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 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, Fjorda Koromani, Richard L. Prince, Joshua R. Lewis, Bente L. Langdahl, A. Pernille Hermann, Jens Erik B Jensen, Stephen Kaptoge, Kay Tee Khaw, Jonathan Reeve, Melissa M. Formosa, Angela Xuereb-Anastasi, Kristina Åkesson, Fiona E. McGuigan, Gaurav Garg, Jose M. Olmos, Maria T. Zarrabeitia, Jose A. Riancho, Stuart H. Ralston, Nerea Alonso, Xi Jiang, David Goltzman, Tomi Pastinen, Elin Grundberg, Dominique Gauguier, Eric Orwoll, David Karasik, George Davey-Smith, Albert V. Smith, Kristin Siggeirsdottir, Tamara B. Harris, M. Carola Zillikens, Joyce B J Van Meurs, Unnur Thorsteinsdottir, Matthew T. Maurano, Nicholas J. Timpson, Nicole Soranzo, Richard Durbin, Scott G. Wilson, Evangelia E. Ntzani, Matthew A. Brown, Kari Stefansson, David A. Hinds, Tim Spector, L. Adrienne Cupples, Claes Ohlsson, Celia M T Greenwood, Rebecca D. Jackson, David W. Rowe, Cynthia A. Loomis, David M. Evans, Cheryl L. Ackert-Bicknell, Alexandra L. Joyner, Emma L. Duncan, Douglas P. Kiel, Fernando Rivadeneira, J. Brent Richards

Research output: Contribution to journalArticle

187 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, 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 (US)
Pages (from-to)112-117
Number of pages6
JournalNature
Volume526
Issue number7571
DOIs
StatePublished - Oct 1 2015

Fingerprint

Bone Fractures
Bone Density
Genome
Gene Frequency
Population
Exome
Osteoporotic Fractures
Bone Remodeling
Spine
Odds Ratio
Bone and Bones

