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

HF Zheng; V Forgetta; YH Hsu; Karol Estrada Gil; A Rosello-Diez; PJ Leo; CL Dahia; KH Park-Min; JH Tobias; C Kooperberg; A Kleinman; U Styrkarsdottir; CT Liu; C Uggla; DS Evans; CM Nielson; K Walter; U Pettersson-Kymmer; S McCarthy; J Eriksson; T Kwan; M Jhamai; Katerina Trajanoska; Y Memari; J Min; J Huang; P Danecek; B Wilmot; R Li; WC Chou; LE Mokry; A Moayyeri; M Claussnitzer; CH Cheng; W Cheung; Maria Medina Gomez; B Ge; SH Chen; K Choi; Ling Oei - Oei; J Fraser; Robert Kraaij; MA Hibbs; CL Gregson; D Paquette; Bert Hofman; C Wibom; GJ Tranah; M Marshall; BB Gardiner; K Cremin; P Auer; L (Lily) Hsu; S Ring; JY Tung; G Thorleifsson; Anke Enneman; NM Schoor; LCPGM (Lisette) de Groot; Nathalie van der Velde; B Melin; JP Kemp; C Christiansen; A Sayers; YH Zhou; S Calderari; J van Rooij; C Carlson; U Peters; S Berlivet; J Dostie; André Uitterlinden; SR Williams; C Farber; D Grinberg; AZ Lacroix; J Haessler; DI Chasman; F Giulianini; LM Rose; PM Ridker; JA Eisman; TV (Tuan) Nguyen; JR Center; X Nogues; N Garcia-Giralt; LL Launer; V Gudnason; D Mellstrom; L Vandenput; Najaf Amin; Cornelia Duijn; MK Karlsson; O Ljunggren; O Svensson; G Hallmans; F Rousseau; S Giroux; J Bussiere; Pascal Arp; Fjorda Koromani; RL Prince; JR Lewis; BL Langdahl; AP Hermann; JEB Jensen; S Kaptoge; KT Khaw; J Reeve; MM Formosa; A Xuereb-Anastasi; K Akesson; FE McGuigan; G Garg; JM Olmos; MT Zarrabeitia; JA Riancho; SH Ralston; N Alonso; X Jiang; D Goltzman; T Pastinen; E Grundberg; D Gauguier; ES Orwoll; D Karasik; G Davey-Smith; AV Smith; K Siggeirsdottir; TB Harris; M.C. Zillikens; Joyce van Meurs; U Thorsteinsdottir; MT Maurano; NJ Timpson; N Soranzo; R Durbin; S Wilson; EE Ntzani; MA Brown; K Stefansson; DA Hinds; T Spector; LA Cupples; C Ohlsson; CMT Greenwood; RD Jackson; DW Rowe; CA Loomis; DM Evans; CL Ackert-Bicknell; AL Joyner; EL Duncan; DP Kiel; Fernando Rivadeneira; JB Richards

