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 M., 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-Gomez, 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, Josee, 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, Mellstrom, Dan, Vandenput, Liesbeth, Amin, Najaf, Van Duijn, Cornelia M., Karlsson, Magnus K., Ljunggren, Osten, Svensson, Olle, Hallmans, Goran, Rousseau, François, Giroux, Sylvie, Bussiere, 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, Akesson, 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 S., 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, AOGC Consortium and UK10K Consortium (2015) Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature, 526 7571: 112-117. doi:10.1038/nature14878


 
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Author 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 M.
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-Gomez, 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, Josee
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
Mellstrom, Dan
Vandenput, Liesbeth
Amin, Najaf
Van Duijn, Cornelia M.
Karlsson, Magnus K.
Ljunggren, Osten
Svensson, Olle
Hallmans, Goran
Rousseau, François
Giroux, Sylvie
Bussiere, 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
Akesson, 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 S.
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
AOGC Consortium
UK10K Consortium
Title Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture
Journal name Nature   Check publisher's open access policy
ISSN 1476-4687
0028-0836
Publication date 2015-10-01
Year available 2015
Sub-type Article (original research)
DOI 10.1038/nature14878
Open Access Status Not Open Access
Volume 526
Issue 7571
Start page 112
End page 117
Total pages 6
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Subject 1000 General
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 ncontrols = 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.
Formatted 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 variants1-8, as well as rare, population‐specific, coding variants9. 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 BMD8 (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 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 = +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.
Keyword Multidisciplinary Sciences
Science & Technology - Other Topics
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID R00 AR061430
MC_UU_12013/3
P30 CA015704
R01 AR035583
RG/08/014/24067
G1000143
MR/L003120/1
R01 AG027576
U01 AR045614
102215
U01 AR045654
P30 CA008748
119462-1
R01 AG005407
MC_PC_15018
G0401527
MC_UU_12013/1
U01 AR045583
U01 AG042140
MC_UU_12013/4
UM1 CA182913
K01 AR062655
U01 AR045647
RC2 AR058973
S10 OD020069
R01 AR035582
P30 AR057235
R01 AG005394
R01 AR063702
20000
U01 AG042143
U01 AR045580
R01 AG027574
U01 AG018197
U01 AR066160
U01 AR045632
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Medicine Publications
UQ Diamantina Institute Publications
 
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