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Enhanced Identification of Potential Pleiotropic Genetic Variants for Bone Mineral Density and Breast Cancer

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Abstract

Epidemiological and clinical evidences have shown that bone mineral density (BMD) has a close relationship with breast cancer (BC). They might potentially have a shared genetic basis. By incorporating information about these pleiotropic effects, we may be able to explore more of the traits’ total heritability. We applied a recently developed conditional false discovery rate (cFDR) method to the summary statistics from two independent GWASs to identify the potential pleiotropic genetic variants for BMD and BC. By jointly analyzing two large independent GWASs of BMD and BC, we found strong pleiotropic enrichment between them and identified 102 single-nucleotide polymorphisms (SNPs) in BMD and 192 SNPs in BC with cFDR < 0.05, including 230 SNPs that might have been overlooked by the standard GWAS analysis. cFDR-significant genes were enriched in GO terms and KEGG pathways which were crucial to bone metabolism and/or BC pathology (adjP < 0.05). Some cFDR-significant genes were partially validated in the gene expressional validation assay. Strong interactions were found between proteins produced by cFDR-significant genes in the context of biological mechanism of bone metabolism and/or BC etiology. Totally, we identified 7 pleiotropic SNPs that were associated with both BMD and BC (conjunction cFDR < 0.05); CCDC170, ESR1, RANKL, CPED1, and MEOX1 might play important roles in the pleiotropy of BMD and BC. Our study highlighted the significant pleiotropy between BMD and BC and shed novel insight into trait-specific as well as the potentially shared genetic architecture for both BMD and BC.

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References

  1. Nguyen TV, Jones G, Sambrook PN, White CP, Kelly PJ, Eisman JA (1995) Effects of estrogen exposure and reproductive factors on bone mineral density and osteoporotic fractures. J Clin Endocrinol Metab 80(9):2709–2714. doi:10.1210/jcem.80.9.7673413

    CAS  PubMed  Google Scholar 

  2. Videman T, Levalahti E, Battie MC, Simonen R, Vanninen E, Kaprio J (2007) Heritability of BMD of femoral neck and lumbar spine: a multivariate twin study of Finnish men. J Bone Miner Res 22(9):1455–1462. doi:10.1359/jbmr.070606

    Article  PubMed  Google Scholar 

  3. Kamangar F, Dores GM, Anderson WF (2006) Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 24(14):2137–2150. doi:10.1200/JCO.2005.05.2308

    Article  PubMed  Google Scholar 

  4. Siegel RL, Miller KD, Jemal A (2017) Cancer statistics. CA Cancer J Clin 67(1):7–30. doi:10.3322/caac.21387

    Article  PubMed  Google Scholar 

  5. Collaborative Group on Hormonal Factors in Breast C (2001) Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease. Lancet 358(9291):1389–1399. doi:10.1016/S0140-6736(01)06524-2

