Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture

H.-F. Zheng, V. Forgetta, Y.-H. Hsu, K. Estrada, A. Rosello-Diez, P.J. Leo, C.L. Dahia, K.H. Park-Min, J.H. Tobias, C. Kooperberg, A. Kleinman, U. Styrkarsdottir, C.-T. Liu, C. Uggla, D.S. Evans, C.M. Nielson, K. Walter, U. Pettersson-Kymmer, S. Mccarthy, J. Eriksson & 136 others T. Kwan, M. Jhamai, K. Trajanoska, Y. Memari, J. Min, J. Huang, P. Danecek, B. Wilmot, R. Li, W.-C. Chou, L.E. Mokry, A. Moayyeri, M. Claussnitzer, C.-H. Cheng, W. Cheung, C. Medina-Gómez, B. Ge, S.-H. Chen, K. Choi, L. Oei, J. Fraser, R. Kraaij, M.A. Hibbs, C.L. Gregson, D. Paquette, A. Hofman, C. Wibom, G.J. Tranah, M. Marshall, B.B. Gardiner, K. Cremin, P. Auer, L. Hsu, S. Ring, J.Y. Tung, G. Thorleifsson, A.W. Enneman, N.M. Van Schoor, L.C.P.G.M. De Groot, N. Van Der Velde, B. Melin, J.P. Kemp, C. Christiansen, A. Sayers, Y. Zhou, S. Calderari, J. Van Rooij, C. Carlson, U. Peters, S. Berlivet, J. Dostie, A.G. Uitterlinden, S.R. Williams, C. Farber, D. Grinberg, A.Z. Lacroix, J. Haessler, D.I. Chasman, F. Giulianini, L.M. Rose, P.M. Ridker, J.A. Eisman, T.V. Nguyen, J.R. Center, X. Nogues, N. Garcia-Giralt, L.L. Launer, V. Gudnason, D. Mellström, L. Vandenput, N. Amin, C.M. Van Duijn, M.K. Karlsson, O. Ljunggren, O. Svensson, G. Hallmans, F. Rousseau, S. Giroux, J. Bussière, P.P. Arp, F. Koromani, Richard Prince, Joshua Lewis, B.L. Langdahl, A.P. Hermann, J.-E.B. Jensen, S. Kaptoge, K.-T. Khaw, J. Reeve, M.M. Formosa, A. Xuereb-Anastasi, K. Åkesson, F.E. Mcguigan, G. Garg, J.M. Olmos, M.T. Zarrabeitia, J.A. Riancho, S.H. Ralston, N. Alonso, X. Jiang, D. Goltzman, T. Pastinen, E. Grundberg, D. Gauguier, E.S. Orwoll, D. Karasik, G. Davey-Smith, A.V. Smith, K. Siggeirsdottir, T.B. Harris, M.C. Zillikens, J.B.J. Van Meurs, U. Thorsteinsdottir, M.T. Maurano, N.J. Timpson, N. Soranzo, R. Durbin, S.G. Wilson, E.E. Ntzani, M.A. Brown, K. Stefansson, D.A. Hinds, T. Spector, L.A. Cupples, C. Ohlsson, C.M.T. Greenwood, R.D. Jackson, D.W. Rowe, C.A. Loomis, D.M. Evans, C.L. Ackert-Bicknell, A.L. Joyner, E.L. Duncan, D.P. Kiel, F. Rivadeneira, J.B. Richards

Research output: Contribution to journalArticle

172 Citations (Scopus)

Abstract

© 2015 Macmillan Publishers Limited. All rights reserved. The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10-14), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10-11; ncases = 98,742 and n controls = 409,511). Using an En1 cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10-11). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.
Original languageEnglish
Pages (from-to)112-117
JournalNature
Volume526
Issue number7571
DOIs
Publication statusPublished - 2015

