Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci

S. Reppe; Y. Wang; W.K. Thompson; L.K. Mcevoy; A.J. Schork; V. Zuber; M. Leblanc; F. Bettella; I.G. Mills; R.S. Desikan; S. Djurovic; K.M. Gautvik; A.M. Dale; O.A. Andreassen; K. Estrada; U. Styrkarsdottir; E. Evangelou; Y.-H. Hsu; E.L. Duncan; E.E. Ntzani; L. Oei; O.M.E. Albagha; N. Amin; J.P. Kemp; D.L. Koller; G. Li; C.-T. Liu; R.L. Minster; A. Moayyeri; L. Vandenput; D. Willner; S.-M. Xiao; L.M. Yerges-Armstrong; H.-F. Zheng; N. Alonso; J. Eriksson; C.M. Kammerer; S.K. Kaptoge; P.J. Leo; G. Thorleifsson; Scott Wilson; J.F. Wilson; V. Aalto; M. Alen; A.K. Aragaki; T. Aspelund; J.R. Center; Z. Dailiana; D.J. Duggan; M. Garcia; N. Garcia-Giralt; S. Giroux; G. Hallmans; L.J. Hocking; L.B. Husted; K.A. Jameson; R. Khusainova; G.S. Kim; C. Kooperberg; T. Koromila; M. Kruk; M. Laaksonen; A.Z. Lacroix; S.H. Lee; P.C. Leung; Joshua Lewis; L. Masi; S. Mencej-Bedrac; T.V. Nguyen; X. Nogues; M.S. Patel; J. Prezelj; L.M. Rose; S. Scollen; K. Siggeirsdottir; A.V. Smith; O. Svensson; S. Trompet; O. Trummer; N.M. Van Schoor; J. Woo; Kun Zhu; S. Balcells; M.L. Brandi; B.M. Buckley; S. Cheng; C. Christiansen; C. Cooper; G. Dedoussis; I. Ford; M. Frost; D. Goltzman; J. González-Macías; M. Kähönen; M. Karlsson; E. Khusnutdinova; J.-M. Koh; P. Kollia; B.L. Langdahl; W.D. Leslie; P. Lips; Ö. Ljunggren; R.S. Lorenc; J. Marc; D. Mellström; B. Obermayer-Pietsch; J.M. Olmos; U. Pettersson-Kymmer; D.M. Reid; J.A. Riancho; P.M. Ridker; F. Rousseau; P.E. Slagboom; N.L.S. Tang; R. Urreizti; W. Van Hul; J. Viikari; M.T. Zarrabeitia; Y.S. Aulchenko; M. Castano-Betancourt; E. Grundberg; L. Herrera; T. Ingvarsson; H. Johannsdottir; T. Kwan; R. Li; R. Luben; C. Medina-Gómez; S.Th. Palsson; J.I. Rotter; G. Sigurdsson; J.B.J. Van Meurs; D. Verlaan; F.M.K. Williams; A.R. Wood; Y. Zhou; T. Pastinen; S. Raychaudhuri; J.A. Cauley; D.I. Chasman; G.R. Clark; S.R. Cummings; P. Danoy; E.M. Dennison; R. Eastell; J.A. Eisman; V. Gudnason; A. Hofman; R.D. Jackson; G. Jones; J.W. Jukema; K.-T. Khaw; T. Lehtimäki; Y. Liu; M. Lorentzon; E. Mccloskey; B.D. Mitchell; K. Nandakumar; G.C. Nicholson; B.A. Oostra; M. Peacock; H.A.P. Pols; Richard Prince; O. Raitakari; I.R. Reid; J. Robbins; P.N. Sambrook; P.C. Sham; A.R. Shuldiner; F.A. Tylavsky; C.M. Van Duijn; N.J. Wareham; L.A. Cupples; M.J. Econs; D.M. Evans; T.B. Harris; A.W.C. Kung; B.M. Psaty; J. Reeve; T.D. Spector; E.A. Streeten; M.C. Zillikens; U. Thorsteinsdottir; C. Ohlsson; D. Karasik; J.B. Richards; M.A. Brown; K. Stefansson; A.G. Uitterlinden; S.H. Ralston; J.P.A. Ioannidis; D.P. Kiel; F. Rivadeneira