    Article  Google Scholar 

  6. Michailidou K, Beesley J, Lindstrom S, Canisius S, Dennis J, Lush MJ, Maranian MJ, Bolla MK, Wang Q, Shah M, Perkins BJ, Czene K, Eriksson M, Darabi H, Brand JS, Bojesen SE, Nordestgaard BG, Flyger H, Nielsen SF, Rahman N, Turnbull C, Bocs Fletcher O, Peto J, Gibson L, dos Santos-Silva I, Chang-Claude J, Flesch-Janys D, Rudolph A, Eilber U, Behrens S, Nevanlinna H, Muranen TA, Aittomaki K, Blomqvist C, Khan S, Aaltonen K, Ahsan H, Kibriya MG, Whittemore AS, John EM, Malone KE, Gammon MD, Santella RM, Ursin G, Makalic E, Schmidt DF, Casey G, Hunter DJ, Gapstur SM, Gaudet MM, Diver WR, Haiman CA, Schumacher F, Henderson BE, Le Marchand L, Berg CD, Chanock SJ, Figueroa J, Hoover RN, Lambrechts D, Neven P, Wildiers H, van Limbergen E, Schmidt MK, Broeks A, Verhoef S, Cornelissen S, Couch FJ, Olson JE, Hallberg E, Vachon C, Waisfisz Q, Meijers-Heijboer H, Adank MA, van der Luijt RB, Li J, Liu J, Humphreys K, Kang D, Choi JY, Park SK, Yoo KY, Matsuo K, Ito H, Iwata H, Tajima K, Guenel P, Truong T, Mulot C, Sanchez M, Burwinkel B, Marme F, Surowy H, Sohn C, Wu AH, Tseng CC, Van Den Berg D, Stram DO, Gonzalez-Neira A, Benitez J, Zamora MP, Perez JI, Shu XO, Lu W, Gao YT, Cai H, Cox A, Cross SS, Reed MW, Andrulis IL, Knight JA, Glendon G, Mulligan AM, Sawyer EJ, Tomlinson I, Kerin MJ, Miller N, kConFab I, Group A, Lindblom A, Margolin S, Teo SH, Yip CH, Taib NA, Tan GH, Hooning MJ, Hollestelle A, Martens JW, Collee JM, Blot W, Signorello LB, Cai Q, Hopper JL, Southey MC, Tsimiklis H, Apicella C, Shen CY, Hsiung CN, Wu PE, Hou MF, Kristensen VN, Nord S, Alnaes GI, Nbcs Giles GG, Milne RL, McLean C, Canzian F, Trichopoulos D, Peeters P, Lund E, Sund M, Khaw KT, Gunter MJ, Palli D, Mortensen LM, Dossus L, Huerta JM, Meindl A, Schmutzler RK, Sutter C, Yang R, Muir K, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Hartman M, Miao H, Chia KS, Chan CW, Fasching PA, Hein A, Beckmann MW, Haeberle L, Brenner H, Dieffenbach AK, Arndt V, Stegmaier C, Ashworth A, Orr N, Schoemaker MJ, Swerdlow AJ, Brinton L, Garcia-Closas M, Zheng W, Halverson SL, Shrubsole M, Long J, Goldberg MS, Labreche F, Dumont M, Winqvist R, Pylkas K, Jukkola-Vuorinen A, Grip M, Brauch H, Hamann U, Bruning T, Network G, Radice P, Peterlongo P, Manoukian S, Bernard L, Bogdanova NV, Dork T, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Devilee P, Tollenaar RA, Seynaeve C, Van Asperen CJ, Jakubowska A, Lubinski J, Jaworska K, Huzarski T, Sangrajrang S, Gaborieau V, Brennan P, McKay J, Slager S, Toland AE, Ambrosone CB, Yannoukakos D, Kabisch M, Torres D, Neuhausen SL, Anton-Culver H, Luccarini C, Baynes C, Ahmed S, Healey CS, Tessier DC, Vincent D, Bacot F, Pita G, Alonso MR, Alvarez N, Herrero D, Simard J, Pharoah PP, Kraft P, Dunning AM, Chenevix-Trench G, Hall P, Easton DF (2015) Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer. Nat Genet 47(4):373–380. doi:10.1038/ng.3242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Qu X, Zhang X, Qin A, Liu G, Zhai Z, Hao Y, Li H, Zhu Z, Dai K (2013) Bone mineral density and risk of breast cancer in postmenopausal women. Breast Cancer Res Treat 138(1):261–271. doi:10.1007/s10549-013-2431-3

    Article  PubMed  Google Scholar 

  8. Fraenkel M, Novack V, Liel Y, Koretz M, Siris E, Norton L, Shafat T, Shany S, Geffen DB (2013) Association between bone mineral density and incidence of breast cancer. PLoS ONE 8(8):e70980. doi:10.1371/journal.pone.0070980

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chen Z, Arendell L, Aickin M, Cauley J, Lewis CE, Chlebowski R, Women’s Health Initiative Program NHL, Blood Institute USDoH, Human S (2008) Hip bone density predicts breast cancer risk independently of Gail score: results from the Women’s Health Initiative. Cancer 113(5):907–915. doi:10.1002/cncr.23674

    Article  PubMed  PubMed Central  Google Scholar 

  10. Bundred NJ (2009) Aromatase inhibitors and bone health. Curr Opin Obstet Gynecol 21(1):60–67. doi:10.1097/GCO.0b013e32831da80e