ASJC Scopus subject areas

  • General

Cite this

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

Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. / Zheng, Hou Feng; Forgetta, Vincenzo; Hsu, Yi Hsiang; Estrada, Karol; Rosello-Diez, Alberto; Leo, Paul J.; Dahia, Chitra L.; Park-Min, Kyung Hyun; Tobias, Jonathan H.; Kooperberg, Charles; Kleinman, Aaron; Styrkarsdottir, Unnur; Liu, Ching Ti; Uggla, Charlotta; Evans, Daniel S.; Nielson, Carrie; Walter, Klaudia; Pettersson-Kymmer, Ulrika; McCarthy, Shane; Eriksson, Joel; Kwan, Tony; Jhamai, Mila; Trajanoska, Katerina; Memari, Yasin; Min, Josine; Huang, Jie; Danecek, Petr; Wilmot, Beth; Li, Rui; Chou, Wen Chi; Mokry, Lauren E.; Moayyeri, Alireza; Claussnitzer, Melina; Cheng, Chia Ho; Cheung, Warren; Medina-Gómez, Carolina; Ge, Bing; Chen, Shu Huang; Choi, Kwangbom; Oei, Ling; Fraser, James; Kraaij, Robert; Hibbs, Matthew A.; Gregson, Celia L.; Paquette, Denis; Hofman, Albert; Wibom, Carl; Tranah, Gregory J.; Marshall, Mhairi; Gardiner, Brooke B.; Cremin, Katie; Auer, Paul; Hsu, Li; Ring, Sue; Tung, Joyce Y.; Thorleifsson, Gudmar; Enneman, Anke W.; Van Schoor, Natasja M.; De Groot, Lisette C P G M; Van Der Velde, Nathalie; Melin, Beatrice; Kemp, John P.; Christiansen, Claus; Sayers, Adrian; Zhou, Yanhua; Calderari, Sophie; Van Rooij, Jeroen; Carlson, Chris; Peters, Ulrike; Berlivet, Soizik; Dostie, Josée; Uitterlinden, Andre G.; Williams, Stephen R.; Farber, Charles; Grinberg, Daniel; LaCroix, Andrea Z.; Haessler, Jeff; Chasman, Daniel I.; Giulianini, Franco; Rose, Lynda M.; Ridker, Paul M.; Eisman, John A.; Nguyen, Tuan V.; Center, Jacqueline R.; Nogues, Xavier; Garcia-Giralt, Natalia; Launer, Lenore L.; Gudnason, Vilmunder; Mellström, Dan; Vandenput, Liesbeth; Amin, Najaf; Van Duijn, Cornelia M.; Karlsson, Magnus K.; Ljunggren, Östen; Svensson, Olle; Hallmans, Göran; Rousseau, Francois; Giroux, Sylvie; Bussière, Johanne; Arp, Pascal P.; Koromani, Fjorda; Prince, Richard L.; Lewis, Joshua R.; Langdahl, Bente L.; Hermann, A. Pernille; Jensen, Jens Erik B; Kaptoge, Stephen; Khaw, Kay Tee; Reeve, Jonathan; Formosa, Melissa M.; Xuereb-Anastasi, Angela; Åkesson, Kristina; McGuigan, Fiona E.; Garg, Gaurav; Olmos, Jose M.; Zarrabeitia, Maria T.; Riancho, Jose A.; Ralston, Stuart H.; Alonso, Nerea; Jiang, Xi; Goltzman, David; Pastinen, Tomi; Grundberg, Elin; Gauguier, Dominique; Orwoll, Eric; Karasik, David; Davey-Smith, George; Smith, Albert V.; Siggeirsdottir, Kristin; Harris, Tamara B.; Zillikens, M. Carola; Van Meurs, Joyce B J; Thorsteinsdottir, Unnur; Maurano, Matthew T.; Timpson, Nicholas J.; Soranzo, Nicole; Durbin, Richard; Wilson, Scott G.; Ntzani, Evangelia E.; Brown, Matthew A.; Stefansson, Kari; Hinds, David A.; Spector, Tim; Cupples, L. Adrienne; Ohlsson, Claes; Greenwood, Celia M T; Jackson, Rebecca D.; Rowe, David W.; Loomis, Cynthia A.; Evans, David M.; Ackert-Bicknell, Cheryl L.; Joyner, Alexandra L.; Duncan, Emma L.; Kiel, Douglas P.; Rivadeneira, Fernando; Richards, J. Brent.

In: Nature, Vol. 526, No. 7571, 01.10.2015, p. 112-117.