doi:10.1371/journal.pone.0144531

Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci

S. Reppe, Y. Wang, W.K. Thompson, L.K. Mcevoy, A.J. Schork, V. Zuber, M. Leblanc, F. Bettella, I.G. Mills, R.S. Desikan, S. Djurovic, K.M. Gautvik, A.M. Dale, O.A. Andreassen, K. Estrada, U. Styrkarsdottir, E. Evangelou, Y.-H. Hsu, E.L. Duncan, E.E. NtzaniL. Oei, O.M.E. Albagha, N. Amin, J.P. Kemp, D.L. Koller, G. Li, C.-T. Liu, R.L. Minster, A. Moayyeri, L. Vandenput, D. Willner, S.-M. Xiao, L.M. Yerges-Armstrong, H.-F. Zheng, N. Alonso, J. Eriksson, C.M. Kammerer, S.K. Kaptoge, P.J. Leo, G. Thorleifsson, Scott Wilson, J.F. Wilson, V. Aalto, M. Alen, A.K. Aragaki, T. Aspelund, J.R. Center, Z. Dailiana, D.J. Duggan, M. Garcia, N. Garcia-Giralt, S. Giroux, G. Hallmans, L.J. Hocking, L.B. Husted, K.A. Jameson, R. Khusainova, G.S. Kim, C. Kooperberg, T. Koromila, M. Kruk, M. Laaksonen, A.Z. Lacroix, S.H. Lee, P.C. Leung, Joshua Lewis, L. Masi, S. Mencej-Bedrac, T.V. Nguyen, X. Nogues, M.S. Patel, J. Prezelj, L.M. Rose, S. Scollen, K. Siggeirsdottir, A.V. Smith, O. Svensson, S. Trompet, O. Trummer, N.M. Van Schoor, J. Woo, Kun Zhu, S. Balcells, M.L. Brandi, B.M. Buckley, S. Cheng, C. Christiansen, C. Cooper, G. Dedoussis, I. Ford, M. Frost, D. Goltzman, J. González-Macías, M. Kähönen, M. Karlsson, E. Khusnutdinova, J.-M. Koh, P. Kollia, B.L. Langdahl, W.D. Leslie, P. Lips, Ö. Ljunggren, R.S. Lorenc, J. Marc, D. Mellström, B. Obermayer-Pietsch, J.M. Olmos, U. Pettersson-Kymmer, D.M. Reid, J.A. Riancho, P.M. Ridker, F. Rousseau, P.E. Slagboom, N.L.S. Tang, R. Urreizti, W. Van Hul, J. Viikari, M.T. Zarrabeitia, Y.S. Aulchenko, M. Castano-Betancourt, E. Grundberg, L. Herrera, T. Ingvarsson, H. Johannsdottir, T. Kwan, R. Li, R. Luben, C. Medina-Gómez, S.Th. Palsson, J.I. Rotter, G. Sigurdsson, J.B.J. Van Meurs, D. Verlaan, F.M.K. Williams, A.R. Wood, Y. Zhou, T. Pastinen, S. Raychaudhuri, J.A. Cauley, D.I. Chasman, G.R. Clark, S.R. Cummings, P. Danoy, E.M. Dennison, R. Eastell, J.A. Eisman, V. Gudnason, A. Hofman, R.D. Jackson, G. Jones, J.W. Jukema, K.-T. Khaw, T. Lehtimäki, Y. Liu, M. Lorentzon, E. Mccloskey, B.D. Mitchell, K. Nandakumar, G.C. Nicholson, B.A. Oostra, M. Peacock, H.A.P. Pols, Richard Prince, O. Raitakari, I.R. Reid, J. Robbins, P.N. Sambrook, P.C. Sham, A.R. Shuldiner, F.A. Tylavsky, C.M. Van Duijn, N.J. Wareham, L.A. Cupples, M.J. Econs, D.M. Evans, T.B. Harris, A.W.C. Kung, B.M. Psaty, J. Reeve, T.D. Spector, E.A. Streeten, M.C. Zillikens, U. Thorsteinsdottir, C. Ohlsson, D. Karasik, J.B. Richards, M.A. Brown, K. Stefansson, A.G. Uitterlinden, S.H. Ralston, J.P.A. Ioannidis, D.P. Kiel, F. Rivadeneira

Research output: Contribution to journal › Article › peer-review

14 Citations (Scopus)

Abstract

© 2015 Reppe et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR <0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity.