    Article  PubMed  Google Scholar 

  11. McVeigh TP, Jung SY, Kerin MJ, Salzman DW, Nallur S, Nemec AA, Dookwah M, Sadofsky J, Paranjape T, Kelly O, Chan E, Miller N, Sweeney KJ, Zelterman D, Sweasy J, Pilarski R, Telesca D, Slack FJ, Weidhaas JB (2015) Estrogen withdrawal, increased breast cancer risk and the KRAS-variant. Cell Cycle 14(13):2091–2099. doi:10.1080/15384101.2015.1041694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Andreassen OA, Thompson WK, Schork AJ, Ripke S, Mattingsdal M, Kelsoe JR, Kendler KS, O’Donovan MC, Rujescu D, Werge T, Sklar P, Psychiatric Genomics C, Bipolar D, Schizophrenia Working G, Roddey JC, Chen CH, McEvoy L, Desikan RS, Djurovic S, Dale AM (2013) Improved detection of common variants associated with schizophrenia and bipolar disorder using pleiotropy-informed conditional false discovery rate. PLoS Genet 9(4):e1003455. doi:10.1371/journal.pgen.1003455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Greenbaum J, Wu K, Zhang L, Shen H, Zhang J, Deng HW (2017) Increased detection of genetic loci associated with risk predictors of osteoporotic fracture using a pleiotropic cFDR method. Bone 99:62–68. doi:10.1016/j.bone.2017.03.052

    Article  CAS  PubMed  Google Scholar 

  14. 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, Koromani F, Prince RL, Lewis JR, Langdahl BL, Hermann AP, Jensen JE, Kaptoge S, Khaw KT, Reeve J, Formosa MM, Xuereb-Anastasi A, Akesson 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, Smith AV, Consortium A, 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, Consortium UK, 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(7571):112–117. doi:10.1038/nature14878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cai Q, Zhang B, Sung H, Low SK, Kweon SS, Lu W, Shi J, Long J, Wen W, Choi JY, Noh DY, Shen CY, Matsuo K, Teo SH, Kim MK, Khoo US, Iwasaki M, Hartman M, Takahashi A, Ashikawa K, Matsuda K, Shin MH, Park MH, Zheng Y, Xiang YB, Ji BT, Park SK, Wu PE, Hsiung CN, Ito H, Kasuga Y, Kang P, Mariapun S, Ahn SH, Kang HS, Chan KY, Man EP, Iwata H, Tsugane S, Miao H, Liao J, Nakamura Y, Kubo M, Consortium DG-O, Delahanty RJ, Zhang Y, Li B, Li C, Gao YT, Shu XO, Kang D, Zheng W (2014) Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1. Nat Genet 46(8):886–890. doi:10.1038/ng.3041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Andreassen OA, Djurovic S, Thompson WK, Schork AJ, Kendler KS, O’Donovan MC, Rujescu D, Werge T, van de Bunt M, Morris AP, McCarthy MI, International Consortium for Blood Pressure G, Diabetes Genetics R, Meta-analysis C, Psychiatric Genomics Consortium Schizophrenia Working G, Roddey JC, McEvoy LK, Desikan RS, Dale AM (2013) Improved detection of common variants associated with schizophrenia by leveraging pleiotropy with cardiovascular-disease risk factors. Am J Hum Genet 92(2):197–209. doi:10.1016/j.ajhg.2013.01.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Liley J, Wallace C (2015) A pleiotropy-informed Bayesian false discovery rate adapted to a shared control design finds new disease associations from GWAS summary statistics. PLoS Genet 11(2):e1004926. doi:10.1371/journal.pgen.1004926

    Article  PubMed  PubMed Central  Google Scholar 

  18. Reppe S, Refvem H, Gautvik VT, Olstad OK, Hovring PI, Reinholt FP, Holden M, Frigessi A, Jemtland R, Gautvik KM (2010) Eight genes are highly associated with BMD variation in postmenopausal Caucasian women. Bone 46(3):604–612. doi:10.1016/j.bone.2009.11.007

    Article  CAS  PubMed  Google Scholar 

  19. Casey T, Bond J, Tighe S, Hunter T, Lintault L, Patel O, Eneman J, Crocker A, White J, Tessitore J, Stanley M, Harlow S, Weaver D, Muss H, Plaut K (2009) Molecular signatures suggest a major role for stromal cells in development of invasive breast cancer. Breast Cancer Res Treat 114(1):47–62. doi:10.1007/s10549-008-9982-8

    Article  CAS  PubMed  Google Scholar 

  20. Wang J, Duncan D, Shi Z, Zhang B (2013) WEB-based GEne SeT AnaLysis Toolkit (WebGestalt): update 2013. Nucl Acids Res 41:W77–83. doi:10.1093/nar/gkt439

    Article  PubMed  PubMed Central  Google Scholar 

  21. Supek F, Bosnjak M, Skunca N, Smuc T (2011) REVIGO summarizes and visualizes long lists of gene ontology terms. PLoS ONE 6(7):e21800. doi:10.1371/journal.pone.0021800

