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

HF Zheng, V Forgetta, YH Hsu, Karol Estrada Gil, A Rosello-Diez, PJ Leo, CL Dahia, KH Park-Min, JH Tobias, C Kooperberg, A Kleinman, U Styrkarsdottir, CT Liu, C Uggla, DS Evans, CM Nielson, K Walter, U Pettersson-Kymmer, S McCarthy, J ErikssonT Kwan, M Jhamai, Katerina Trajanoska, Y Memari, J Min, J Huang, P Danecek, B Wilmot, R Li, WC Chou, LE Mokry, A Moayyeri, M Claussnitzer, CH Cheng, W Cheung, Maria Medina Gomez, B Ge, SH Chen, K Choi, Ling Oei - Oei, J Fraser, Robert Kraaij, MA Hibbs, CL Gregson, D Paquette, Bert Hofman, C Wibom, GJ Tranah, M Marshall, BB Gardiner, K Cremin, P Auer, L (Lily) Hsu, S Ring, JY Tung, G Thorleifsson, Anke Enneman, NM Schoor, LCPGM (Lisette) de Groot, Nathalie van der Velde, B Melin, JP Kemp, C Christiansen, A Sayers, YH Zhou, S Calderari, J van Rooij, C Carlson, U Peters, S Berlivet, J Dostie, André Uitterlinden, SR Williams, C Farber, D Grinberg, AZ Lacroix, J Haessler, DI Chasman, F Giulianini, LM Rose, PM Ridker, JA Eisman, TV (Tuan) Nguyen, JR Center, X Nogues, N Garcia-Giralt, LL Launer, V Gudnason, D Mellstrom, L Vandenput, Najaf Amin, Cornelia Duijn, MK Karlsson, O Ljunggren, O Svensson, G Hallmans, F Rousseau, S Giroux, J Bussiere, Pascal Arp, Fjorda Koromani, RL Prince, JR Lewis, BL Langdahl, AP Hermann, JEB Jensen, S Kaptoge, KT Khaw, J Reeve, MM Formosa, A Xuereb-Anastasi, K Akesson, FE McGuigan, G Garg, JM Olmos, MT Zarrabeitia, JA Riancho, SH Ralston, N Alonso, X Jiang, D Goltzman, T Pastinen, E Grundberg, D Gauguier, ES Orwoll, D Karasik, G Davey-Smith, AV Smith, K Siggeirsdottir, TB Harris, M.C. Zillikens, Joyce van Meurs, U Thorsteinsdottir, MT Maurano, NJ Timpson, N Soranzo, R Durbin, S Wilson, EE Ntzani, MA Brown, K Stefansson, DA Hinds, T Spector, LA Cupples, C Ohlsson, CMT Greenwood, RD Jackson, DW Rowe, CA Loomis, DM Evans, CL Ackert-Bicknell, AL Joyner, EL Duncan, DP Kiel, Fernando Rivadeneira, JB Richards

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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(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 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), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 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 +10.41 s.d., P-meta = 1 x 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 languageUndefined/Unknown
Pages (from-to)112-+
JournalNature
Volume526
Issue number7571
DOIs
Publication statusPublished - 2015

Research programs

  • EMC MM-01-39-02
  • EMC MM-01-39-09-A
  • EMC NIHES-01-64-02
  • EMC OR-01-39-08

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