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

Zheng, H-F Forgetta, V Hsu, Y-H Estrada, K Rosello-Diez, A Leo, PJ Dahia, CL Park-Min, KH Tobias, JH Kooperberg, C Kleinman, A Styrkarsdottir, U Liu, C-T 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, W-C Mokry, LE Moayyeri, A Claussnitzer, M Cheng, C-H Cheung, W Medina-Gómez, C Ge, B Chen, S-H 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 Koromani, F Prince, RL Lewis, JR Langdahl, BL Hermann, AP Jensen, J-EB Kaptoge, S Khaw, K-T Reeve, J Formosa, MM Xuereb-Anastasi, A Åkesson, K McGuigan, FE Garg, G Olmos, JM Zarrabeitia, MT Riancho, JA Ralston, SH Alonso, N Jiang, X Goltzman, D Pastinen, T Grundberg, E Gauguier, D Orwoll, ES Karasik, D Davey-Smith, G AOGC Consortium Smith, AV Siggeirsdottir, K Harris, TB Zillikens, MC van Meurs, JBJ Thorsteinsdottir, U Maurano, MT Timpson, NJ Soranzo, N Durbin, R Wilson, SG Ntzani, EE Brown, MA Stefansson, K Hinds, DA Spector, T Cupples, LA Ohlsson, C Greenwood, CMT UK10K Consortium Jackson, RD Rowe, DW Loomis, CA Evans, DM Ackert-Bicknell, CL Joyner, AL Duncan, EL Kiel, DP Rivadeneira, F Richards, JB
Publication Type:
Journal Article
Citation:
Nature, 2015, 526 (7571), pp. 112 - 117
Issue Date:
2015-10-01
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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.
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