doi:10.1038/nature14878

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

HF Zheng, V Forgetta, YH Hsu, Karol Estrada Gil, A Rosello-Diez, PJ Leo, CL Dahia, KH Park-Min, JH Tobias, C Kooperberg, A Kleinman, U Styrkarsdottir, CT Liu, C Uggla, DS Evans, CM Nielson, K Walter, U Pettersson-Kymmer, S McCarthy, J ErikssonT Kwan, M Jhamai, Katerina Trajanoska, Y Memari, J Min, J Huang, P Danecek, B Wilmot, R Li, WC Chou, LE Mokry, A Moayyeri, M Claussnitzer, CH Cheng, W Cheung, Maria Medina Gomez, B Ge, SH Chen, K Choi, Ling Oei - Oei, J Fraser, Robert Kraaij, MA Hibbs, CL Gregson, D Paquette, Bert Hofman, C Wibom, GJ Tranah, M Marshall, BB Gardiner, K Cremin, P Auer, L (Lily) Hsu, S Ring, JY Tung, G Thorleifsson, Anke Enneman, NM Schoor, LCPGM (Lisette) de Groot, Nathalie van der Velde, B Melin, JP Kemp, C Christiansen, A Sayers, YH Zhou, S Calderari, J van Rooij, C Carlson, U Peters, S Berlivet, J Dostie, André Uitterlinden, SR Williams, C Farber, D Grinberg, AZ Lacroix, J Haessler, DI Chasman, F Giulianini, LM Rose, PM Ridker, JA Eisman, TV (Tuan) Nguyen, JR Center, X Nogues, N Garcia-Giralt, LL Launer, V Gudnason, D Mellstrom, L Vandenput, Najaf Amin, Cornelia Duijn, MK Karlsson, O Ljunggren, O Svensson, G Hallmans, F Rousseau, S Giroux, J Bussiere, Pascal Arp, Fjorda Koromani, RL Prince, JR Lewis, BL Langdahl, AP Hermann, JEB Jensen, S Kaptoge, KT Khaw, J Reeve, MM Formosa, A Xuereb-Anastasi, K Akesson, FE McGuigan, G Garg, JM Olmos, MT Zarrabeitia, JA Riancho, SH Ralston, N Alonso, X Jiang, D Goltzman, T Pastinen, E Grundberg, D Gauguier, ES Orwoll, D Karasik, G Davey-Smith, AV Smith, K Siggeirsdottir, TB Harris, M.C. Zillikens, Joyce van Meurs, U Thorsteinsdottir, MT Maurano, NJ Timpson, N Soranzo, R Durbin, S Wilson, EE Ntzani, MA Brown, K Stefansson, DA Hinds, T Spector, LA Cupples, C Ohlsson, CMT Greenwood, RD Jackson, DW Rowe, CA Loomis, DM Evans, CL Ackert-Bicknell, AL Joyner, EL Duncan, DP Kiel, Fernando Rivadeneira, JB Richards

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

473 Citations (Scopus)

Abstract

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(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 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 BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1cre/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 +10.41 s.d., P-meta = 1 x 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 language	Undefined/Unknown
Pages (from-to)	112-+
Journal	Nature
Volume	526
Issue number	7571
DOIs	https://doi.org/10.1038/nature14878
Publication status	Published - 2015

Research programs

EMC MM-01-39-02
EMC MM-01-39-09-A
EMC NIHES-01-64-02
EMC OR-01-39-08

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10.1038/nature14878

Cite this

Zheng, HF., Forgetta, V., Hsu, YH., Estrada Gil, 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., ... Richards, JB. (2015). Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature, 526(7571), 112-+. https://doi.org/10.1038/nature14878