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Zheng, H-F., Forgetta, V., Hsu, Y-H., Estrada, K., Rosello-Diez, A., Leo, P. J., ... Richards, J. B. (2015). Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature, 526(7571), 112-117. https://doi.org/10.1038/nature14878
Zheng, H.-F. ; Forgetta, V. ; Hsu, Y.-H. ; Estrada, K. ; Rosello-Diez, A. ; Leo, P.J. ; Dahia, C.L. ; Park-Min, K.H. ; Tobias, J.H. ; Kooperberg, C. ; Kleinman, A. ; Styrkarsdottir, U. ; Liu, C.-T. ; Uggla, C. ; Evans, D.S. ; Nielson, C.M. ; 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, W.-C. ; Mokry, L.E. ; Moayyeri, A. ; Claussnitzer, M. ; Cheng, C.-H. ; Cheung, W. ; Medina-Gómez, C. ; Ge, B. ; Chen, S.-H. ; Choi, K. ; Oei, L. ; Fraser, J. ; Kraaij, R. ; Hibbs, M.A. ; Gregson, C.L. ; Paquette, D. ; Hofman, A. ; Wibom, C. ; Tranah, G.J. ; Marshall, M. ; Gardiner, B.B. ; Cremin, K. ; Auer, P. ; Hsu, L. ; Ring, S. ; Tung, J.Y. ; Thorleifsson, G. ; Enneman, A.W. ; Van Schoor, N.M. ; De Groot, L.C.P.G.M. ; Van Der Velde, N. ; Melin, B. ; Kemp, J.P. ; Christiansen, C. ; Sayers, A. ; Zhou, Y. ; Calderari, S. ; Van Rooij, J. ; Carlson, C. ; Peters, U. ; Berlivet, S. ; Dostie, J. ; Uitterlinden, A.G. ; Williams, S.R. ; Farber, C. ; Grinberg, D. ; Lacroix, A.Z. ; Haessler, J. ; Chasman, D.I. ; Giulianini, F. ; Rose, L.M. ; Ridker, P.M. ; Eisman, J.A. ; Nguyen, T.V. ; Center, J.R. ; Nogues, X. ; Garcia-Giralt, N. ; Launer, L.L. ; Gudnason, V. ; Mellström, D. ; Vandenput, L. ; Amin, N. ; Van Duijn, C.M. ; Karlsson, M.K. ; Ljunggren, O. ; Svensson, O. ; Hallmans, G. ; Rousseau, F. ; Giroux, S. ; Bussière, J. ; Arp, P.P. ; Koromani, F. ; Prince, Richard ; Lewis, Joshua ; Langdahl, B.L. ; Hermann, A.P. ; Jensen, J.-E.B. ; Kaptoge, S. ; Khaw, K.-T. ; Reeve, J. ; Formosa, M.M. ; Xuereb-Anastasi, A. ; Åkesson, K. ; Mcguigan, F.E. ; Garg, G. ; Olmos, J.M. ; Zarrabeitia, M.T. ; Riancho, J.A. ; Ralston, S.H. ; Alonso, N. ; Jiang, X. ; Goltzman, D. ; Pastinen, T. ; Grundberg, E. ; Gauguier, D. ; Orwoll, E.S. ; Karasik, D. ; Davey-Smith, G. ; Smith, A.V. ; Siggeirsdottir, K. ; Harris, T.B. ; Zillikens, M.C. ; Van Meurs, J.B.J. ; Thorsteinsdottir, U. ; Maurano, M.T. ; Timpson, N.J. ; Soranzo, N. ; Durbin, R. ; Wilson, S.G. ; Ntzani, E.E. ; Brown, M.A. ; Stefansson, K. ; Hinds, D.A. ; Spector, T. ; Cupples, L.A. ; Ohlsson, C. ; Greenwood, C.M.T. ; Jackson, R.D. ; Rowe, D.W. ; Loomis, C.A. ; Evans, D.M. ; Ackert-Bicknell, C.L. ; Joyner, A.L. ; Duncan, E.L. ; Kiel, D.P. ; Rivadeneira, F. ; Richards, J.B. / Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. In: Nature. 2015 ; Vol. 526, No. 7571. pp. 112-117.
@article{84bd885a56fd4c33bc8471ec4f05fe74,
title = "Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture",
abstract = "{\circledC} 2015 Macmillan Publishers Limited. All rights reserved. The extent to which low-frequency (minor allele frequency (MAF) between 1-5{\%}) and rare (MAF ≤ 1{\%}) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6{\%}, replication effect size = +0.20 s.d., Pmeta = 2 × 10-14), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10-11; ncases = 98,742 and n controls = 409,511). Using an En1 cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2{\%}, replication effect size = +0.41 s.d., Pmeta = 1 × 10-11). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.",
