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

Hou Feng Zheng; Vincenzo Forgetta; Yi Hsiang Hsu; Karol Estrada; Alberto Rosello-Diez; Paul J. Leo; Chitra L. Dahia; Kyung Hyun Park-Min; Jonathan H. Tobias; Charles Kooperberg; Aaron Kleinman; Unnur Styrkarsdottir; Ching Ti Liu; Charlotta Uggla; Daniel S. Evans; Carrie M. Nielson; Klaudia Walter; Ulrika Pettersson-Kymmer; Shane McCarthy; Joel Eriksson; Tony Kwan; Mila Jhamai; Katerina Trajanoska; Yasin Memari; Josine Min; Jie Huang; Petr Danecek; Beth Wilmot; Rui Li; Wen Chi Chou; Lauren E. Mokry; Alireza Moayyeri; Melina Claussnitzer; Chia Ho Cheng; Warren Cheung; Carolina Medina-Gómez; Bing Ge; Shu Huang Chen; Kwangbom Choi; Ling Oei; James Fraser; Robert Kraaij; Matthew A. Hibbs; Celia L. Gregson; Denis Paquette; Albert Hofman; Carl Wibom; Gregory J. Tranah; Mhairi Marshall; Brooke B. Gardiner; Katie Cremin; Paul Auer; Li Hsu; Sue Ring; Joyce Y. Tung; Gudmar Thorleifsson; Anke W. Enneman; Natasja M. Van Schoor; Lisette C.P.G.M. De Groot; Nathalie Van Der Velde; Beatrice Melin; John P. Kemp; Claus Christiansen; Adrian Sayers; Yanhua Zhou; Sophie Calderari; Jeroen Van Rooij; Chris Carlson; Ulrike Peters; Soizik Berlivet; Josée Dostie; Andre G. Uitterlinden; Stephen R. Williams; Charles Farber; Daniel Grinberg; Andrea Z. LaCroix; Jeff Haessler; Daniel I. Chasman; Franco Giulianini; Lynda M. Rose; Paul M. Ridker; John A. Eisman; Tuan V. Nguyen; Jacqueline R. Center; Xavier Nogues; Natalia Garcia-Giralt; Lenore L. Launer; Vilmunder Gudnason; Dan Mellström; Liesbeth Vandenput; Najaf Amin; Cornelia M. Van Duijn; Magnus K. Karlsson; Östen Ljunggren; Olle Svensson; Göran Hallmans; Francois Rousseau; Sylvie Giroux; Johanne Bussière; Pascal P. Arp

doi:10.1038/nature14878

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

Hou Feng Zheng, Vincenzo Forgetta, Yi Hsiang Hsu, Karol Estrada, Alberto Rosello-Diez, Paul J. Leo, Chitra L. Dahia, Kyung Hyun Park-Min, Jonathan H. Tobias, Charles Kooperberg, Aaron Kleinman, Unnur Styrkarsdottir, Ching Ti Liu, Charlotta Uggla, Daniel S. Evans, Carrie M. Nielson, Klaudia Walter, Ulrika Pettersson-Kymmer, Shane McCarthy, Joel ErikssonTony Kwan, Mila Jhamai, Katerina Trajanoska, Yasin Memari, Josine Min, Jie Huang, Petr Danecek, Beth Wilmot, Rui Li, Wen Chi Chou, Lauren E. Mokry, Alireza Moayyeri, Melina Claussnitzer, Chia Ho Cheng, Warren Cheung, Carolina Medina-Gómez, Bing Ge, Shu Huang Chen, Kwangbom Choi, Ling Oei, James Fraser, Robert Kraaij, Matthew A. Hibbs, Celia L. Gregson, Denis Paquette, Albert Hofman, Carl Wibom, Gregory J. Tranah, Mhairi Marshall, Brooke B. Gardiner, Katie Cremin, Paul Auer, Li Hsu, Sue Ring, Joyce Y. Tung, Gudmar Thorleifsson, Anke W. Enneman, Natasja M. Van Schoor, Lisette C.P.G.M. De Groot, Nathalie Van Der Velde, Beatrice Melin, John P. Kemp, Claus Christiansen, Adrian Sayers, Yanhua Zhou, Sophie Calderari, Jeroen Van Rooij, Chris Carlson, Ulrike Peters, Soizik Berlivet, Josée Dostie, Andre G. Uitterlinden, Stephen R. Williams, Charles Farber, Daniel Grinberg, Andrea Z. LaCroix, Jeff Haessler, Daniel I. Chasman, Franco Giulianini, Lynda M. Rose, Paul M. Ridker, John A. Eisman, Tuan V. Nguyen, Jacqueline R. Center, Xavier Nogues, Natalia Garcia-Giralt, Lenore L. Launer, Vilmunder Gudnason, Dan Mellström, Liesbeth Vandenput, Najaf Amin, Cornelia M. Van Duijn, Magnus K. Karlsson, Östen Ljunggren, Olle Svensson, Göran Hallmans, Francois Rousseau, Sylvie Giroux, Johanne Bussière, Pascal P. Arp