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Baron R, Kneissel M (2013) WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med 19(2):179–192. doi:10.1038/nm.3074

    Article  CAS  PubMed  Google Scholar 

  23. 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, 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-Gomez 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, Lehtimaki 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(5):491–501. doi:10.1038/ng.2249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yu Y, Elble RC (2016) Homeostatic signaling by cell-cell junctions and its dysregulation during cancer progression. J Clin Med 5(2):26. doi:10.3390/jcm5020026

    Article  PubMed Central  Google Scholar 

  25. Cordes T, Diesing D, Becker S, Diedrich K, Reichrath J, Friedrich M (2006) Modulation of MAPK ERK1 and ERK2 in VDR-positive and -negative breast cancer cell lines. Anticancer Res 26(4A):2749–2753

    CAS  PubMed  Google Scholar 

  26. Hu X, Guo J, Zheng L, Li C, Zheng TM, Tanyi JL, Liang S, Benedetto C, Mitidieri M, Katsaros D, Zhao X, Zhang Y, Huang Q, Zhang L (2013) The heterochronic microRNA let-7 inhibits cell motility by regulating the genes in the actin cytoskeleton pathway in breast cancer. Mol Cancer Res 11(3):240–250. doi:10.1158/1541-7786.MCR-12-0432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Reppe S, Wang Y, Thompson WK, McEvoy LK, Schork AJ, Zuber V, LeBlanc M, Bettella F, Mills IG, Desikan RS, Djurovic S, Gautvik KM, Dale AM, Andreassen OA, Consortium G (2015) Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density Loci. PLoS ONE 10(12):e0144531. doi:10.1371/journal.pone.0144531

    Article  PubMed  PubMed Central  Google Scholar 

  28. Ichikawa S, Koller DL, Padgett LR, Lai D, Hui SL, Peacock M, Foroud T, Econs MJ (2010) Replication of previous genome-wide association studies of bone mineral density in premenopausal American women. J Bone Miner Res 25(8):1821–1829. doi:10.1002/jbmr.62

    Article  PubMed  PubMed Central  Google Scholar 

  29. Han J, Jiang T, Bai H, Gu H, Dong J, Ma H, Hu Z, Shen H (2011) Genetic variants of 6q25 and breast cancer susceptibility: a two-stage fine mapping study in a Chinese population. Breast Cancer Res Treat 129(3):901–907. doi:10.1007/s10549-011-1527-x

    Article  PubMed  Google Scholar 

  30. Zheng W, Long J, Gao YT, Li C, Zheng Y, Xiang YB, Wen W, Levy S, Deming SL, Haines JL, Gu K, Fair AM, Cai Q, Lu W, Shu XO (2009) Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1. Nat Genet 41(3):324–328. doi:10.1038/ng.318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yoskovitz G, Garcia-Giralt N, Rodriguez-Sanz M, Urreizti R, Guerri R, Arino-Ballester S, Prieto-Alhambra D, Mellibovsky L, Grinberg D, Nogues X, Balcells S, Diez-Perez A (2013) Analyses of RANK and RANKL in the post-GWAS context: functional evidence of vitamin D stimulation through a RANKL distal region. J Bone Miner Res 28(12):2550–2560. doi:10.1002/jbmr.2001

    Article  CAS  PubMed  Google Scholar 

  32. Lou J, Tu Y, Li S, Manske PR (2000) Involvement of ERK in BMP-2 induced osteoblastic differentiation of mesenchymal progenitor cell line C3H10T1/2. Biochem Biophys Res Commun 268(3):757–762. doi:10.1006/bbrc.2000.2210

    Article  CAS  PubMed  Google Scholar 

  33. 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(11):1199–1206. doi:10.1038/ng.446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mullin BH, Walsh JP, Zheng HF, Brown SJ, Surdulescu GL, Curtis C, Breen G, Dudbridge F, Richards JB, Spector TD, Wilson SG (2016) Genome-wide association study using family-based cohorts identifies the WLS and CCDC170/ESR1 loci as associated with bone mineral density. BMC Genom 17:136. doi:10.1186/s12864-016-2481-0

    Article  Google Scholar 

  35. Luo L, Xia W, Nie M, Sun Y, Jiang Y, Zhao J, He S, Xu L (2014) Association of ESR1 and C6orf97 gene polymorphism with osteoporosis in postmenopausal women. Mol Biol Rep 41(5):3235–3243. doi:10.1007/s11033-014-3186-6