Research output: Contribution to journalArticle

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, C, 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, Koromani, F, Prince, RL, Lewis, JR, Langdahl, BL, Hermann, AP, Jensen, JEB, Kaptoge, S, Khaw, KT, 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, E, 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
Zheng HF, Forgetta V, Hsu YH, Estrada K, Rosello-Diez A, Leo PJ et al. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature. 2015 Oct 1;526(7571):112-117. https://doi.org/10.1038/nature14878
Zheng, Hou Feng ; Forgetta, Vincenzo ; Hsu, Yi Hsiang ; Estrada, Karol ; Rosello-Diez, Alberto ; Leo, Paul J. ; Dahia, Chitra L. ; Park-Min, Kyung Hyun ; Tobias, Jonathan H. ; Kooperberg, Charles ; Kleinman, Aaron ; Styrkarsdottir, Unnur ; Liu, Ching Ti ; Uggla, Charlotta ; Evans, Daniel S. ; Nielson, Carrie ; Walter, Klaudia ; Pettersson-Kymmer, Ulrika ; McCarthy, Shane ; Eriksson, Joel ; Kwan, Tony ; Jhamai, Mila ; Trajanoska, Katerina ; Memari, Yasin ; Min, Josine ; Huang, Jie ; Danecek, Petr ; Wilmot, Beth ; Li, Rui ; Chou, Wen Chi ; Mokry, Lauren E. ; Moayyeri, Alireza ; Claussnitzer, Melina ; Cheng, Chia Ho ; Cheung, Warren ; Medina-Gómez, Carolina ; Ge, Bing ; Chen, Shu Huang ; Choi, Kwangbom ; Oei, Ling ; Fraser, James ; Kraaij, Robert ; Hibbs, Matthew A. ; Gregson, Celia L. ; Paquette, Denis ; Hofman, Albert ; Wibom, Carl ; Tranah, Gregory J. ; Marshall, Mhairi ; Gardiner, Brooke B. ; Cremin, Katie ; Auer, Paul ; Hsu, Li ; Ring, Sue ; Tung, Joyce Y. ; Thorleifsson, Gudmar ; Enneman, Anke W. ; Van Schoor, Natasja M. ; De Groot, Lisette C P G M ; Van Der Velde, Nathalie ; Melin, Beatrice ; Kemp, John P. ; Christiansen, Claus ; Sayers, Adrian ; Zhou, Yanhua ; Calderari, Sophie ; Van Rooij, Jeroen ; Carlson, Chris ; Peters, Ulrike ; Berlivet, Soizik ; Dostie, Josée ; Uitterlinden, Andre G. ; Williams, Stephen R. ; Farber, Charles ; Grinberg, Daniel ; LaCroix, Andrea Z. ; Haessler, Jeff ; Chasman, Daniel I. ; Giulianini, Franco ; Rose, Lynda M. ; Ridker, Paul M. ; Eisman, John A. ; Nguyen, Tuan V. ; Center, Jacqueline R. ; Nogues, Xavier ; Garcia-Giralt, Natalia ; Launer, Lenore L. ; Gudnason, Vilmunder ; Mellström, Dan ; Vandenput, Liesbeth ; Amin, Najaf ; Van Duijn, Cornelia M. ; Karlsson, Magnus K. ; Ljunggren, Östen ; Svensson, Olle ; Hallmans, Göran ; Rousseau, Francois ; Giroux, Sylvie ; Bussière, Johanne ; Arp, Pascal P. ; Koromani, Fjorda ; Prince, Richard L. ; Lewis, Joshua R. ; Langdahl, Bente L. ; Hermann, A. Pernille ; Jensen, Jens Erik B ; Kaptoge, Stephen ; Khaw, Kay Tee ; Reeve, Jonathan ; Formosa, Melissa M. ; Xuereb-Anastasi, Angela ; Åkesson, Kristina ; McGuigan, Fiona E. ; Garg, Gaurav ; Olmos, Jose M. ; Zarrabeitia, Maria T. ; Riancho, Jose A. ; Ralston, Stuart H. ; Alonso, Nerea ; Jiang, Xi ; Goltzman, David ; Pastinen, Tomi ; Grundberg, Elin ; Gauguier, Dominique ; Orwoll, Eric ; Karasik, David ; Davey-Smith, George ; Smith, Albert V. ; Siggeirsdottir, Kristin ; Harris, Tamara B. ; Zillikens, M. Carola ; Van Meurs, Joyce B J ; Thorsteinsdottir, Unnur ; Maurano, Matthew T. ; Timpson, Nicholas J. ; Soranzo, Nicole ; Durbin, Richard ; Wilson, Scott G. ; Ntzani, Evangelia E. ; Brown, Matthew A. ; Stefansson, Kari ; Hinds, David A. ; Spector, Tim ; Cupples, L. Adrienne ; Ohlsson, Claes ; Greenwood, Celia M T ; Jackson, Rebecca D. ; Rowe, David W. ; Loomis, Cynthia A. ; Evans, David M. ; Ackert-Bicknell, Cheryl L. ; Joyner, Alexandra L. ; Duncan, Emma L. ; Kiel, Douglas P. ; Rivadeneira, Fernando ; Richards, J. Brent. / Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. In: Nature. 2015 ; Vol. 526, No. 7571. pp. 112-117.
@article{49a0e3ab570648f8b894a260f38f2f0d,
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, 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 Carrie Nielson 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.} and Fjorda Koromani and Prince, {Richard L.} and Lewis, {Joshua R.} and Langdahl, {Bente L.} and Hermann, {A. Pernille} and Jensen, {Jens Erik B} and Stephen Kaptoge and Khaw, {Kay Tee} and Jonathan Reeve and Formosa, {Melissa M.} and Angela Xuereb-Anastasi and Kristina {\AA}kesson and McGuigan, {Fiona E.} and Gaurav Garg and Olmos, {Jose M.} and Zarrabeitia, {Maria T.} and Riancho, {Jose A.} and Ralston, {Stuart H.} and Nerea Alonso and Xi Jiang and David Goltzman and Tomi Pastinen and Elin Grundberg and Dominique Gauguier and Eric Orwoll and David Karasik and George Davey-Smith and Smith, {Albert V.} and Kristin Siggeirsdottir and Harris, {Tamara B.} and Zillikens, {M. Carola} and {Van Meurs}, {Joyce B J} and Unnur Thorsteinsdottir and Maurano, {Matthew T.} and Timpson, {Nicholas J.} and Nicole Soranzo and Richard Durbin and Wilson, {Scott G.} and Ntzani, {Evangelia E.} and Brown, {Matthew A.} and Kari Stefansson and Hinds, {David A.} and Tim Spector and Cupples, {L. Adrienne} and Claes Ohlsson and Greenwood, {Celia M T} and Jackson, {Rebecca D.} and Rowe, {David W.} and Loomis, {Cynthia A.} and Evans, {David M.} and Ackert-Bicknell, {Cheryl L.} and Joyner, {Alexandra L.} and Duncan, {Emma L.} and Kiel, {Douglas P.} and Fernando Rivadeneira and Richards, {J. Brent}",
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language = "English (US)",
volume = "526",
pages = "112--117",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
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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