Department of Medicine

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

481 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 language	English
Pages (from-to)	112-117
Journal	Nature
Volume	526
DOIs	https://doi.org/10.1038/nature14878
Publication status	Published - 1 Oct 2015

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10.1038/nature14878

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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., ... Arp, P. P. (2015). Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature, 526, 112-117. https://doi.org/10.1038/nature14878

@article{912c063dd28945088d6cfb464a5ec73e,

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

abstract = "{\textcopyright} 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 = "Zheng, {Hou Feng} and Vincenzo Forgetta and Hsu, {Yi Hsiang} and Karol Estrada and Alberto Rosello-Diez and Leo, {Paul J.} and Dahia, {Chitra L.} and Park-Min, {Kyung Hyun} and Tobias, {Jonathan H.} and Charles Kooperberg and Aaron Kleinman and Unnur Styrkarsdottir and Liu, {Ching Ti} and Charlotta Uggla and Evans, {Daniel S.} and Nielson, {Carrie M.} and Klaudia Walter and Ulrika Pettersson-Kymmer and Shane McCarthy and Joel Eriksson and Tony Kwan and Mila Jhamai and Katerina Trajanoska and Yasin Memari and Josine Min and Jie Huang and Petr Danecek and Beth Wilmot and Rui Li and Chou, {Wen Chi} and Mokry, {Lauren E.} and Alireza Moayyeri and Melina Claussnitzer and Cheng, {Chia Ho} and Warren Cheung and Carolina Medina-G{\'o}mez and Bing Ge and Chen, {Shu Huang} and Kwangbom Choi and Ling Oei and James Fraser and Robert Kraaij and Hibbs, {Matthew A.} and Gregson, {Celia L.} and Denis Paquette and Albert Hofman and Carl Wibom and Tranah, {Gregory J.} and Mhairi Marshall and Gardiner, {Brooke B.} and Katie Cremin and Paul Auer and Li Hsu and Sue Ring and Tung, {Joyce Y.} and Gudmar Thorleifsson and Enneman, {Anke W.} and {Van Schoor}, {Natasja M.} and {De Groot}, {Lisette C.P.G.M.} and {Van Der Velde}, Nathalie and Beatrice Melin and Kemp, {John P.} and Claus Christiansen and Adrian Sayers and Yanhua Zhou and Sophie Calderari and {Van Rooij}, Jeroen and Chris Carlson and Ulrike Peters and Soizik Berlivet and Jos{\'e}e Dostie and Uitterlinden, {Andre G.} and Williams, {Stephen R.} and Charles Farber and Daniel Grinberg and LaCroix, {Andrea Z.} and Jeff Haessler and Chasman, {Daniel I.} and Franco Giulianini and Rose, {Lynda M.} and Ridker, {Paul M.} and Eisman, {John A.} and Nguyen, {Tuan V.} and Center, {Jacqueline R.} and Xavier Nogues and Natalia Garcia-Giralt and Launer, {Lenore L.} and Vilmunder Gudnason and Dan Mellstr{\"o}m and Liesbeth Vandenput and Najaf Amin and {Van Duijn}, {Cornelia M.} and Karlsson, {Magnus K.} and {\"O}sten Ljunggren and Olle Svensson and G{\"o}ran Hallmans and Francois Rousseau and Sylvie Giroux and Johanne Bussi{\`e}re and Arp, {Pascal P.}",

year = "2015",

month = oct,

day = "1",

doi = "10.1038/nature14878",

language = "English",

volume = "526",

pages = "112--117",

}

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-Gómez, 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, 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, Ö, Svensson, O, Hallmans, G, Rousseau, F, Giroux, S, Bussière, J & Arp, PP 2015, 'Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture', Nature, vol. 526, pp. 112-117. https://doi.org/10.1038/nature14878

