Human Genetics

, Volume 138, Issue 2, pp 167–185 | Cite as

Integrative genomic analysis predicts novel functional enhancer-SNPs for bone mineral density

  • Chuan Qiu
  • Hui ShenEmail author
  • Xiaoying Fu
  • Chao Xu
  • Qing Tian
  • Hongwen Deng
Original Investigation


Osteoporosis is a skeletal disorder characterized by low bone mineral density (BMD) and deterioration of bone microarchitecture. To identify novel genetic loci underlying osteoporosis, an effective strategy is to focus on scanning of variants with high potential functional impacts. Enhancers play a crucial role in regulating cell-type-specific transcription. Therefore, single-nucleotide polymorphisms (SNPs) located in enhancers (enhancer-SNPs) may represent strong candidate functional variants. Here, we performed a targeted analysis for potential functional enhancer-SNPs that may affect gene expression and biological processes in bone-related cells, specifically, osteoblasts, and peripheral blood monocytes (PBMs), using five independent cohorts (n = 5905) and the genetics factors for osteoporosis summary statistics, followed by comprehensive integrative genomic analyses of chromatin states, transcription, and metabolites. We identified 15 novel enhancer-SNPs associated with femoral neck and lumbar spine BMD, including 5 SNPs mapped to novel genes (e.g., rs10840343 and rs10770081 in IGF2 gene) and 10 novel SNPs mapped to known BMD-associated genes (e.g., rs2941742 in ESR1 gene, and rs10249092 and rs4342522 in SHFM1 gene). Interestingly, enhancer-SNPs rs10249092 and rs4342522 in SHFM1 were tightly linked, but annotated to different enhancers in PBMs and osteoblasts, respectively, suggesting that even tightly linked SNPs may regulate the same target gene and contribute to the phenotype variation in cell-type-specific manners. Importantly, ten enhancer-SNPs may also regulate BMD variation by affecting the serum metabolite levels. Our findings revealed novel susceptibility loci that may regulate BMD variation and provided intriguing insights into the genetic mechanisms of osteoporosis.



This study was partially supported or benefited by grants from the National Institutes of Health [R01AR059781, P20GM109036, R01MH107354, R01MH104680, R01GM109068, R01AR069055, and U19AG055373], the Franklin D. Dickson/Missouri Endowment, and the Edward G. Schlieder Endowment and the Drs. W. C. Tsai and P. T. Kung Professorship in Biostatistics from Tulane University. The Women’s Health Initiative (WHI) program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. This manuscript was not prepared in collaboration with the investigators of the WHI, has not been reviewed and/or approved by, and does not necessarily reflect the opinions of the WHI investigators or the NHLBI. WHI Population Architecture Using Genomics and Epidemiology (PAGE) funded through the NHGRI Population Architecture Using Genomics and Epidemiology (PAGE) network (Grant number U01 HG004790). Assistance with phenotype harmonization, SNP selection, data cleaning, meta-analyses, data management and dissemination, and general study coordination was provided by the PAGE Coordinating Center [U01HG004801-01]. The data sets used for the analyses described in this manuscript were obtained from dbGaP at through dbGaP accession phs000200.v6.p2.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

439_2019_1971_MOESM1_ESM.docx (62 kb)
Supplementary material 1 (DOCX 61 KB)
439_2019_1971_MOESM2_ESM.xlsx (13.1 mb)
Supplementary material 2 (XLSX 13451 KB)


  1. Anderson DM, Arredondo J, Hahn K, Valente G, Martin JF, Wilson-Rawls J, Rawls A (2006) Mohawk is a novel homeobox gene expressed in the developing mouse embryo. Dev Dyn 235:792–801. Google Scholar