Original language	English
Pages (from-to)	1-20
Journal	PLoS One
Volume	10
Issue number	12
DOIs	https://doi.org/10.1371/journal.pone.0144531
Publication status	Published - 2015

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10.1371/journal.pone.0144531

Cite this

Reppe, S., Wang, Y., Thompson, W. K., Mcevoy, L. K., Schork, A. J., Zuber, V., Leblanc, M., Bettella, F., Mills, I. G., Desikan, R. S., Djurovic, S., Gautvik, K. M., Dale, A. M., Andreassen, O. A., Estrada, K., Styrkarsdottir, U., Evangelou, E., Hsu, Y-H., Duncan, E. L., ... Rivadeneira, F. (2015). Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci. PLoS One, 10(12), 1-20. https://doi.org/10.1371/journal.pone.0144531

@article{f95c1a7b67f740979401398529882664,

title = "Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci",

abstract = "{\textcopyright} 2015 Reppe et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR <0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity.",

author = "S. Reppe and Y. Wang and W.K. Thompson and L.K. Mcevoy and A.J. Schork and V. Zuber and M. Leblanc and F. Bettella and I.G. Mills and R.S. Desikan and S. Djurovic and K.M. Gautvik and A.M. Dale and O.A. Andreassen and K. Estrada and U. Styrkarsdottir and E. Evangelou and Y.-H. Hsu and E.L. Duncan and E.E. Ntzani and L. Oei and O.M.E. Albagha and N. Amin and J.P. Kemp and D.L. Koller and G. Li and C.-T. Liu and R.L. Minster and A. Moayyeri and L. Vandenput and D. Willner and S.-M. Xiao and L.M. Yerges-Armstrong and H.-F. Zheng and N. Alonso and J. Eriksson and C.M. Kammerer and S.K. Kaptoge and P.J. Leo and G. Thorleifsson and Scott Wilson and J.F. Wilson and V. Aalto and M. Alen and A.K. Aragaki and T. Aspelund and J.R. Center and Z. Dailiana and D.J. Duggan and M. Garcia and N. Garcia-Giralt and S. Giroux and G. Hallmans and L.J. Hocking and L.B. Husted and K.A. Jameson and R. Khusainova and G.S. Kim and C. Kooperberg and T. Koromila and M. Kruk and M. Laaksonen and A.Z. Lacroix and S.H. Lee and P.C. Leung and Joshua Lewis and L. Masi and S. Mencej-Bedrac and T.V. Nguyen and X. Nogues and M.S. Patel and J. Prezelj and L.M. Rose and S. Scollen and K. Siggeirsdottir and A.V. Smith and O. Svensson and S. Trompet and O. Trummer and {Van Schoor}, N.M. and J. Woo and Kun Zhu and S. Balcells and M.L. Brandi and B.M. Buckley and S. Cheng and C. Christiansen and C. Cooper and G. Dedoussis and I. Ford and M. Frost and D. Goltzman and J. Gonz{\'a}lez-Mac{\'i}as and M. K{\"a}h{\"o}nen and M. Karlsson and E. Khusnutdinova and J.-M. Koh and P. Kollia and B.L. Langdahl and W.D. Leslie and P. Lips and {\"O}. Ljunggren and R.S. Lorenc and J. Marc and D. Mellstr{\"o}m and B. Obermayer-Pietsch and J.M. Olmos and U. Pettersson-Kymmer and D.M. Reid and J.A. Riancho and P.M. Ridker and F. Rousseau and P.E. Slagboom and N.L.S. Tang and R. Urreizti and {Van Hul}, W. and J. Viikari and M.T. Zarrabeitia and Y.S. Aulchenko and M. Castano-Betancourt and E. Grundberg and L. Herrera and T. Ingvarsson and H. Johannsdottir and T. Kwan and R. Li and R. Luben and C. Medina-G{\'o}mez and S.Th. Palsson and J.I. Rotter and G. Sigurdsson and {Van Meurs}, J.B.J. and D. Verlaan and F.M.K. Williams and A.R. Wood and Y. Zhou and T. Pastinen and S. Raychaudhuri and J.A. Cauley and D.I. Chasman and G.R. Clark and S.R. Cummings and P. Danoy and E.M. Dennison and R. Eastell and J.A. Eisman and V. Gudnason and A. Hofman and R.D. Jackson and G. Jones and J.W. Jukema and K.-T. Khaw and T. Lehtim{\"a}ki and Y. Liu and M. Lorentzon and E. Mccloskey and B.D. Mitchell and K. Nandakumar and G.C. Nicholson and B.A. Oostra and M. Peacock and H.A.P. Pols and Richard Prince and O. Raitakari and I.R. Reid and J. Robbins and P.N. Sambrook and P.C. Sham and A.R. Shuldiner and F.A. Tylavsky and {Van Duijn}, C.M. and N.J. Wareham and L.A. Cupples and M.J. Econs and D.M. Evans and T.B. Harris and A.W.C. Kung and B.M. Psaty and J. Reeve and T.D. Spector and E.A. Streeten and M.C. Zillikens and U. Thorsteinsdottir and C. Ohlsson and D. Karasik and J.B. Richards and M.A. Brown and K. Stefansson and A.G. Uitterlinden and S.H. Ralston and J.P.A. Ioannidis and D.P. Kiel and F. Rivadeneira",