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.

AU - Koromani, Fjorda

AU - Prince, Richard L.

AU - Lewis, Joshua R.

AU - Langdahl, Bente L.

AU - Hermann, A. Pernille

AU - Jensen, Jens Erik B

AU - Kaptoge, Stephen

AU - Khaw, Kay Tee

AU - Reeve, Jonathan

AU - Formosa, Melissa M.

AU - Xuereb-Anastasi, Angela

AU - Åkesson, Kristina

AU - McGuigan, Fiona E.

AU - Garg, Gaurav

AU - Olmos, Jose M.

AU - Zarrabeitia, Maria T.

AU - Riancho, Jose A.

AU - Ralston, Stuart H.

AU - Alonso, Nerea

AU - Jiang, Xi

AU - Goltzman, David

AU - Pastinen, Tomi

AU - Grundberg, Elin

AU - Gauguier, Dominique

AU - Orwoll, Eric

AU - Karasik, David

AU - Davey-Smith, George

AU - Smith, Albert V.

AU - Siggeirsdottir, Kristin

AU - Harris, Tamara B.

AU - Zillikens, M. Carola

AU - Van Meurs, Joyce B J

AU - Thorsteinsdottir, Unnur

AU - Maurano, Matthew T.

AU - Timpson, Nicholas J.

AU - Soranzo, Nicole

AU - Durbin, Richard

AU - Wilson, Scott G.

AU - Ntzani, Evangelia E.

AU - Brown, Matthew A.

AU - Stefansson, Kari

AU - Hinds, David A.

AU - Spector, Tim

AU - Cupples, L. Adrienne

AU - Ohlsson, Claes

AU - Greenwood, Celia M T

AU - Jackson, Rebecca D.

AU - Rowe, David W.

AU - Loomis, Cynthia A.

AU - Evans, David M.

AU - Ackert-Bicknell, Cheryl L.

AU - Joyner, Alexandra L.

AU - Duncan, Emma L.

AU - Kiel, Douglas P.

AU - Rivadeneira, Fernando

AU - Richards, J. Brent

PY - 2015/10/1

Y1 - 2015/10/1

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, 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 - 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.

UR - http://www.scopus.com/inward/record.url?scp=84943191109&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84943191109&partnerID=8YFLogxK

U2 - 10.1038/nature14878

DO - 10.1038/nature14878

M3 - Article

C2 - 26367794

AN - SCOPUS:84943191109

VL - 526

SP - 112

EP - 117

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7571

ER -