@article{a661bc039ad84047988281067cfc5e17,

title = "Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture",

abstract = "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(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 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 BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1cre/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 +10.41 s.d., P-meta = 1 x 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 = "HF Zheng and V Forgetta and YH Hsu and {Estrada Gil}, Karol and A Rosello-Diez and PJ Leo and CL Dahia and KH Park-Min and JH Tobias and C Kooperberg and A Kleinman and U Styrkarsdottir and CT Liu and C Uggla and DS Evans and CM Nielson and K Walter and U Pettersson-Kymmer and S McCarthy and J Eriksson and T Kwan and M Jhamai and Katerina Trajanoska and Y Memari and J Min and J Huang and P Danecek and B Wilmot and R Li and WC Chou and LE Mokry and A Moayyeri and M Claussnitzer and CH Cheng and W Cheung and {Medina Gomez}, Maria and B Ge and SH Chen and K Choi and {Oei - Oei}, Ling and J Fraser and Robert Kraaij and MA Hibbs and CL Gregson and D Paquette and Bert Hofman and C Wibom and GJ Tranah and M Marshall and BB Gardiner and K Cremin and P Auer and Hsu, {L (Lily)} and S Ring and JY Tung and G Thorleifsson and Anke Enneman and NM Schoor and {de Groot}, {LCPGM (Lisette)} and {van der Velde}, Nathalie and B Melin and JP Kemp and C Christiansen and A Sayers and YH Zhou and S Calderari and {van Rooij}, J and C Carlson and U Peters and S Berlivet and J Dostie and Andr{\'e} Uitterlinden and SR Williams and C Farber and D Grinberg and AZ Lacroix and J Haessler and DI Chasman and F Giulianini and LM Rose and PM Ridker and JA Eisman and Nguyen, {TV (Tuan)} and JR Center and X Nogues and N Garcia-Giralt and LL Launer and V Gudnason and D Mellstrom and L Vandenput and Najaf Amin and Cornelia Duijn and MK Karlsson and O Ljunggren and O Svensson and G Hallmans and F Rousseau and S Giroux and J Bussiere and Pascal Arp and Fjorda Koromani and RL Prince and JR Lewis and BL Langdahl and AP Hermann and JEB Jensen and S Kaptoge and KT Khaw and J Reeve and MM Formosa and A Xuereb-Anastasi and K Akesson and FE McGuigan and G Garg and JM Olmos and MT Zarrabeitia and JA Riancho and SH Ralston and N Alonso and X Jiang and D Goltzman and T Pastinen and E Grundberg and D Gauguier and ES Orwoll and D Karasik and G Davey-Smith and AV Smith and K Siggeirsdottir and TB Harris and M.C. Zillikens and {van Meurs}, Joyce and U Thorsteinsdottir and MT Maurano and NJ Timpson and N Soranzo and R Durbin and S Wilson and EE Ntzani and MA Brown and K Stefansson and DA Hinds and T Spector and LA Cupples and C Ohlsson and CMT Greenwood and RD Jackson and DW Rowe and CA Loomis and DM Evans and CL Ackert-Bicknell and AL Joyner and EL Duncan and DP Kiel and Fernando Rivadeneira and JB Richards",

year = "2015",

doi = "10.1038/nature14878",

language = "Undefined/Unknown",

volume = "526",

pages = "112--+",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7571",

}

Zheng, HF, Forgetta, V, Hsu, YH, Estrada Gil, 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, M, Ge, B, Chen, SH, Choi, K, Oei - Oei, L, Fraser, J, Kraaij, R, Hibbs, MA, Gregson, CL, Paquette, D, Hofman, B, Wibom, C, Tranah, GJ, Marshall, M, Gardiner, BB, Cremin, K, Auer, P, Hsu, L, Ring, S, Tung, JY, Thorleifsson, G, Enneman, A, Schoor, NM, de Groot, LCPGM, van der Velde, N, Melin, B, Kemp, JP, Christiansen, C, Sayers, A, Zhou, YH, Calderari, S, van Rooij, J, Carlson, C, Peters, U, Berlivet, S, Dostie, J, Uitterlinden, A, 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, Duijn, C, Karlsson, MK, Ljunggren, O, Svensson, O, Hallmans, G, Rousseau, F, Giroux, S, Bussiere, J, Arp, P, Koromani, F, Prince, RL, Lewis, JR, Langdahl, BL, Hermann, AP, Jensen, JEB, 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, Siggeirsdottir, K, Harris, TB, Zillikens, MC, van Meurs, J, Thorsteinsdottir, U, Maurano, MT, Timpson, NJ, Soranzo, N, Durbin, R, Wilson, S, 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-+. https://doi.org/10.1038/nature14878