author = "H.-F. Zheng and V. Forgetta and Y.-H. Hsu and K. Estrada and A. Rosello-Diez and P.J. Leo and C.L. Dahia and K.H. Park-Min and J.H. Tobias and C. Kooperberg and A. Kleinman and U. Styrkarsdottir and C.-T. Liu and C. Uggla and D.S. Evans and C.M. Nielson and K. Walter and U. Pettersson-Kymmer and S. Mccarthy and J. Eriksson and T. Kwan and M. Jhamai and K. Trajanoska and Y. Memari and J. Min and J. Huang and P. Danecek and B. Wilmot and R. Li and W.-C. Chou and L.E. Mokry and A. Moayyeri and M. Claussnitzer and C.-H. Cheng and W. Cheung and C. Medina-G{\'o}mez and B. Ge and S.-H. Chen and K. Choi and L. Oei and J. Fraser and R. Kraaij and M.A. Hibbs and C.L. Gregson and D. Paquette and A. Hofman and C. Wibom and G.J. Tranah and M. Marshall and B.B. Gardiner and K. Cremin and P. Auer and L. Hsu and S. Ring and J.Y. Tung and G. Thorleifsson and A.W. Enneman and {Van Schoor}, N.M. and {De Groot}, L.C.P.G.M. and {Van Der Velde}, N. and B. Melin and J.P. Kemp and C. Christiansen and A. Sayers and Y. Zhou and S. Calderari and {Van Rooij}, J. and C. Carlson and U. Peters and S. Berlivet and J. Dostie and A.G. Uitterlinden and S.R. Williams and C. Farber and D. Grinberg and A.Z. Lacroix and J. Haessler and D.I. Chasman and F. Giulianini and L.M. Rose and P.M. Ridker and J.A. Eisman and T.V. Nguyen and J.R. Center and X. Nogues and N. Garcia-Giralt and L.L. Launer and V. Gudnason and D. Mellstr{\"o}m and L. Vandenput and N. Amin and {Van Duijn}, C.M. and M.K. Karlsson and O. Ljunggren and O. Svensson and G. Hallmans and F. Rousseau and S. Giroux and J. Bussi{\`e}re and P.P. Arp and F. Koromani and Richard Prince and Joshua Lewis and B.L. Langdahl and A.P. Hermann and J.-E.B. Jensen and S. Kaptoge and K.-T. Khaw and J. Reeve and M.M. Formosa and A. Xuereb-Anastasi and K. {\AA}kesson and F.E. Mcguigan and G. Garg and J.M. Olmos and M.T. Zarrabeitia and J.A. Riancho and S.H. Ralston and N. Alonso and X. Jiang and D. Goltzman and T. Pastinen and E. Grundberg and D. Gauguier and E.S. Orwoll and D. Karasik and G. Davey-Smith and A.V. Smith and K. Siggeirsdottir and T.B. Harris and M.C. Zillikens and {Van Meurs}, J.B.J. and U. Thorsteinsdottir and M.T. Maurano and N.J. Timpson and N. Soranzo and R. Durbin and S.G. Wilson and E.E. Ntzani and M.A. Brown and K. Stefansson and D.A. Hinds and T. Spector and L.A. Cupples and C. Ohlsson and C.M.T. Greenwood and R.D. Jackson and D.W. Rowe and C.A. Loomis and D.M. Evans and C.L. Ackert-Bicknell and A.L. Joyner and E.L. Duncan and D.P. Kiel and F. Rivadeneira and J.B. Richards",
year = "2015",
doi = "10.1038/nature14878",
language = "English",
volume = "526",
pages = "112--117",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group - Macmillan Publishers",
number = "7571",

