS One 11:e0150070.  https://doi.org/10.1371/journal.pone.0150070 Google Scholar
  28. Ralston SH, Uitterlinden AG (2010) Genetics of osteoporosis. Endocr Rev 31:629–662.  https://doi.org/10.1210/er.2009-0044 Google Scholar
  29. Richards JB, Rivadeneira F, Inouye M, Pastinen TM, Soranzo N, Wilson SG, Andrew T, Falchi M, Gwilliam R, Ahmadi KR, Valdes AM, Arp P, Whittaker P, Verlaan DJ, Jhamai M, Kumanduri V, Moorhouse M, van Meurs JB, Hofman A, Pols HA, Hart D, Zhai G, Kato BS, Mullin BH, Zhang F, Deloukas P, Uitterlinden AG, Spector TD (2008) Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet 371:1505–1512.  https://doi.org/10.1016/S0140-6736(08)60599-1 Google Scholar
  30. Rivadeneira F, Styrkársdottir U, Estrada K, Halldórsson BV, Hsu YH, Richards JB, Zillikens MC, Kavvoura FK, Amin N, Aulchenko YS, Cupples LA, Deloukas P, Demissie S, Grundberg E, Hofman A, Kong A, Karasik D, van Meurs JB, Oostra B, Pastinen T, Pols HA, Sigurdsson G, Soranzo N, Thorleifsson G, Thorsteinsdottir U, Williams FM, Wilson SG, Zhou Y, Ralston SH, van Duijn CM, Spector T, Kiel DP, Stefansson K, Ioannidis JP, Uitterlinden AG, Genetic Factors for Osteoporosis (GEFOS) Consortium (2009) Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet 41:1199–1206.  https://doi.org/10.1038/ng.446 Google Scholar
  31. Sato K, Suematsu A, Nakashima T, Takemoto-Kimura S, Aoki K, Morishita Y, Asahara H, Ohya K, Yamaguchi A, Takai T, Kodama T, Chatila TA, Bito H, Takayanagi H (2006) Regulation of osteoclast differentiation and function by the CaMK–CREB pathway. Nat Med 12: 1410–1416.  https://doi.org/10.1038/nm1515 Google Scholar
  32. Streeten EA, McBride DJ, Pollin TI, Ryan K, Shapiro J, Ott S, Mitchell BD, Shuldiner AR, O’Connell JR (2006) Quantitative trait loci for bone mineral density identified by autosome-wide linkage scan to chromosomes 7q and 21q in men from the Amish Family Osteoporosis Study. J Bone Miner Res 21:1433–1442.  https://doi.org/10.1359/jbmr.060602 Google Scholar
  33. Styrkarsdottir U, Halldorsson BV, Gretarsdottir S, Gudbjartsson DF, Walters GB, Ingvarsson T, Jonsdottir T, Saemundsdottir J, Center JR, Nguyen TV, Bagger Y, Gulcher JR, Eisman JA, Christiansen C, Sigurdsson G, Kong A, Thorsteinsdottir U, Stefansson K (2008) Multiple genetic loci for bone mineral density and fractures. N Engl J Med 358:2355–2365.  https://doi.org/10.1056/NEJMoa0801197 Google Scholar
  34. Styrkarsdottir U, Halldorsson BV, Gretarsdottir S, Gudbjartsson DF, Walters GB, Ingvarsson T, Jonsdottir T, Saemundsdottir J, Snorradóttir S, Center JR, Nguyen TV, Alexandersen P, Gulcher JR, Eisman JA, Christiansen C, Sigurdsson G, Kong A, Thorsteinsdottir U, Stefansson K (2009) New sequence variants associated with bone mineral density. Nat Genet 41:15–17.  https://doi.org/10.1038/ng.284 Google Scholar
  35. Swarthout JT, Doggett TA, Lemker JL, Partridge NC (2001) Stimulation of extracellular signal-regulated kinases and proliferation in rat osteoblastic cells by parathyroid hormone is protein kinase C-dependent. J Biol Chem 276:7586–7592.  https://doi.org/10.1074/jbc.M007400200 Google Scholar
  36. Wada T, Nakashima T, Hiroshi N, Penninger JM (2006) RANKL–RANK signaling in osteoclastogenesis and bone disease. Trends Mol Med 12:17–25.  https://doi.org/10.1016/j.molmed.2005.11.007 Google Scholar
  37. Wang Y, He H, Li W, Phay J, Shen R, Yu L, de la Chapelle A (2017a) MYH9 binds to lncRNA gene PTCSC2 and regulates FOXE1 in the 9q22 thyroid cancer risk locus. Proc Natl Acad Sci USA 114: 474–479.  https://doi.org/10.1073/pnas.1619917114 Google Scholar
  38. Wang Q, Li Y, Zhang Y, Ma L, Lin L, Meng J, Jiang L, Wang L, Zhou P, Zhang Y (2017b) LncRNA MEG3 inhibited osteogenic differentiation of bone marrow mesenchymal stem cells from postmenopausal osteoporosis by targeting miR-133a-3p. Biomed Pharmacother 89: 1178–1186.  https://doi.org/10.1016/j.biopha.2017.02.090 Google Scholar
  39. Warrington NM, Kemp JP, Tilling K, Tobias JH, Evans DM (2015) Genetic variants in adult bone mineral density and fracture risk genes are associated with the rate of bone mineral density acquisition in adolescence. Hum Mol Genet 24:4158–4166.  https://doi.org/10.1093/hmg/ddv143 Google Scholar