TY - JOUR

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

AU - Zheng, HF

AU - Forgetta, V

AU - Hsu, YH

AU - Estrada Gil, Karol

AU - Rosello-Diez, A

AU - Leo, PJ

AU - Dahia, CL

AU - Park-Min, KH

AU - Tobias, JH

AU - Kooperberg, C

AU - Kleinman, A

AU - Styrkarsdottir, U

AU - Liu, CT

AU - Uggla, C

AU - Evans, DS

AU - Nielson, CM

AU - Walter, K

AU - Pettersson-Kymmer, U

AU - McCarthy, S

AU - Eriksson, J

AU - Kwan, T

AU - Jhamai, M

AU - Trajanoska, Katerina

AU - Memari, Y

AU - Min, J

AU - Huang, J

AU - Danecek, P

AU - Wilmot, B

AU - Li, R

AU - Chou, WC

AU - Mokry, LE

AU - Moayyeri, A

AU - Claussnitzer, M

AU - Cheng, CH

AU - Cheung, W

AU - Medina Gomez, Maria

AU - Ge, B

AU - Chen, SH

AU - Choi, K

AU - Oei - Oei, Ling

AU - Fraser, J

AU - Kraaij, Robert

AU - Hibbs, MA

AU - Gregson, CL

AU - Paquette, D

AU - Hofman, Bert

AU - Wibom, C

AU - Tranah, GJ

AU - Marshall, M

AU - Gardiner, BB

AU - Cremin, K

AU - Auer, P

AU - Hsu, L (Lily)

AU - Ring, S

AU - Tung, JY

AU - Thorleifsson, G

AU - Enneman, Anke

AU - Schoor, NM

AU - de Groot, LCPGM (Lisette)

AU - van der Velde, Nathalie

AU - Melin, B

AU - Kemp, JP

AU - Christiansen, C

AU - Sayers, A

AU - Zhou, YH

AU - Calderari, S

AU - van Rooij, J

AU - Carlson, C

AU - Peters, U

AU - Berlivet, S

AU - Dostie, J

AU - Uitterlinden, André

AU - Williams, SR

AU - Farber, C

AU - Grinberg, D

AU - Lacroix, AZ

AU - Haessler, J

AU - Chasman, DI

AU - Giulianini, F

AU - Rose, LM

AU - Ridker, PM

AU - Eisman, JA

AU - Nguyen, TV (Tuan)

AU - Center, JR

AU - Nogues, X

AU - Garcia-Giralt, N

AU - Launer, LL

AU - Gudnason, V

AU - Mellstrom, D

AU - Vandenput, L

AU - Amin, Najaf

AU - Duijn, Cornelia

AU - Karlsson, MK

AU - Ljunggren, O

AU - Svensson, O

AU - Hallmans, G

AU - Rousseau, F

AU - Giroux, S

AU - Bussiere, J

AU - Arp, Pascal

AU - Koromani, Fjorda

AU - Prince, RL

AU - Lewis, JR

AU - Langdahl, BL

AU - Hermann, AP

AU - Jensen, JEB

AU - Kaptoge, S

AU - Khaw, KT

AU - Reeve, J

AU - Formosa, MM

AU - Xuereb-Anastasi, A

AU - Akesson, K

AU - McGuigan, FE

AU - Garg, G

AU - Olmos, JM

AU - Zarrabeitia, MT

AU - Riancho, JA

AU - Ralston, SH

AU - Alonso, N

AU - Jiang, X

AU - Goltzman, D

AU - Pastinen, T

AU - Grundberg, E

AU - Gauguier, D

AU - Orwoll, ES

AU - Karasik, D

AU - Davey-Smith, G

AU - Smith, AV

AU - Siggeirsdottir, K

AU - Harris, TB

AU - Zillikens, M.C.

AU - van Meurs, Joyce

AU - Thorsteinsdottir, U

AU - Maurano, MT

AU - Timpson, NJ

AU - Soranzo, N

AU - Durbin, R

AU - Wilson, S

AU - Ntzani, EE

AU - Brown, MA

AU - Stefansson, K

AU - Hinds, DA

AU - Spector, T

AU - Cupples, LA

AU - Ohlsson, C

AU - Greenwood, CMT

AU - Jackson, RD

AU - Rowe, DW

AU - Loomis, CA

AU - Evans, DM

AU - Ackert-Bicknell, CL

AU - Joyner, AL

AU - Duncan, EL

AU - Kiel, DP

AU - Rivadeneira, Fernando

AU - Richards, JB

PY - 2015

Y1 - 2015

N2 - 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(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 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 BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1cre/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 +10.41 s.d., P-meta = 1 x 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 - 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(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 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 BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1cre/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 +10.41 s.d., P-meta = 1 x 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

SN - 0028-0836

VL - 526

SP - 112-+

JO - Nature

JF - Nature

IS - 7571

ER -