}

Zheng, H-F, Forgetta, V, Hsu, Y-H, Estrada, K, Rosello-Diez, A, Leo, PJ, Dahia, CL, Park-Min, KH, Tobias, JH, Kooperberg, C, Kleinman, A, Styrkarsdottir, U, Liu, C-T, 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, W-C, Mokry, LE, Moayyeri, A, Claussnitzer, M, Cheng, C-H, Cheung, W, Medina-Gómez, C, Ge, B, Chen, S-H, 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, LCPGM, 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, O, Svensson, O, Hallmans, G, Rousseau, F, Giroux, S, Bussière, J, Arp, PP, Koromani, F, Prince, R, Lewis, J, Langdahl, BL, Hermann, AP, Jensen, J-EB, Kaptoge, S, Khaw, K-T, 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, Smith, AV, Siggeirsdottir, K, Harris, TB, Zillikens, MC, Van Meurs, JBJ, 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, CMT, 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, vol. 526, no. 7571, pp. 112-117. https://doi.org/10.1038/nature14878

Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. / Zheng, H.-F.; Forgetta, V.; Hsu, Y.-H.; Estrada, K.; Rosello-Diez, A.; Leo, P.J.; Dahia, C.L.; Park-Min, K.H.; Tobias, J.H.; Kooperberg, C.; Kleinman, A.; Styrkarsdottir, U.; Liu, C.-T.; Uggla, C.; Evans, D.S.; Nielson, C.M.; 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, W.-C.; Mokry, L.E.; Moayyeri, A.; Claussnitzer, M.; Cheng, C.-H.; Cheung, W.; Medina-Gómez, C.; Ge, B.; Chen, S.-H.; Choi, K.; Oei, L.; Fraser, J.; Kraaij, R.; Hibbs, M.A.; Gregson, C.L.; Paquette, D.; Hofman, A.; Wibom, C.; Tranah, G.J.; Marshall, M.; Gardiner, B.B.; Cremin, K.; Auer, P.; Hsu, L.; Ring, S.; Tung, J.Y.; Thorleifsson, G.; Enneman, A.W.; Van Schoor, N.M.; De Groot, L.C.P.G.M.; Van Der Velde, N.; Melin, B.; Kemp, J.P.; Christiansen, C.; Sayers, A.; Zhou, Y.; Calderari, S.; Van Rooij, J.; Carlson, C.; Peters, U.; Berlivet, S.; Dostie, J.; Uitterlinden, A.G.; Williams, S.R.; Farber, C.; Grinberg, D.; Lacroix, A.Z.; Haessler, J.; Chasman, D.I.; Giulianini, F.; Rose, L.M.; Ridker, P.M.; Eisman, J.A.; Nguyen, T.V.; Center, J.R.; Nogues, X.; Garcia-Giralt, N.; Launer, L.L.; Gudnason, V.; Mellström, D.; Vandenput, L.; Amin, N.; Van Duijn, C.M.; Karlsson, M.K.; Ljunggren, O.; Svensson, O.; Hallmans, G.; Rousseau, F.; Giroux, S.; Bussière, J.; Arp, P.P.; Koromani, F.; Prince, Richard; Lewis, Joshua; Langdahl, B.L.; Hermann, A.P.; Jensen, J.-E.B.; Kaptoge, S.; Khaw, K.-T.; Reeve, J.; Formosa, M.M.; Xuereb-Anastasi, A.; Åkesson, K.; Mcguigan, F.E.; Garg, G.; Olmos, J.M.; Zarrabeitia, M.T.; Riancho, J.A.; Ralston, S.H.; Alonso, N.; Jiang, X.; Goltzman, D.; Pastinen, T.; Grundberg, E.; Gauguier, D.; Orwoll, E.S.; Karasik, D.; Davey-Smith, G.; Smith, A.V.; Siggeirsdottir, K.; Harris, T.B.; Zillikens, M.C.; Van Meurs, J.B.J.; Thorsteinsdottir, U.; Maurano, M.T.; Timpson, N.J.; Soranzo, N.; Durbin, R.; Wilson, S.G.; Ntzani, E.E.; Brown, M.A.; Stefansson, K.; Hinds, D.A.; Spector, T.; Cupples, L.A.; Ohlsson, C.; Greenwood, C.M.T.; Jackson, R.D.; Rowe, D.W.; Loomis, C.A.; Evans, D.M.; Ackert-Bicknell, C.L.; Joyner, A.L.; Duncan, E.L.; Kiel, D.P.; Rivadeneira, F.; Richards, J.B.

In: Nature, Vol. 526, No. 7571, 2015, p. 112-117.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture

AU - Zheng, H.-F.

AU - Forgetta, V.

AU - Hsu, Y.-H.

AU - Estrada, K.

AU - Rosello-Diez, A.

AU - Leo, P.J.

AU - Dahia, C.L.

AU - Park-Min, K.H.

AU - Tobias, J.H.

AU - Kooperberg, C.

AU - Kleinman, A.

AU - Styrkarsdottir, U.

AU - Liu, C.-T.

AU - Uggla, C.

AU - Evans, D.S.

AU - Nielson, C.M.

AU - Walter, K.

AU - Pettersson-Kymmer, U.

AU - Mccarthy, S.

AU - Eriksson, J.

AU - Kwan, T.

AU - Jhamai, M.

AU - Trajanoska, K.

AU - Memari, Y.

AU - Min, J.

AU - Huang, J.

AU - Danecek, P.

AU - Wilmot, B.

AU - Li, R.

AU - Chou, W.-C.

AU - Mokry, L.E.

AU - Moayyeri, A.

AU - Claussnitzer, M.

AU - Cheng, C.-H.

AU - Cheung, W.

AU - Medina-Gómez, C.

AU - Ge, B.

AU - Chen, S.-H.

AU - Choi, K.