  2. Anderson DM, Beres BJ, Wilson-Rawls J, Rawls A (2009) The homeobox gene Mohawk represses transcription by recruiting the sin3A/HDAC co-repressor complex. Dev Dyn 238:572–580. Google Scholar
  3. Arnold M, Raffler J, Pfeufer A, Suhre K, Kastenmuller G (2015) SNiPA: an interactive, genetic variant-centered annotation browser. Bioinformatics 31:1334–1336. Google Scholar
  4. Bacanu SA, Devlin B, Roeder K (2000) The power of genomic control. Am J Hum Genet 66:1933–1944. Google Scholar
  5. Baron R, Rawadi G (2007) Targeting the Wnt/beta-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology 148:2635–2643. Google Scholar
  6. Begemann M, Zirn B, Santen G, Wirthgen E, Soellner L, Buttel HM, Schweizer R, van Workum W, Binder G, Eggermann T (2015) Paternally inherited IGF2 mutation and growth restriction. N Engl J Med 373:349–356. Google Scholar
  7. Bhatia V, Barroso SI, Garcia-Rubio ML, Tumini E, Herrera-Moyano E, Aguilera A (2014) BRCA2 prevents R-loop accumulation and associates with TREX-2 mRNA export factor PCID2. Nature 511:362–365. Google Scholar
  8. Buecker C, Wysocka J (2012) Enhancers as information integration hubs in development: lessons from genomics. Trends Genet 28:276–284. Google Scholar
  9. Chelala C, Khan A, Lemoine NR (2009) SNPnexus: a web database for functional annotation of newly discovered and public domain single nucleotide polymorphisms. Bioinformatics 25:655–661. Google Scholar
  10. Chen L, Jiang W, Huang J, He BC, Zuo GW, Zhang W, Luo Q, Shi Q, Zhang BQ, Wagner ER, Luo J, Tang M, Wietholt C, Luo X, Bi Y, Su Y, Liu B, Kim SH, He CJ, Hu Y, Shen J, Rastegar F, Huang E, Gao Y, Gao JL, Zhou JZ, Reid RR, Luu HH, Haydon RC, He TC, Deng ZL (2010) Insulin-like growth factor 2 (IGF-2) potentiates BMP-9-induced osteogenic differentiation and bone formation. J Bone Miner Res 25:2447–2459. Google Scholar
  11. Choi YA, Lim J, Kim KM, Acharya B, Cho JY, Bae YC, Shin HI, Kim SY, Park EK (2010) Secretome analysis of human BMSCs and identification of SMOC1 as an important ECM protein in osteoblast differentiation. J Proteome Res 9:2946–2956. Google Scholar
  12. Chuan Qiu CJP, Deng H-W, Hui S (2011) Genetics of osteoporotic fracture. Orthop Res Rev 3:11–21. Google Scholar
  13. Corradin O, Saiakhova A, Akhtar-Zaidi B, Myeroff L, Willis J, Cowper-Sal lari R, Lupien M, Markowitz S, Scacheri PC (2014) Combinatorial effects of multiple enhancer variants in linkage disequilibrium dictate levels of gene expression to confer susceptibility to common traits. Genome Res 24:1–13. Google Scholar
  14. Crackower MA, Scherer SW, Rommens JM, Hui CC, Poorkaj P, Soder S, Cobben JM, Hudgins L, Evans JP, Tsui LC (1996) Characterization of the split hand/split foot malformation locus SHFM1 at 7q21.3-q22.1 and analysis of a candidate gene for its expression during limb development. Hum Mol Genet 5:571–579Google Scholar
  15. Draisma HHM, Pool R, Kobl M, Jansen R, Petersen AK, Vaarhorst AAM, Yet I, Haller T, Demirkan A, Esko T, Zhu G, Bohringer S, Beekman M, van Klinken JB, Romisch-Margl W, Prehn C, Adamski J, de Craen AJM, van Leeuwen EM, Amin N, Dharuri H, Westra HJ, Franke L, de Geus EJC, Hottenga JJ, Willemsen G, Henders AK, Montgomery GW, Nyholt DR, Whitfield JB, Penninx BW, Spector TD, Metspalu A, Slagboom PE, van Dijk KW, t Hoen PAC, Strauch K, Martin NG, van Ommen GB, Illig T, Bell JT, Mangino M, Suhre K, McCarthy MI, Gieger C, Isaacs A, van Duijn CM, Boomsma DI (2015) Genome-wide association study identifies novel genetic variants contributing to variation in blood metabolite levels. Nat Commun 6:7208. Google Scholar
