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

Authors :
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-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 CPGM
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, François
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 S
Karasik, David
Davey-Smith, George
AOGC Consortium
Smith, Albert V
Siggeirsdottir, Kristin
Harris, Tamara B
Zillikens, M Carola
Van Meurs, Joyce BJ
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 MT
UK10K Consortium
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
Rosello-Diez, Alberto [0000-0002-5550-9846]
Kaptoge, Stephen [0000-0002-1155-4872]
Khaw, Kay-Tee [0000-0002-8802-2903]
Soranzo, Nicole [0000-0003-1095-3852]
Apollo - University of Cambridge Repository
Source :
Nature, r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu, instname, r-FSJD: Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu, Fundació Sant Joan de Déu
Publication Year :
2015
Publisher :
Springer Science and Business Media LLC, 2015.

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.

Details

ISSN :
00280836
Database :
OpenAIRE
Journal :
Nature, r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu, instname, r-FSJD: Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu, Fundació Sant Joan de Déu
Accession number :
edsair.doi.dedup.....3b07c1f45c5ae18b94cfbfa33e1b3cd6