TY - JOUR

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

AU - Zheng, Hou Feng

AU - Forgetta, Vincenzo

AU - Hsu, Yi Hsiang

AU - Estrada, Karol

AU - Rosello-Diez, Alberto

AU - Leo, Paul J.

AU - Dahia, Chitra L.

AU - Park-Min, Kyung Hyun

AU - Tobias, Jonathan H.

AU - Kooperberg, Charles

AU - Kleinman, Aaron

AU - Styrkarsdottir, Unnur

AU - Liu, Ching Ti

AU - Uggla, Charlotta

AU - Evans, Daniel S.

AU - Nielson, Carrie M.

AU - Walter, Klaudia

AU - Pettersson-Kymmer, Ulrika

AU - McCarthy, Shane

AU - Eriksson, Joel

AU - Kwan, Tony

AU - Jhamai, Mila

AU - Trajanoska, Katerina

AU - Memari, Yasin

AU - Min, Josine

AU - Huang, Jie

AU - Danecek, Petr

AU - Wilmot, Beth

AU - Li, Rui

AU - Chou, Wen Chi

AU - Mokry, Lauren E.

AU - Moayyeri, Alireza

AU - Claussnitzer, Melina

AU - Cheng, Chia Ho

AU - Cheung, Warren

AU - Medina-Gómez, Carolina

AU - Ge, Bing

AU - Chen, Shu Huang

AU - Choi, Kwangbom

AU - Oei, Ling

AU - Fraser, James

AU - Kraaij, Robert

AU - Hibbs, Matthew A.

AU - Gregson, Celia L.

AU - Paquette, Denis

AU - Hofman, Albert

AU - Wibom, Carl

AU - Tranah, Gregory J.

AU - Marshall, Mhairi

AU - Gardiner, Brooke B.

AU - Cremin, Katie

AU - Auer, Paul

AU - Hsu, Li

AU - Ring, Sue

AU - Tung, Joyce Y.

AU - Thorleifsson, Gudmar

AU - Enneman, Anke W.

AU - Van Schoor, Natasja M.

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

AU - Van Der Velde, Nathalie

AU - Melin, Beatrice

AU - Kemp, John P.

AU - Christiansen, Claus

AU - Sayers, Adrian

AU - Zhou, Yanhua

AU - Calderari, Sophie

AU - Van Rooij, Jeroen

AU - Carlson, Chris

AU - Peters, Ulrike

AU - Berlivet, Soizik

AU - Dostie, Josée

AU - Uitterlinden, Andre G.

AU - Williams, Stephen R.

AU - Farber, Charles

AU - Grinberg, Daniel

AU - LaCroix, Andrea Z.

AU - Haessler, Jeff

AU - Chasman, Daniel I.

AU - Giulianini, Franco

AU - Rose, Lynda M.

AU - Ridker, Paul M.

AU - Eisman, John A.

AU - Nguyen, Tuan V.

AU - Center, Jacqueline R.

AU - Nogues, Xavier

AU - Garcia-Giralt, Natalia

AU - Launer, Lenore L.

AU - Gudnason, Vilmunder

AU - Mellström, Dan

AU - Vandenput, Liesbeth

AU - Amin, Najaf

AU - Van Duijn, Cornelia M.

AU - Karlsson, Magnus K.

AU - Ljunggren, Östen

AU - Svensson, Olle

AU - Hallmans, Göran

AU - Rousseau, Francois

AU - Giroux, Sylvie

AU - Bussière, Johanne

AU - Arp, Pascal P.

PY - 2015/10/1

Y1 - 2015/10/1

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

SN - 0028-0836

VL - 526

SP - 112

EP - 117

JO - Nature

JF - Nature

ER -

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

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