    Article  CAS  PubMed  Google Scholar 

  36. Ariazi EA, Ariazi JL, Cordera F, Jordan VC (2006) Estrogen receptors as therapeutic targets in breast cancer. Curr Top Med Chem 6(3):181–202

    Article  CAS  PubMed  Google Scholar 

  37. Veeraraghavan J, Tan Y, Cao XX, Kim JA, Wang X, Chamness GC, Maiti SN, Cooper LJ, Edwards DP, Contreras A, Hilsenbeck SG, Chang EC, Schiff R, Wang XS (2014) Recurrent ESR1-CCDC170 rearrangements in an aggressive subset of oestrogen receptor-positive breast cancers. Nat Commun 5:4577. doi:10.1038/ncomms5577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Turnbull C, Ahmed S, Morrison J, Pernet D, Renwick A, Maranian M, Seal S, Ghoussaini M, Hines S, Healey CS, Hughes D, Warren-Perry M, Tapper W, Eccles D, Evans DG, Breast Cancer Susceptibility C, Hooning M, Schutte M, van den Ouweland A, Houlston R, Ross G, Langford C, Pharoah PD, Stratton MR, Dunning AM, Rahman N, Easton DF (2010) Genome-wide association study identifies five new breast cancer susceptibility loci. Nat Genet 42(6):504–507. doi:10.1038/ng.586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Yamamoto-Ibusuki M, Yamamoto Y, Fujiwara S, Sueta A, Yamamoto S, Hayashi M, Tomiguchi M, Takeshita T, Iwase H (2015) C6ORF97-ESR1 breast cancer susceptibility locus: influence on progression and survival in breast cancer patients. Eur J Hum Genet 23(7):949–956. doi:10.1038/ejhg.2014.219

    Article  CAS  PubMed  Google Scholar 

  40. Nolan E, Vaillant F, Branstetter D, Pal B, Giner G, Whitehead L, Lok SW, Mann GB, Kathleen Cuningham Foundation Consortium for Research into Familial Breast C, Rohrbach K, Huang LY, Soriano R, Smyth GK, Dougall WC, Visvader JE, Lindeman GJ (2016) RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers. Nat Med 22(8):933–939. doi:10.1038/nm.4118

    Article  CAS  PubMed  Google Scholar 

  41. Sigl V, Owusu-Boaitey K, Joshi PA, Kavirayani A, Wirnsberger G, Novatchkova M, Kozieradzki I, Schramek D, Edokobi N, Hersl J, Sampson A, Odai-Afotey A, Lazaro C, Gonzalez-Suarez E, Pujana MA, Cimba F, Heyn H, Vidal E, Cruickshank J, Berman H, Sarao R, Ticevic M, Uribesalgo I, Tortola L, Rao S, Tan Y, Pfeiler G, Lee EY, Bago-Horvath Z, Kenner L, Popper H, Singer C, Khokha R, Jones LP, Penninger JM (2016) RANKL/RANK control Brca1 mutation-driven mammary tumors. Cell Res 26(7):761–774. doi:10.1038/cr.2016.69

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Alam I, Alkhouli M, Gerard-O’Riley RL, Wright WB, Acton D, Gray AK, Patel B, Reilly AM, Lim KE, Robling AG, Econs MJ (2016) Osteoblast-specific overexpression of human WNT16 Increases both cortical and trabecular bone mass and structure in mice. Endocrinology 157(2):722–736. doi:10.1210/en.2015-1281

    Article  CAS  PubMed  Google Scholar 

  43. Benhaj K, Akcali KC, Ozturk M (2006) Redundant expression of canonical Wnt ligands in human breast cancer cell lines. Oncol Rep 15(3):701–707

    CAS  PubMed  Google Scholar 

  44. Minelli C, Dean CH, Hind M, Alves AC, Amaral AF, Siroux V, Huikari V, Soler Artigas M, Evans DM, Loth DW, Bosse Y, Postma DS, Sin D, Thompson J, Demenais F, Henderson J, SpiroMeta c, consortium C, Bouzigon E, Jarvis D, Jarvelin MR, Burney P (2016) Association of forced vital capacity with the developmental gene NCOR2. PLoS ONE 11(2):e0147388. doi:10.1371/journal.pone.0147388