year = "2015",

doi = "10.1371/journal.pone.0144531",

language = "English",

volume = "10",

pages = "1--20",

journal = "PLoS One",

issn = "1932-6203",

publisher = "Public Library of Science (PLoS)",

number = "12",

}

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, Estrada, K, Styrkarsdottir, U, Evangelou, E, Hsu, Y-H, Duncan, EL, Ntzani, EE, Oei, L, Albagha, OME, Amin, N, Kemp, JP, Koller, DL, Li, G, Liu, C-T, Minster, RL, Moayyeri, A, Vandenput, L, Willner, D, Xiao, S-M, Yerges-Armstrong, LM, Zheng, H-F, Alonso, N, Eriksson, J, Kammerer, CM, Kaptoge, SK, Leo, PJ, Thorleifsson, G, Wilson, S, 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, J, 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, González-Macías, J, Kähönen, M, Karlsson, M, Khusnutdinova, E, Koh, J-M, 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, NLS, 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, Rotter, JI, Sigurdsson, G, Van Meurs, JBJ, Verlaan, D, Williams, FMK, Wood, AR, Zhou, Y, 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, K-T, Lehtimäki, T, Liu, Y, Lorentzon, M, Mccloskey, E, Mitchell, BD, Nandakumar, K, Nicholson, GC, Oostra, BA, Peacock, M, Pols, HAP, Prince, R, 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, AWC, 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, JPA, Kiel, DP & Rivadeneira, F 2015, 'Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci', PLoS One, vol. 10, no. 12, pp. 1-20. https://doi.org/10.1371/journal.pone.0144531

TY - JOUR

T1 - Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci

AU - Reppe, S.

AU - Wang, Y.

AU - Thompson, W.K.

AU - Mcevoy, L.K.

AU - Schork, A.J.

AU - Zuber, V.

AU - Leblanc, M.

AU - Bettella, F.

AU - Mills, I.G.

AU - Desikan, R.S.

AU - Djurovic, S.

AU - Gautvik, K.M.

AU - Dale, A.M.

AU - Andreassen, O.A.

AU - Estrada, K.

AU - Styrkarsdottir, U.

AU - Evangelou, E.

AU - Hsu, Y.-H.

AU - Duncan, E.L.

AU - Ntzani, E.E.

AU - Oei, L.

AU - Albagha, O.M.E.

AU - Amin, N.

AU - Kemp, J.P.

AU - Koller, D.L.

AU - Li, G.

AU - Liu, C.-T.

AU - Minster, R.L.

AU - Moayyeri, A.

AU - Vandenput, L.

AU - Willner, D.

AU - Xiao, S.-M.

AU - Yerges-Armstrong, L.M.

AU - Zheng, H.-F.

AU - Alonso, N.

AU - Eriksson, J.

AU - Kammerer, C.M.

AU - Kaptoge, S.K.

AU - Leo, P.J.

AU - Thorleifsson, G.

AU - Wilson, Scott

AU - Wilson, J.F.

AU - Aalto, V.

AU - Alen, M.

AU - Aragaki, A.K.

AU - Aspelund, T.

AU - Center, J.R.

AU - Dailiana, Z.

AU - Duggan, D.J.

AU - Garcia, M.

AU - Garcia-Giralt, N.

AU - Giroux, S.

AU - Hallmans, G.

AU - Hocking, L.J.

AU - Husted, L.B.

AU - Jameson, K.A.

AU - Khusainova, R.

AU - Kim, G.S.

AU - Kooperberg, C.

AU - Koromila, T.

AU - Kruk, M.

AU - Laaksonen, M.

AU - Lacroix, A.Z.

AU - Lee, S.H.

AU - Leung, P.C.

AU - Lewis, Joshua

AU - Masi, L.

AU - Mencej-Bedrac, S.

