Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture
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
- Publication Type:
- Journal Article
- Citation:
- Nature, 2015, 526 (7571), pp. 112 - 117
- Issue Date:
- 2015-10-01
Closed Access
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ContentServer (59).pdf | Published Version | 9.49 MB | Adobe PDF |
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Full metadata record
Field | Value | Language |
---|---|---|
dc.contributor.author | Zheng, HF | en_US |
dc.contributor.author | Forgetta, V | en_US |
dc.contributor.author | Hsu, YH | en_US |
dc.contributor.author | Estrada, K | en_US |
dc.contributor.author | Rosello-Diez, A | en_US |
dc.contributor.author | Leo, PJ | en_US |
dc.contributor.author | Dahia, CL | en_US |
dc.contributor.author | Park-Min, KH | en_US |
dc.contributor.author | Tobias, JH | en_US |
dc.contributor.author | Kooperberg, C | en_US |
dc.contributor.author | Kleinman, A | en_US |
dc.contributor.author | Styrkarsdottir, U | en_US |
dc.contributor.author | Liu, CT | en_US |
dc.contributor.author | Uggla, C | en_US |
dc.contributor.author | Evans, DS | en_US |
dc.contributor.author | Nielson, CM | en_US |
dc.contributor.author | Walter, K | en_US |
dc.contributor.author | Pettersson-Kymmer, U | en_US |
dc.contributor.author | McCarthy, S | en_US |
dc.contributor.author | Eriksson, J | en_US |
dc.contributor.author | Kwan, T | en_US |
dc.contributor.author | Jhamai, M | en_US |
dc.contributor.author | Trajanoska, K | en_US |
dc.contributor.author | Memari, Y | en_US |
dc.contributor.author | Min, J | en_US |
dc.contributor.author | Huang, J | en_US |
dc.contributor.author | Danecek, P | en_US |
dc.contributor.author | Wilmot, B | en_US |
dc.contributor.author | Li, R | en_US |
dc.contributor.author | Chou, WC | en_US |
dc.contributor.author | Mokry, LE | en_US |
dc.contributor.author | Moayyeri, A | en_US |
dc.contributor.author | Claussnitzer, M | en_US |
dc.contributor.author | Cheng, CH | en_US |
dc.contributor.author | Cheung, W | en_US |
dc.contributor.author | Medina-Gómez, C | en_US |
dc.contributor.author | Ge, B | en_US |
dc.contributor.author | Chen, SH | en_US |
dc.contributor.author | Choi, K | en_US |
dc.contributor.author | Oei, L | en_US |
dc.contributor.author | Fraser, J | en_US |
dc.contributor.author | Kraaij, R | en_US |
dc.contributor.author | Hibbs, MA | en_US |
dc.contributor.author | Gregson, CL | en_US |
dc.contributor.author | Paquette, D | en_US |
dc.contributor.author | Hofman, A | en_US |
dc.contributor.author | Wibom, C | en_US |
dc.contributor.author | Tranah, GJ | en_US |
dc.contributor.author | Marshall, M | en_US |
dc.contributor.author | Gardiner, BB | en_US |
dc.contributor.author | Cremin, K | en_US |
dc.contributor.author | Auer, P | en_US |
dc.contributor.author | Hsu, L | en_US |
dc.contributor.author | Ring, S | en_US |
dc.contributor.author | Tung, JY | en_US |
dc.contributor.author | Thorleifsson, G | en_US |
dc.contributor.author | Enneman, AW | en_US |
dc.contributor.author | Van Schoor, NM | en_US |
dc.contributor.author | De Groot, LCPGM | en_US |
dc.contributor.author | Van Der Velde, N | en_US |
dc.contributor.author | Melin, B | en_US |
dc.contributor.author | Kemp, JP | en_US |
dc.contributor.author | Christiansen, C | en_US |
dc.contributor.author | Sayers, A | en_US |
dc.contributor.author | Zhou, Y | en_US |
dc.contributor.author | Calderari, S | en_US |
dc.contributor.author | Van Rooij, J | en_US |
dc.contributor.author | Carlson, C | en_US |
dc.contributor.author | Peters, U | en_US |
dc.contributor.author | Berlivet, S | en_US |
dc.contributor.author | Dostie, J | en_US |
