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

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.

Citation

Hou-Feng Zheng, Vincenzo Forgetta, Yi-Hsiang Hsu, Karol Estrada, Alberto Rosello-Diez, Paul J Leo, Chitra L Dahia, Kyung Hyun Park-Min, Jonathan H Tobias, Charles Kooperberg, Aaron Kleinman, Unnur Styrkarsdottir, Ching-Ti Liu, Charlotta Uggla, Daniel S Evans, Carrie M Nielson, Klaudia Walter, Ulrika Pettersson-Kymmer, Shane McCarthy, Joel Eriksson, Tony Kwan, Mila Jhamai, Katerina Trajanoska, Yasin Memari, Josine Min, Jie Huang, Petr Danecek, Beth Wilmot, Rui Li, Wen-Chi Chou, Lauren E Mokry, Alireza Moayyeri, Melina Claussnitzer, Chia-Ho Cheng, Warren Cheung, Carolina Medina-Gómez, Bing Ge, Shu-Huang Chen, Kwangbom Choi, Ling Oei, James Fraser, Robert Kraaij, Matthew A Hibbs, Celia L Gregson, Denis Paquette, Albert Hofman, Carl Wibom, Gregory J Tranah, Mhairi Marshall, Brooke B Gardiner, Katie Cremin, Paul Auer, Li Hsu, Sue Ring, Joyce Y Tung, Gudmar Thorleifsson, Anke W Enneman, Natasja M van Schoor, Lisette C P G M de Groot, Nathalie van der Velde, Beatrice Melin, John P Kemp, Claus Christiansen, Adrian Sayers, Yanhua Zhou, Sophie Calderari, Jeroen van Rooij, Chris Carlson, Ulrike Peters, Soizik Berlivet, Josée Dostie, Andre G Uitterlinden, Stephen R Williams, Charles Farber, Daniel Grinberg, Andrea Z LaCroix, Jeff Haessler, Daniel I Chasman, Franco Giulianini, Lynda M Rose, Paul M Ridker, John A Eisman, Tuan V Nguyen, Jacqueline R Center, Xavier Nogues, Natalia Garcia-Giralt, Lenore L Launer, Vilmunder Gudnason, Dan Mellström, Liesbeth Vandenput, Najaf Amin, Cornelia M van Duijn, Magnus K Karlsson, Östen Ljunggren, Olle Svensson, Göran Hallmans, François Rousseau, Sylvie Giroux, Johanne Bussière, Pascal P Arp, Fjorda Koromani, Richard L Prince, Joshua R Lewis, Bente L Langdahl, A Pernille Hermann, Jens-Erik B Jensen, Stephen Kaptoge, Kay-Tee Khaw, Jonathan Reeve, Melissa M Formosa, Angela Xuereb-Anastasi, Kristina Åkesson, Fiona E McGuigan, Gaurav Garg, Jose M Olmos, Maria T Zarrabeitia, Jose A Riancho, Stuart H Ralston, Nerea Alonso, Xi Jiang, David Goltzman, Tomi Pastinen, Elin Grundberg, Dominique Gauguier, Eric S Orwoll, David Karasik, George Davey-Smith, AOGC Consortium, Albert V Smith, Kristin Siggeirsdottir, Tamara B Harris, M Carola Zillikens, Joyce B J van Meurs, Unnur Thorsteinsdottir, Matthew T Maurano, Nicholas J Timpson, Nicole Soranzo, Richard Durbin, Scott G Wilson, Evangelia E Ntzani, Matthew A Brown, Kari Stefansson, David A Hinds, Tim Spector, L Adrienne Cupples, Claes Ohlsson, Celia M T Greenwood, UK10K Consortium, Rebecca D Jackson, David W Rowe, Cynthia A Loomis, David M Evans, Cheryl L Ackert-Bicknell, Alexandra L Joyner, Emma L Duncan, Douglas P Kiel, Fernando Rivadeneira, J Brent Richards. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature. 2015 Oct 01;526(7571):112-7

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PMID: 26367794

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