  16. Durand M, Komarova SV, Bhargava A, Trebec-Reynolds DP, Li K, Fiorino C, Maria O, Nabavi N, Manolson MF, Harrison RE, Dixon SJ, Sims SM, Mizianty MJ, Kurgan L, Haroun S, Boire G, de F Lucena-Fernandes, de Brum-Fernandes M AJ (2013) Monocytes from patients with osteoarthritis display increased osteoclastogenesis and bone resorption: the in vitro osteoclast differentiation in arthritis study. Arthritis Rheum 65:148–158. Google Scholar
  17. Ernst J, Kellis M (2010) Discovery and characterization of chromatin states for systematic annotation of the human genome. Nat Biotechnol 28:817–825. Google Scholar
  18. 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 LM, 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, Gonzalez-Macias J, Kahonen M, Karlsson M, Khusnutdinova E, Koh JM, Kollia P, Langdahl BL, Leslie WD, Lips P, Ljunggren O, Lorenc RS, Marc J, Mellstrom D, Obermayer-Pietsch B, Olmos JM, Pettersson-Kymmer U, Reid DM, Riancho JA, Ridker PM, Rousseau F, Slagboom PE, Tang NL et al (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. Google Scholar
  19. Farber CR (2010) Identification of a gene module associated with BMD through the integration of network analysis and genome-wide association data. J Bone Miner Res 25:2359–2367. Google Scholar
  20. Fisher MC, Meyer C, Garber G, Dealy CN (2005) Role of IGFBP2, IGF-I and IGF-II in regulating long bone growth. Bone 37:741–750. Google Scholar
  21. Fu J, Jiang M, Mirando AJ, Yu HM, Hsu W (2009) Reciprocal regulation of Wnt and Gpr177/mouse Wntless is required for embryonic axis formation. Proc Natl Acad Sci USA 106:18598–18603. Google Scholar
  22. Fujikawa Y, Quinn JM, Sabokbar A, McGee JO, Athanasou NA (1996) The human osteoclast precursor circulates in the monocyte fraction. Endocrinology 137:4058–4060. Google Scholar
  23. Genomes Project C, Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, Gibbs RA, Hurles ME, McVean GA (2010) A map of human genome variation from population-scale sequencing. Nature 467:1061–1073. Google Scholar
  24. Grills BL, Schuijers JA, Ward AR (1997) Topical application of nerve growth factor improves fracture healing in rats. J Orthop Res 15:235–242. Google Scholar
  25. Guo Y, Tan LJ, Lei SF, Yang TL, Chen XD, Zhang F, Chen Y, Pan F, Yan H, Liu X, Tian Q, Zhang ZX, Zhou Q, Qiu C, Dong SS, Xu XH, Guo YF, Zhu XZ, Liu SL, Wang XL, Li X, Luo Y, Zhang LS, Li M, Wang JT, Wen T, Drees B, Hamilton J, Papasian CJ, Recker RR, Song XP, Cheng J, Deng HW (2010) Genome-wide association study identifies ALDH7A1 as a novel susceptibility gene for osteoporosis. PLoS Genet 6:e1000806. Google Scholar
  26. Guo LJ, Liao L, Yang L, Li Y, Jiang TJ (2014) MiR-125a TNF receptor-associated factor 6 to inhibit osteoclastogenesis. Exp Cell Res 321:142–152. Google Scholar
  27. Han B, Eskin E (2011) Random-effects model aimed at discovering associations in meta-analysis of genome-wide association studies. Am J Hum Genet 88:586–598. Google Scholar
  28. Han B, Tang B, Nimni ME (2003) Combined effects of phosphatidylcholine and demineralized bone matrix on bone induction. Connect Tissue Res 44:160–166Google Scholar
  29. Heinz S, Romanoski CE, Benner C, Glass CK (2015) The selection and function of cell type-specific enhancers. Nat Rev Mol Cell Biol 16:144–154. Google Scholar
  30. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560. Google Scholar
  31. Higuchi S, Tabata N, Tajima M, Ito M, Tsurudome M, Sudo A, Uchida A, Ito Y (1998) Induction of human osteoclast-like cells by treatment of blood monocytes with anti-fusion regulatory protein-1/CD98 monoclonal antibodies. J Bone Miner Res 13:44–49. Google Scholar
  32. Hoffman MM, Ernst J, Wilder SP, Kundaje A, Harris RS, Libbrecht M, Giardine B, Ellenbogen PM, Bilmes JA, Birney E, Hardison RC, Dunham I, Kellis M, Noble WS (2013) Integrative annotation of chromatin elements from ENCODE data. Nucleic Acids Res 41:827–841. Google Scholar