    Article  PubMed  PubMed Central  Google Scholar 

  45. Bayrakli F, Guclu B, Yakicier C, Balaban H, Kartal U, Erguner B, Sagiroglu MS, Yuksel S, Ozturk AR, Kazanci B, Ozum U, Kars HZ (2013) Mutation in MEOX1 gene causes a recessive Klippel-Feil syndrome subtype. BMC Genet 14:95. doi:10.1186/1471-2156-14-95

    Article  PubMed  PubMed Central  Google Scholar 

  46. Sun L, Burnett J, Gasparyan M, Xu F, Jiang H, Lin CC, Myers I, Korkaya H, Liu Y, Connarn J, He H, Zhang N, Wicha MS, Sun D (2016) Novel cancer stem cell targets during epithelial to mesenchymal transition in PTEN-deficient trastuzumab-resistant breast cancer. Oncotarget. doi:10.18632/oncotarget.9839

    Google Scholar 

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Acknowledgements

Hong-Wen Deng was partially supported by Grants from the National Institutes of Health [R01AR057049, R01AR059781, D43TW009107, P20 GM109036, R01MH107354, R01MH104680, R01GM109068], the Edward G. Schlieder Endowment fund to Tulane University. The GWAS datasets for BMD were obtained from GEFOS at http://www.gefos.org/. We acknowledge GEFOS-seq Consortium, AOGC Consortium, and The UK10 K Consortium for their GWAS summary statistics posted online, and we also acknowledge Wei Zheng for providing the BC GWAS data. Chun-Ping Zeng was partially supported by Medical Research Fund of Guangdong Province, Guangdong, China (A2017575). Cheng Peng was partially supported by Guangzhou Planned Project of Science and Technology, Guangzhou, China [201704020105] and Department of Geriatrics, National Key Clinical Specialty, Guangzhou First People’s Hospital during this study.

Author’s Contribution

Hong-Wen Deng conceived and initiated the development of this study, is responsible for general development and design of the study, and contributed to critical revisions and finalization of the manuscript, and he is guarantor. Cheng Peng contributed to the acquisition and analysis of the data and drafted the manuscript. Xu Lin, Chun-Ping Zeng, and Kuan-Jui Su contributed to data analysis. Ji-Rong Long contributed to the data acquisition. Lan Zhang, Jonathan Greenbaum, Yu-Mei Li, and Wei-Feng Deng contributed to critical revisions. Feng Liu, Hui-Ling Lou, and Jie Shen contributed to the general study design and development. All authors have given approval to the final version of the manuscript. All authors agree to be accountable for the work and ensure that any questions relating to the accuracy and integrity of the paper are investigated and properly resolved.

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Authors and Affiliations

  1. Department of Geriatrics, National Key Clinical Specialty, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, 510180, People’s Republic of China

    Cheng Peng, Hui-Ling Lou & Feng Liu

  2. Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, People’s Republic of China

    Jie Shen, Xu Lin & Hong-Wen Deng

  3. Department of Endocrinology and Metabolism, Affiliated Nanhai Hospital of Southern Medical University, Guangzhou, People’s Republic of China

    Chun-Ping Zeng

  4. Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA

    Ji-Rong Long

  5. Department of Global Statistics and Data Science, School of Public Health and Tropical Medicine, Center for Bioinformatics and Genomics, Tulane University, New Orleans, LA, 70112, USA

    Kuan-Jui Su, Lan Zhang, Jonathan Greenbaum & Hong-Wen Deng

  6. Hunan University of Medicine, Huaihua, 418000, People’s Republic of China

    Wei-Feng Deng

  7. School of Mathematics and Computational Science, Huaihua University, Huaihua, 418008, Hunan, People’s Republic of China

    Yu-Mei Li

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  1. Cheng Peng
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Correspondence to Hong-Wen Deng.

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Conflict of interest

Cheng Peng, Hui-Ling Lou, Feng Liu, Jie Shen, Xu Lin, Chun-Ping Zeng, Ji-Rong Long, Kuan-Jui Su, Lan Zhang, Jonathan Greenbaum, Wei-Feng Deng, Yu-Mei Li, and Hong-Wen Deng declare that they have no conflicts of interest.

Human and Animal Rights and Informed Consent

No human participants or animals were involved in this empirical study. We only analyzed the existing data published on public websites.

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Peng, C., Lou, HL., Liu, F. et al. Enhanced Identification of Potential Pleiotropic Genetic Variants for Bone Mineral Density and Breast Cancer. Calcif Tissue Int 101, 489–500 (2017). https://doi.org/10.1007/s00223-017-0308-x

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