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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 and Kooperberg, Charles , et al. (2015) In Nature 526(7571). p.112-117
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),... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature
volume
526
issue
7571
pages
112 - 117
publisher
Nature Publishing Group
external identifiers
  • pmid:26367794
  • wos:000362095100044
  • scopus:84943191109
  • pmid:26367794
ISSN
0028-0836
DOI
10.1038/nature14878
language
English
LU publication?
yes
id
02c32828-4f0a-48a0-b047-d9e47bace05c (old id 8042189)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26367794?dopt=Abstract
date added to LUP
2016-04-01 10:08:09
date last changed
2025-04-04 14:37:08
@article{02c32828-4f0a-48a0-b047-d9e47bace05c,
  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.}},
  author       = {{Zheng, Hou-Feng and Forgetta, Vincenzo and Hsu, Yi-Hsiang and Estrada, Karol and Rosello-Diez, Alberto and Leo, Paul J and Dahia, Chitra L and Park-Min, Kyung Hyun and Tobias, Jonathan H and Kooperberg, Charles and Kleinman, Aaron and Styrkarsdottir, Unnur and Liu, Ching-Ti and Uggla, Charlotta and Evans, Daniel S and Nielson, Carrie M and Walter, Klaudia and Pettersson-Kymmer, Ulrika and McCarthy, Shane and Eriksson, Joel and Kwan, Tony and Jhamai, Mila and Trajanoska, Katerina and Memari, Yasin and Min, Josine and Huang, Jie and Danecek, Petr and Wilmot, Beth and Li, Rui and Chou, Wen-Chi and Mokry, Lauren E and Moayyeri, Alireza and Claussnitzer, Melina and Cheng, Chia-Ho and Cheung, Warren and Medina-Gómez, Carolina and Ge, Bing and Chen, Shu-Huang and Choi, Kwangbom and Oei, Ling and Fraser, James and Kraaij, Robert and Hibbs, Matthew A and Gregson, Celia L and Paquette, Denis and Hofman, Albert and Wibom, Carl and Tranah, Gregory J and Marshall, Mhairi and Gardiner, Brooke B and Cremin, Katie and Auer, Paul and Hsu, Li and Ring, Sue and Tung, Joyce Y and Thorleifsson, Gudmar and Enneman, Anke W and van Schoor, Natasja M and de Groot, Lisette C P G M and van der Velde, Nathalie and Melin, Beatrice and Kemp, John P and Christiansen, Claus and Sayers, Adrian and Zhou, Yanhua and Calderari, Sophie and van Rooij, Jeroen and Carlson, Chris and Peters, Ulrike and Berlivet, Soizik and Dostie, Josée and Uitterlinden, Andre G and Williams, Stephen R and Farber, Charles and Grinberg, Daniel and LaCroix, Andrea Z and Haessler, Jeff and Chasman, Daniel I and Giulianini, Franco and Rose, Lynda M and Ridker, Paul M and Eisman, John A and Nguyen, Tuan V and Center, Jacqueline R and Nogues, Xavier and Garcia-Giralt, Natalia and Launer, Lenore L and Gudnason, Vilmunder and Mellström, Dan and Vandenput, Liesbeth and Amin, Najaf and van Duijn, Cornelia M and Karlsson, Magnus and Ljunggren, Östen and Svensson, Olle and Hallmans, Göran and Rousseau, François and Giroux, Sylvie and Bussière, Johanne and Arp, Pascal P and Koromani, Fjorda and Prince, Richard L and Lewis, Joshua R and Langdahl, Bente L and Pernille Hermann, A and Jensen, Jens-Erik B and Kaptoge, Stephen and Khaw, Kay-Tee and Reeve, Jonathan and Formosa, Melissa M and Xuereb-Anastasi, Angela and Åkesson, Kristina and McGuigan, Fiona and Garg, Gaurav and Olmos, Jose M and Zarrabeitia, Maria T and Riancho, Jose A and Ralston, Stuart H and Alonso, Nerea and Jiang, Xi and Goltzman, David and Pastinen, Tomi and Grundberg, Elin and Gauguier, Dominique and Orwoll, Eric S and Karasik, David and Davey-Smith, George and Smith, Albert V and Siggeirsdottir, Kristin and Harris, Tamara B and Carola Zillikens, M and van Meurs, Joyce B J and Thorsteinsdottir, Unnur and Maurano, Matthew T and Timpson, Nicholas J and Soranzo, Nicole and Durbin, Richard and Wilson, Scott G and Ntzani, Evangelia E and Brown, Matthew A and Stefansson, Kari and Hinds, David A and Spector, Tim and Adrienne Cupples, L and Ohlsson, Claes 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 Rivadeneira, Fernando and Richards, J Brent}},
  issn         = {{0028-0836}},
  language     = {{eng}},
  number       = {{7571}},
  pages        = {{112--117}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature}},
  title        = {{Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture.}},
  url          = {{http://dx.doi.org/10.1038/nature14878}},
  doi          = {{10.1038/nature14878}},
  volume       = {{526}},
  year         = {{2015}},
}