  33. Howie B, Fuchsberger C, Stephens M, Marchini J, Abecasis GR (2012) Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat Genet 44:955–959. Google Scholar
  34. Kanis JA (2002) Diagnosis of osteoporosis and assessment of fracture risk. Lancet 359:1929–1936. Google Scholar
  35. Karasik D, Cheung CL, Zhou Y, Cupples LA, Kiel DP, Demissie S (2012) Genome-wide association of an integrated osteoporosis-related phenotype: is there evidence for pleiotropic genes? J Bone Miner Res 27:319–330. Google Scholar
  36. Karczewski KJ, Dudley JT, Kukurba KR, Chen R, Butte AJ, Montgomery SB, Snyder M (2013) Systematic functional regulatory assessment of disease-associated variants. Proc Natl Acad Sci USA 110:9607–9612. Google Scholar
  37. 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. Google Scholar
  38. Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, Haussler D (2002) The human genome browser at UCSC. Genome Res 12:996–1006. Google Scholar
  39. Khan A, Zhang X (2016) dbSUPER: a database of super-enhancers in mouse and human genome. Nucleic Acids Res 44:D164–D171. Google Scholar
  40. Kim HR, Duc NM, Chung KY (2018) Comprehensive analysis of non-synonymous natural variants of g protein-coupled receptors. Biomol Ther (Seoul) 26:101–108. Google Scholar
  41. Koller DL, Zheng HF, Karasik D, Yerges-Armstrong L, Liu CT, McGuigan F, Kemp JP, Giroux S, Lai D, Edenberg HJ, Peacock M, Czerwinski SA, Choh AC, McMahon G, St Pourcain B, Timpson NJ, Lawlor DA, Evans DM, Towne B, Blangero J, Carless MA, Kammerer C, Goltzman D, Kovacs CS, Prior JC, Spector TD, Rousseau F, Tobias JH, Akesson K, Econs MJ, Mitchell BD, Richards JB, Kiel DP, Foroud T (2013) Meta-analysis of genome-wide studies identifies WNT16 and ESR1 SNPs associated with bone mineral density in premenopausal women. J Bone Miner Res 28:547–558. Google Scholar
  42. Komano Y, Nanki T, Hayashida K, Taniguchi K, Miyasaka N (2006) Identification of a human peripheral blood monocyte subset that differentiates into osteoclasts. Arthritis Res Ther 8:R152. Google Scholar
  43. Kotani M, Kikuta J, Klauschen F, Chino T, Kobayashi Y, Yasuda H, Tamai K, Miyawaki A, Kanagawa O, Tomura M, Ishii M (2013) Systemic circulation and bone recruitment of osteoclast precursors tracked by using fluorescent imaging techniques. J Immunol 190:605–612. Google Scholar
  44. Koues OI, Kowalewski RA, Chang LW, Pyfrom SC, Schmidt JA, Luo H, Sandoval LE, Hughes TB, Bednarski JJ, Cashen AF, Payton JE, Oltz EM (2015) Enhancer sequence variants and transcription-factor deregulation synergize to construct pathogenic regulatory circuits in B-cell lymphoma. Immunity 42:186–198. Google Scholar
  45. Krishnan V, Bryant HU, Macdougald OA (2006) Regulation of bone mass by Wnt signaling. J Clin Investig 116:1202–1209. Google Scholar
  46. Lari R, Kitchener PD, Hamilton JA (2009) The proliferative human monocyte subpopulation contains osteoclast precursors. Arthritis Res Ther 11:R23. Google Scholar
  47. Lei SF, Papasian CJ, Deng HW (2011) Polymorphisms in predicted miRNA binding sites and osteoporosis. J Bone Miner Res 26:72–78. Google Scholar
  48. Leung R, Cuddy K, Wang Y, Rommens J, Glogauer M (2011) Sbds is required for Rac2-mediated monocyte migration and signaling downstream of RANK during osteoclastogenesis. Blood 117:2044–2053. Google Scholar
  49. Li Y, Willer CJ, Ding J, Scheet P, Abecasis GR (2010) MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol 34:816–834. Google Scholar
  50. Liu L, Wen Y, Zhang L, Xu P, Liang X, Du Y, Li P, He A, Fan Q, Hao J, Wang W, Guo X, Shen H, Tian Q, Zhang F, Deng HW (2018) Assessing the associations of blood metabolites with osteoporosis: a mendelian randomization study. J Clin Endocrinol Metab 103:1850–1855. Google Scholar