AU - Oei, L.

AU - Fraser, J.

AU - Kraaij, R.

AU - Hibbs, M.A.

AU - Gregson, C.L.

AU - Paquette, D.

AU - Hofman, A.

AU - Wibom, C.

AU - Tranah, G.J.

AU - Marshall, M.

AU - Gardiner, B.B.

AU - Cremin, K.

AU - Auer, P.

AU - Hsu, L.

AU - Ring, S.

AU - Tung, J.Y.

AU - Thorleifsson, G.

AU - Enneman, A.W.

AU - Van Schoor, N.M.

AU - De Groot, L.C.P.G.M.

AU - Van Der Velde, N.

AU - Melin, B.

AU - Kemp, J.P.

AU - Christiansen, C.

AU - Sayers, A.

AU - Zhou, Y.

AU - Calderari, S.

AU - Van Rooij, J.

AU - Carlson, C.

AU - Peters, U.

AU - Berlivet, S.

AU - Dostie, J.

AU - Uitterlinden, A.G.

AU - Williams, S.R.

AU - Farber, C.

AU - Grinberg, D.

AU - Lacroix, A.Z.

AU - Haessler, J.

AU - Chasman, D.I.

AU - Giulianini, F.

AU - Rose, L.M.

AU - Ridker, P.M.

AU - Eisman, J.A.

AU - Nguyen, T.V.

AU - Center, J.R.

AU - Nogues, X.

AU - Garcia-Giralt, N.

AU - Launer, L.L.

AU - Gudnason, V.

AU - Mellström, D.

AU - Vandenput, L.

AU - Amin, N.

AU - Van Duijn, C.M.

AU - Karlsson, M.K.

AU - Ljunggren, O.

AU - Svensson, O.

AU - Hallmans, G.

AU - Rousseau, F.

AU - Giroux, S.

AU - Bussière, J.

AU - Arp, P.P.

AU - Koromani, F.

AU - Prince, Richard

AU - Lewis, Joshua

AU - Langdahl, B.L.

AU - Hermann, A.P.

AU - Jensen, J.-E.B.

AU - Kaptoge, S.

AU - Khaw, K.-T.

AU - Reeve, J.

AU - Formosa, M.M.

AU - Xuereb-Anastasi, A.

AU - Åkesson, K.

AU - Mcguigan, F.E.

AU - Garg, G.

AU - Olmos, J.M.

AU - Zarrabeitia, M.T.

AU - Riancho, J.A.

AU - Ralston, S.H.

AU - Alonso, N.

AU - Jiang, X.

AU - Goltzman, D.

AU - Pastinen, T.

AU - Grundberg, E.

AU - Gauguier, D.

AU - Orwoll, E.S.

AU - Karasik, D.

AU - Davey-Smith, G.

AU - Smith, A.V.

AU - Siggeirsdottir, K.

AU - Harris, T.B.

AU - Zillikens, M.C.

AU - Van Meurs, J.B.J.

AU - Thorsteinsdottir, U.

AU - Maurano, M.T.

AU - Timpson, N.J.

AU - Soranzo, N.

AU - Durbin, R.

AU - Wilson, S.G.

AU - Ntzani, E.E.

AU - Brown, M.A.

AU - Stefansson, K.

AU - Hinds, D.A.

AU - Spector, T.

AU - Cupples, L.A.

AU - Ohlsson, C.

AU - Greenwood, C.M.T.

AU - Jackson, R.D.

AU - Rowe, D.W.

AU - Loomis, C.A.

AU - Evans, D.M.

AU - Ackert-Bicknell, C.L.

AU - Joyner, A.L.

AU - Duncan, E.L.

AU - Kiel, D.P.

AU - Rivadeneira, F.

AU - Richards, J.B.

PY - 2015

Y1 - 2015

N2 - © 2015 Macmillan Publishers Limited. All rights reserved. The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10-14), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10-11; ncases = 98,742 and n controls = 409,511). Using an En1 cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10-11). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.

AB - © 2015 Macmillan Publishers Limited. All rights reserved. The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10-14), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10-11; ncases = 98,742 and n controls = 409,511). Using an En1 cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10-11). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.

U2 - 10.1038/nature14878

DO - 10.1038/nature14878

M3 - Article

VL - 526

SP - 112

EP - 117

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7571

ER -

Zheng H-F, Forgetta V, Hsu Y-H, Estrada K, Rosello-Diez A, Leo PJ et al. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature. 2015;526(7571):112-117. https://doi.org/10.1038/nature14878