  40. Wuerfel C, Hoffmann C, Kawelke N, Aszodi A, Nakchbandi I (2012) Deletion of cdc42 in osteoblast progenitors leads to increased adipocyte differentiation and decreased bone formation. Bone 50:S43.  https://doi.org/10.1016/j.bone.2012.02.113 Google Scholar
  41. Xu Y, Wang S, Tang C, Chen W (2015) Upregulation of long non-coding RNA HIF 1α-anti-sense 1 induced by transforming growth factor-β-mediated targeting of sirtuin 1 promotes osteoblastic differentiation of human bone marrow stromal cells. Mol Med Rep 12: 7233–7238.  https://doi.org/10.3892/mmr.2015.4415 Google Scholar
  42. Yu B, Chang J, Liu Y, Li J, Kevork K, Al-Hezaimi K, Graves DT, Park NH, Wang CY (2014) Wnt4 signaling prevents skeletal aging and inflammation by inhibiting nuclear factor-[kappa] B. Nat Med 20:1009–1017.  https://doi.org/10.1038/nm.3586 Google Scholar
  43. Zhang J, Glatfelter AA, Taetle R, Trent JM (1999) Frequent alterations of evolutionarily conserved regions of chromosome 1 in human malignant melanoma. Cancer Genet Cytogenet 111: 119–123.  https://doi.org/10.1016/S0165-4608(98)00196-4 Google Scholar
  44. Zhang L, Choi HJ, Estrada K, Leo PJ, Li J, Pei YF, Zhang Y, Lin Y, Shen H, Liu YZ, Liu Y, Zhao Y, Zhang JG, Tian Q, Wang YP, Han Y, Ran S, Hai R, Zhu XZ, Wu S, Yan H, Liu X, Yang TL, Guo Y, Zhang F, Guo YF, Chen Y, Chen X, Tan L, Zhang L, Deng FY, Deng H, Rivadeneira F, Duncan EL, Lee JY, Han BG, Cho NH, Nicholson GC, McCloskey E, Eastell R, Prince RL, Eisman JA, Jones G, Reid IR, Sambrook PN, Dennison EM, Danoy P, Yerges-Armstrong LM, Streeten EA, Hu T, Xiang S, Papasian CJ, Brown MA, Shin CS, Uitterlinden AG, Deng HW (2014) Multistage genome-wide association meta-analyses identified two new loci for bone mineral density. Hum Mol Genet 23:1923–1933.  https://doi.org/10.1093/hmg/ddt575 Google Scholar
  45. Zheng HF, Forgetta V, Hsu YH, Estrada K, Rosello-Diez A, Leo PJ, Dahia CL, Park-Min KH, Tobias JH, Kooperberg C, Kleinman A, Styrkarsdottir U, Liu CT, Uggla C, Evans DS, Nielson CM, Walter K, Pettersson-Kymmer U, McCarthy S, Eriksson J, Kwan T, Jhamai M, Trajanoska K, Memari Y, Min J, Huang J, Danecek P, Wilmot B, Li R, Chou WC, Mokry LE, Moayyeri A, Claussnitzer M, Cheng CH, Cheung W, Medina-Gómez C, Ge B, Chen SH,Choi K, Oei L, Fraser J, Kraaij R, Hibbs MA, Gregson CL, Paquette D, Hofman A, Wibom C, Tranah GJ, Marshall M, Gardiner BB, Cremin K, Auer P, Hsu L, Ring S, Tung JY, Thorleifsson G, Enneman AW, van Schoor NM, de Groot LC, van der Velde N, Melin B, Kemp JP, Christiansen C, Sayers A, Zhou Y, Calderari S, van Rooij J, Carlson C, Peters U, Berlivet S, Dostie J, Uitterlinden AG, Williams SR, Farber C, Grinberg D, LaCroix AZ, Haessler J, Chasman DI, Giulianini F, Rose LM, Ridker PM, Eisman JA, Nguyen TV, Center JR, Nogues X, Garcia-Giralt N, Launer LL, Gudnason V, Mellström D, Vandenput L, Amin N, van Duijn CM, Karlsson MK, Ljunggren Ö, Svensson O, Hallmans G, Rousseau F, Giroux S, Bussière J, Arp PP,Koromani F, Prince RL, Lewis JR, Langdahl BL, Hermann AP, Jensen JE, Kaptoge S, Khaw KT, Reeve J, Formosa MM, Xuereb-Anastasi A, Åkesson K, McGuigan FE, Garg G, Olmos JM, Zarrabeitia MT, Riancho JA, Ralston SH, Alonso N, Jiang X, Goltzman D, Pastinen T, Grundberg E, Gauguier D, Orwoll ES, Karasik D, Davey-Smith G, AOGC Consortium,Smith AV, Siggeirsdottir K, Harris TB, Zillikens MC, van Meurs JB, Thorsteinsdottir U, Maurano MT, Timpson NJ, Soranzo N, Durbin R, Wilson SG, Ntzani EE, Brown MA, Stefansson K, Hinds DA, Spector T, Cupples LA, Ohlsson C, Greenwood CM, UK10K Consortium, Jackson RD, Rowe DW, Loomis CA, Evans DM, Ackert-Bicknell CL, Joyner AL, Duncan EL, Kiel DP,Rivadeneira F, Richards JB (2015) Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature 526:112–117.  https://doi.org/10.1038/nature14878
  46. Zheng J, Huang X, Tan W, Yu D, Du Z, Chang J, Wei L, Han Y, Wang C, Che X, Zhou Y, Miao X, Jiang G, Yu X, Yang X, Cao G, Zuo C, Li Z, Wang C, Cheung ST, Jiam Y, Zheng X, Shen H, Wu C, Lin D (2016) Pancreatic cancer risk variant in LINC00673 creates a miR-1231 binding site and interferes with PTPN11 degradation. Nat Genet 48:747–757.  https://doi.org/10.1038/ng.3568 Google Scholar

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© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life SciencesCentral China Normal UniversityWuhanChina

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