  51. Lu Y, Quan C, Chen H, Bo X, Zhang C (2017) 3DSNP: a database for linking human noncoding SNPs to their three-dimensional interacting genes. Nucleic Acids Res 45:D643–D649. Google Scholar
  52. Manolagas SC, O’Brien CA, Almeida M (2013) The role of estrogen and androgen receptors in bone health and disease. Nat Rev Endocrinol 9:699–712. Google Scholar
  53. Matayoshi A, Brown C, DiPersio JF, Haug J, Abu-Amer Y, Liapis H, Kuestner R, Pacifici R (1996) Human blood-mobilized hematopoietic precursors differentiate into osteoclasts in the absence of stromal cells. Proc Natl Acad Sci USA 93:10785–10790Google Scholar
  54. Matsubara R, Kukita T, Ichigi Y, Takigawa I, Qu PF, Funakubo N, Miyamoto H, Nonaka K, Kukita A (2012) Characterization and identification of subpopulations of mononuclear preosteoclasts induced by TNF-alpha in combination with TGF-beta in rats. PLoS One 7:e47930. Google Scholar
  55. Maurano MT, Humbert R, Rynes E, Thurman RE, Haugen E, Wang H, Reynolds AP, Sandstrom R, Qu H, Brody J, Shafer A, Neri F, Lee K, Kutyavin T, Stehling-Sun S, Johnson AK, Canfield TK, Giste E, Diegel M, Bates D, Hansen RS, Neph S, Sabo PJ, Heimfeld S, Raubitschek A, Ziegler S, Cotsapas C, Sotoodehnia N, Glass I, Sunyaev SR, Kaul R, Stamatoyannopoulos JA (2012) Systematic localization of common disease-associated variation in regulatory DNA. Science 337:1190–1195. Google Scholar
  56. Medina-Gomez C, Kemp JP, Trajanoska K, Luan J, Chesi A, Ahluwalia TS, Mook-Kanamori DO, Ham A, Hartwig FP, Evans DS, Joro R, Nedeljkovic I, Zheng HF, Zhu K, Atalay M, Liu CT, Nethander M, Broer L, Porleifsson G, Mullin BH, Handelman SK, Nalls MA, Jessen LE, Heppe DHM, Richards JB, Wang C, Chawes B, Schraut KE, Amin N, Wareham N, Karasik D, Van der Velde N, Ikram MA, Zemel BS, Zhou Y, Carlsson CJ, Liu Y, McGuigan FE, Boer CG, Bonnelykke K, Ralston SH, Robbins JA, Walsh JP, Zillikens MC, Langenberg C, Li-Gao R, Williams FMK, Harris TB, Akesson K, Jackson RD, Sigurdsson G, den Heijer M, van der Eerden BCJ, van de Peppel J, Spector TD, Pennell C, Horta BL, Felix JF, Zhao JH, Wilson SG, de Mutsert R, Bisgaard H, Styrkarsdottir U, Jaddoe VW, Orwoll E, Lakka TA, Scott R, Grant SFA, Lorentzon M, van Duijn CM, Wilson JF, Stefansson K, Psaty BM, Kiel DP, Ohlsson C, Ntzani E, van Wijnen AJ, Forgetta V, Ghanbari M, Logan JG, Williams GR, Bassett JHD, Croucher PI, Evangelou E, Uitterlinden AG, Ackert-Bicknell CL, Tobias JH, Evans DM, Rivadeneira F (2018) Life-course genome-wide association study meta-analysis of total body BMD and assessment of age-specific effects. Am J Hum Genet 102:88–102. Google Scholar
  57. Miyamoto T, Hirayama A, Sato Y, Koboyashi T, Katsuyama E, Kanagawa H, Fujie A, Morita M, Watanabe R, Tando T, Miyamoto K, Tsuji T, Funayama A, Soga T, Tomita M, Nakamura M, Matsumoto M (2018) Metabolomics-based profiles predictive of low bone mass in menopausal women. Bone Rep 9:11–18. Google Scholar
  58. Miyauchi A, Hruska KA, Greenfield EM, Duncan R, Alvarez J, Barattolo R, Colucci S, Zambonin-Zallone A, Teitelbaum SL, Teti A (1990) Osteoclast cytosolic calcium, regulated by voltage-gated calcium channels and extracellular calcium, controls podosome assembly and bone resorption. J Cell Biol 111:2543–2552Google Scholar
  59. Mori Y, Tsuji S, Inui M, Sakamoto Y, Endo S, Ito Y, Fujimura S, Koga T, Nakamura A, Takayanagi H, Itoi E, Takai T (2008) Inhibitory immunoglobulin-like receptors LILRB and PIR-B negatively regulate osteoclast development. J Immunol 181:4742–4751 doi: 181/7/4742 [pii]Google Scholar
  60. Muller HP, Schaffner W (1990) Transcriptional enhancers can act in trans. Trends Genet 6:300–304Google Scholar