AU - Nguyen, T.V.

AU - Nogues, X.

AU - Patel, M.S.

AU - Prezelj, J.

AU - Rose, L.M.

AU - Scollen, S.

AU - Siggeirsdottir, K.

AU - Smith, A.V.

AU - Svensson, O.

AU - Trompet, S.

AU - Trummer, O.

AU - Van Schoor, N.M.

AU - Woo, J.

AU - Zhu, Kun

AU - Balcells, S.

AU - Brandi, M.L.

AU - Buckley, B.M.

AU - Cheng, S.

AU - Christiansen, C.

AU - Cooper, C.

AU - Dedoussis, G.

AU - Ford, I.

AU - Frost, M.

AU - Goltzman, D.

AU - González-Macías, J.

AU - Kähönen, M.

AU - Karlsson, M.

AU - Khusnutdinova, E.

AU - Koh, J.-M.

AU - Kollia, P.

AU - Langdahl, B.L.

AU - Leslie, W.D.

AU - Lips, P.

AU - Ljunggren, Ö.

AU - Lorenc, R.S.

AU - Marc, J.

AU - Mellström, D.

AU - Obermayer-Pietsch, B.

AU - Olmos, J.M.

AU - Pettersson-Kymmer, U.

AU - Reid, D.M.

AU - Riancho, J.A.

AU - Ridker, P.M.

AU - Rousseau, F.

AU - Slagboom, P.E.

AU - Tang, N.L.S.

AU - Urreizti, R.

AU - Van Hul, W.

AU - Viikari, J.

AU - Zarrabeitia, M.T.

AU - Aulchenko, Y.S.

AU - Castano-Betancourt, M.

AU - Grundberg, E.

AU - Herrera, L.

AU - Ingvarsson, T.

AU - Johannsdottir, H.

AU - Kwan, T.

AU - Li, R.

AU - Luben, R.

AU - Medina-Gómez, C.

AU - Palsson, S.Th.

AU - Rotter, J.I.

AU - Sigurdsson, G.

AU - Van Meurs, J.B.J.

AU - Verlaan, D.

AU - Williams, F.M.K.

AU - Wood, A.R.

AU - Zhou, Y.

AU - Pastinen, T.

AU - Raychaudhuri, S.

AU - Cauley, J.A.

AU - Chasman, D.I.

AU - Clark, G.R.

AU - Cummings, S.R.

AU - Danoy, P.

AU - Dennison, E.M.

AU - Eastell, R.

AU - Eisman, J.A.

AU - Gudnason, V.

AU - Hofman, A.

AU - Jackson, R.D.

AU - Jones, G.

AU - Jukema, J.W.

AU - Khaw, K.-T.

AU - Lehtimäki, T.

AU - Liu, Y.

AU - Lorentzon, M.

AU - Mccloskey, E.

AU - Mitchell, B.D.

AU - Nandakumar, K.

AU - Nicholson, G.C.

AU - Oostra, B.A.

AU - Peacock, M.

AU - Pols, H.A.P.

AU - Prince, Richard

AU - Raitakari, O.

AU - Reid, I.R.

AU - Robbins, J.

AU - Sambrook, P.N.

AU - Sham, P.C.

AU - Shuldiner, A.R.

AU - Tylavsky, F.A.

AU - Van Duijn, C.M.

AU - Wareham, N.J.

AU - Cupples, L.A.

AU - Econs, M.J.

AU - Evans, D.M.

AU - Harris, T.B.

AU - Kung, A.W.C.

AU - Psaty, B.M.

AU - Reeve, J.

AU - Spector, T.D.

AU - Streeten, E.A.

AU - Zillikens, M.C.

AU - Thorsteinsdottir, U.

AU - Ohlsson, C.

AU - Karasik, D.

AU - Richards, J.B.

AU - Brown, M.A.

AU - Stefansson, K.

AU - Uitterlinden, A.G.

AU - Ralston, S.H.

AU - Ioannidis, J.P.A.

AU - Kiel, D.P.

AU - Rivadeneira, F.

PY - 2015

Y1 - 2015

N2 - © 2015 Reppe et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR <0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity.

AB - © 2015 Reppe et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR <0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity.

U2 - 10.1371/journal.pone.0144531

DO - 10.1371/journal.pone.0144531

M3 - Article

C2 - 26695485

SN - 1932-6203

VL - 10

SP - 1

EP - 20

JO - PLoS One

JF - PLoS One

IS - 12

ER -

Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci

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