dc.contributor.author | Uitterlinden, AG | en_US |
dc.contributor.author | Williams, SR | en_US |
dc.contributor.author | Farber, C | en_US |
dc.contributor.author | Grinberg, D | en_US |
dc.contributor.author | LaCroix, AZ | en_US |
dc.contributor.author | Haessler, J | en_US |
dc.contributor.author | Chasman, DI | en_US |
dc.contributor.author | Giulianini, F | en_US |
dc.contributor.author | Rose, LM | en_US |
dc.contributor.author | Ridker, PM | en_US |
dc.contributor.author | Eisman, JA | en_US |
dc.contributor.author |
Nguyen, TV |
en_US |
dc.contributor.author | Center, JR | en_US |
dc.contributor.author | Nogues, X | en_US |
dc.contributor.author | Garcia-Giralt, N | en_US |
dc.contributor.author | Launer, LL | en_US |
dc.contributor.author | Gudnason, V | en_US |
dc.contributor.author | Mellström, D | en_US |
dc.contributor.author | Vandenput, L | en_US |
dc.contributor.author | Amin, N | en_US |
dc.contributor.author | Van Duijn, CM | en_US |
dc.contributor.author | Karlsson, MK | en_US |
dc.contributor.author | Ljunggren, Ö | en_US |
dc.contributor.author | Svensson, O | en_US |
dc.contributor.author | Hallmans, G | en_US |
dc.contributor.author | Rousseau, F | en_US |
dc.contributor.author | Giroux, S | en_US |
dc.contributor.author | Bussière, J | en_US |
dc.contributor.author | Arp, PP | en_US |
dc.date.available | 2015-06-30 | en_US |
dc.date.issued | 2015-10-01 | en_US |
dc.identifier.citation | Nature, 2015, 526 (7571), pp. 112 - 117 | en_US |
dc.identifier.issn | 0028-0836 | en_US |
dc.identifier.uri | http://hdl.handle.net/10453/119115 | |
dc.description.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. | en_US |
dc.relation.ispartof | Nature | en_US |
dc.relation.isbasedon | 10.1038/nature14878 | en_US |
dc.rights | info:eu-repo/semantics/closedAccess | |
dc.subject.classification | General Science & Technology | en_US |
dc.subject.mesh | Bone and Bones | en_US |
dc.subject.mesh | Animals | en_US |
dc.subject.mesh | Humans | en_US |
dc.subject.mesh | Mice | en_US |
dc.subject.mesh | Disease Models, Animal | en_US |
dc.subject.mesh | Genetic Predisposition to Disease | en_US |
dc.subject.mesh | Homeodomain Proteins | en_US |
dc.subject.mesh | Sequence Analysis, DNA | en_US |
dc.subject.mesh | Genomics | en_US |
dc.subject.mesh | Bone Density | en_US |
dc.subject.mesh | Gene Frequency | en_US |
dc.subject.mesh | Genotype | en_US |
dc.subject.mesh | Genome, Human | en_US |
dc.subject.mesh | European Continental Ancestry Group | en_US |
dc.subject.mesh | Europe | en_US |
dc.subject.mesh | Female | en_US |
dc.subject.mesh | Fractures, Bone | en_US |
dc.subject.mesh | Wnt Proteins | en_US |
dc.subject.mesh | Genetic Variation | en_US |
dc.subject.mesh | Exome | en_US |
dc.title | Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture | en_US |
dc.type | Journal Article | |
utslib.citation.volume | 7571 | en_US |
utslib.citation.volume | 526 | en_US |
utslib.for | 0903 Biomedical Engineering | en_US |
utslib.for | 0604 Genetics | en_US |
pubs.embargo.period | Not known | en_US |
pubs.organisational-group | /University of Technology Sydney | |
pubs.organisational-group | /University of Technology Sydney/Faculty of Engineering and Information Technology | |
pubs.organisational-group | /University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering | |
pubs.organisational-group | /University of Technology Sydney/Strength - CHT - Health Technologies | |
utslib.copyright.status | closed_access | * |
pubs.issue | 7571 | en_US |
pubs.publication-status | Published | en_US |
pubs.volume | 526 | en_US |
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.
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