  61. Niu T, Liu N, Yu X, Zhao M, Choi HJ, Leo PJ, Brown MA, Zhang L, Pei YF, Shen H, He H, Fu X, Lu S, Chen XD, Tan LJ, Yang TL, Guo Y, Cho NH, Shen J, Guo YF, Nicholson GC, Prince RL, Eisman JA, Jones G, Sambrook PN, Tian Q, Zhu XZ, Papasian CJ, Duncan EL, Uitterlinden AG, Shin CS, Xiang S, Deng HW (2016) Identification of IDUA and WNT16 phosphorylation-related non-synonymous polymorphisms for bone mineral density in meta-analyses of genome-wide association studies. J Bone Miner Res 31:358–368. Google Scholar
  62. Okada I, Hamanoue H, Terada K, Tohma T, Megarbane A, Chouery E, Abou-Ghoch J, Jalkh N, Cogulu O, Ozkinay F, Horie K, Takeda J, Furuichi T, Ikegawa S, Nishiyama K, Miyatake S, Nishimura A, Mizuguchi T, Niikawa N, Hirahara F, Kaname T, Yoshiura K, Tsurusaki Y, Doi H, Miyake N, Furukawa T, Matsumoto N, Saitsu H (2011) SMOC1 is essential for ocular and limb development in humans and mice. Am J Hum Genet 88:30–41. Google Scholar
  63. Park KY, Li WA, Platt MO (2012) Patient specific proteolytic activity of monocyte-derived macrophages and osteoclasts predicted with temporal kinase activation states during differentiation. Integr Biol (Camb) 4:1459–1469. Google Scholar
  64. Patel TD, Jackman A, Rice FL, Kucera J, Snider WD (2000) Development of sensory neurons in the absence of NGF/TrkA signaling in vivo. Neuron 25:345–357Google Scholar
  65. Powell CB, Alabaster A, Stoller N, Armstrong MA, Salyer C, Hamilton I, Raine-Bennett T (2018) Bone loss in women with BRCA1 and BRCA2 mutations. Gynecol Oncol 148:535–539. Google Scholar
  66. Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP, Boehnke M, Abecasis GR, Willer CJ (2010) LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26:2336–2337. Google Scholar
  67. Pruitt KD, Tatusova T, Maglott DR (2007) NCBI reference sequences (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins. Nucleic Acids Res 35:D61–D65. Google Scholar
  68. Qiu C, Shen H, Fu X, Xu C, Deng H (2018) Meta-analysis of genome-wide association studies identifies novel functional CpG-SNPs associated with bone mineral density at lumbar spine. Int J Genom 2018:6407257. Google Scholar
  69. Ralston SH, de Crombrugghe B (2006) Genetic regulation of bone mass and susceptibility to osteoporosis. Genes Dev 20:2492–2506. Google Scholar
  70. Ralston SH, Uitterlinden AG (2010) Genetics of osteoporosis. Endocr Rev 31:629–662. Google Scholar
  71. Reinecke M, Schmid AC, Heyberger-Meyer B, Hunziker EB, Zapf J (2000) Effect of growth hormone and insulin-like growth factor I (IGF-I) on the expression of IGF-I messenger ribonucleic acid and peptide in rat tibial growth plate and articular chondrocytes in vivo. Endocrinology 141:2847–2853. Google Scholar
  72. Rivadeneira F, Styrkarsdottir U, Estrada K, Halldorsson 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 C (2009) Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet 41:1199–1206. Google Scholar
  73. Roadmap EC, Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, Heravi-Moussavi A, Kheradpour P, Zhang Z, Wang J, Ziller MJ, Amin V, Whitaker JW, Schultz MD, Ward LD, Sarkar A, Quon G, Sandstrom RS, Eaton ML, Wu YC, Pfenning AR, Wang X, Claussnitzer M, Liu Y, Coarfa C, Harris RA, Shoresh N, Epstein CB, Gjoneska E, Leung D, Xie W, Hawkins RD, Lister R, Hong C, Gascard P, Mungall AJ, Moore R, Chuah E, Tam A, Canfield TK, Hansen RS, Kaul R, Sabo PJ, Bansal MS, Carles A, Dixon JR, Farh KH, Feizi S, Karlic R, Kim AR, Kulkarni A, Li D, Lowdon R, Elliott G, Mercer TR, Neph SJ, Onuchic V, Polak P, Rajagopal N, Ray P, Sallari RC, Siebenthall KT, Sinnott-Armstrong NA, Stevens M, Thurman RE, Wu J, Zhang B, Zhou X, Beaudet AE, Boyer LA, De Jager PL, Farnham PJ, Fisher SJ, Haussler D, Jones SJ, Li W, Marra MA, McManus MT, Sunyaev S, Thomson JA, Tlsty TD, Tsai LH, Wang W, Waterland RA, Zhang MQ, Chadwick LH, Bernstein BE, Costello JF, Ecker JR, Hirst M, Meissner A, Milosavljevic A, Ren B, Stamatoyannopoulos JA, Wang T, Kellis M (2015) Integrative analysis of 111 reference human epigenomes. Nature 518:317–330. Google Scholar
  74. Sang XG, Wang ZY, Cheng L, Liu YH, Li YG, Qin T, Di K (2017) Analysis of the mechanism by which nerve growth factor promotes callus formation in mice with tibial fracture. Exp Ther Med 13:1376–1380. Google Scholar
  75. Sasaki-Iwaoka H, Maruyama K, Endoh H, Komori T, Kato S, Kawashima H (1999) A trans-acting enhancer modulates estrogen-mediated transcription of reporter genes in osteoblasts. J Bone Miner Res 14:248–255. Google Scholar
  76. Schlegel W, Halbauer D, Raimann A, Albrecht C, Scharmer D, Sagmeister S, Helmreich M, Hausler G, Egerbacher M (2010) IGF expression patterns and regulation in growth plate chondrocytes. Mol Cell Endocrinol 327:65–71. Google Scholar
  77. Shen H, Li J, Zhang J, Xu C, Jiang Y, Wu Z, Zhao F, Liao L, Chen J, Lin Y, Tian Q, Papasian CJ, Deng HW (2013) Comprehensive characterization of human genome variation by high coverage whole-genome sequencing of forty four Caucasians. PLoS One 8:e59494. Google Scholar
  78. Shin SY, Fauman EB, Petersen AK, Krumsiek J, Santos R, Huang J, Arnold M, Erte I, Forgetta V, Yang TP, Walter K, Menni C, Chen L, Vasquez L, Valdes AM, Hyde CL, Wang V, Ziemek D, Roberts P, Xi L, Grundberg E, Multiple Tissue Human Expression Resource C, Waldenberger M, Richards JB, Mohney RP, Milburn MV, John SL, Trimmer J, Theis FJ, Overington JP, Suhre K, Brosnan MJ, Gieger C, Kastenmuller G, Spector TD, Soranzo N (2014) An atlas of genetic influences on human blood metabolites. Nat Genet 46:543–550. Google Scholar
  79. Shinar DM, Endo N, Halperin D, Rodan GA, Weinreb M (1993) Differential expression of insulin-like growth factor-I (IGF-I) and IGF-II messenger ribonucleic acid in growing rat bone. Endocrinology 132:1158–1167. Google Scholar
  80. Soltanoff CS, Yang S, Chen W, Li YP (2009) Signaling networks that control the lineage commitment and differentiation of bone cells. Crit Rev Eukaryot Gene Expr 19:1–46Google Scholar
  81. Sowinska-Seidler A, Socha M, Jamsheer A (2014) Split-hand/foot malformation—molecular cause and implications in genetic counseling. J Appl Genet 55:105–115. Google Scholar
  82. Stucke VM, Timmerman E, Vandekerckhove J, Gevaert K, Hall A (2007) The MAGUK protein MPP7 binds to the polarity protein hDlg1 and facilitates epithelial tight junction formation. Mol Biol Cell 18:1744–1755. Google Scholar
  83. Suhre K, Gieger C (2012) Genetic variation in metabolic phenotypes: study designs and applications. Nat Rev Genet 13:759–769. Google Scholar
  84. Suhre K, Shin SY, Petersen AK, Mohney RP, Meredith D, Wagele B, Altmaier E, CardioGram, Deloukas P, Erdmann J, Grundberg E, Hammond CJ, de Angelis MH, Kastenmuller G, Kottgen A, Kronenberg F, Mangino M, Meisinger C, Meitinger T, Mewes HW, Milburn MV, Prehn C, Raffler J, Ried JS, Romisch-Margl W, Samani NJ, Small KS, Wichmann HE, Zhai G, Illig T, Spector TD, Adamski J, Soranzo N, Gieger C (2011) Human metabolic individuality in biomedical and pharmaceutical research. Nature 477:54–60. Google Scholar
  85. Sung B, Murakami A, Oyajobi BO, Aggarwal BB (2009) Zerumbone abolishes RANKL-induced NF-kappaB activation, inhibits osteoclastogenesis, and suppresses human breast cancer-induced bone loss in athymic nude mice. Cancer Res 69:1477–1484. Google Scholar
  86. Takata A, Ionita-Laza I, Gogos JA, Xu B, Karayiorgou M (2016) De novo synonymous mutations in regulatory elements contribute to the genetic etiology of autism and schizophrenia. Neuron 89:940–947. Google Scholar
  87. Tsang KY, Chan D, Cheslett D, Chan WC, So CL, Melhado IG, Chan TW, Kwan KM, Hunziker EB, Yamada Y, Bateman JF, Cheung KM, Cheah KS (2007) Surviving endoplasmic reticulum stress is coupled to altered chondrocyte differentiation and function. PLoS Biol 5:e44. Google Scholar
  88. Uchimura T, Hollander JM, Nakamura DS, Liu Z, Rosen CJ, Georgakoudi I, Zeng L (2017) An essential role for IGF2 in cartilage development and glucose metabolism during postnatal long bone growth. Development 144:3533–3546. Google Scholar
  89. Ward LD, Kellis M (2012) HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res 40:D930–D934. Google Scholar
  90. Willer CJ, Li Y, Abecasis GR (2010) METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26:2190–2191. Google Scholar
  91. Wright NC, Looker AC, Saag KG, Curtis JR, Delzell ES, Randall S, Dawson-Hughes B (2014) The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. J Bone Miner Res 29:2520–2526. Google Scholar
  92. Xiao ZS, Quarles LD, Chen QQ, Yu YH, Qu XP, Jiang CH, Deng HW, Li YJ, Zhou HH (2001) Effect of asymmetric dimethylarginine on osteoblastic differentiation. Kidney Int 60:1699–1704. Google Scholar
  93. Xiao SM, Kung AW, Gao Y, Lau KS, Ma A, Zhang ZL, Liu JM, Xia W, He JW, Zhao L, Nie M, Fu WZ, Zhang MJ, Sun J, Kwan JS, Tso GH, Dai ZJ, Cheung CL, Bow CH, Leung AY, Tan KC, Sham PC (2012) Post-genome wide association studies and functional analyses identify association of MPP7 gene variants with site-specific bone mineral density. Hum Mol Genet 21:1648–1657. Google Scholar
  94. Xie W, Ren B (2013) Developmental biology. Enhancing pluripotency and lineage specification. Science 341:245–247. Google Scholar
  95. Yang J, Ferreira T, Morris AP, Medland SE, Genetic Investigation of ATC, Replication DIG, Meta-analysis C, Madden PA, Heath AC, Martin NG, Montgomery GW, Weedon MN, Loos RJ, Frayling TM, McCarthy MI, Hirschhorn JN, Goddard ME, Visscher PM (2012) Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits. Nat Genet 44:369–375. Google Scholar
  96. Yang PT, Meng XH, Yang Y, Xiao WG (2013) Inhibition of osteoclast differentiation and matrix metalloproteinase production by CD4+ CD25+ T cells in mice. Osteoporos Int 24:1113–1114. Google Scholar
  97. 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. Google Scholar
  98. Zhao Z, Wang K, Wu F, Wang W, Zhang K, Hu H, Liu Y, Jiang T (2018) circRNA disease: a manually curated database of experimentally supported circRNA-disease associations. Cell Death Dis 9:475. Google Scholar
  99. Zheng Q, Wang XJ (2008) GOEAST: a web-based software toolkit for gene ontology enrichment analysis. Nucleic Acids Res 36:W358–W363. Google Scholar
  100. 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-Gomez 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, Mellstrom D, Vandenput L, Amin N, van Duijn CM, Karlsson MK, Ljunggren O, Svensson O, Hallmans G, Rousseau F, Giroux S, Bussiere J, Arp PP et al (2015) Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature 526:112–117. Google Scholar
  101. Zhou Y, Deng HW, Shen H (2015) Circulating monocytes: an appropriate model for bone-related study. Osteoporos Int doi. Google Scholar

Copyright information

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

Authors and Affiliations

  • Chuan Qiu
    • 1
  • Hui Shen
    • 1
    Email author
  • Xiaoying Fu
    • 1
  • Chao Xu
    • 1
    • 2
  • Qing Tian
    • 1
  • Hongwen Deng
    • 1
    • 3
  1. 1.Department of Global Biostatistics and Data Science, Center for Bioinformatics and Genomics, School of Public Health and Tropical MedicineTulane UniversityNew OrleansUSA
  2. 2.Department of Biostatistics and EpidemiologyUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  3. 3.School of Basic Medical ScienceCentral South UniversityChangshaChina

Personalised recommendations