| Literature DB >> 26367794 |
Hou-Feng Zheng1,2, Vincenzo Forgetta1,2, Yi-Hsiang Hsu3,4,5, Karol Estrada4,5,6,7, Alberto Rosello-Diez8, Paul J Leo9, Chitra L Dahia10,11, Kyung Hyun Park-Min12, Jonathan H Tobias13,14, Charles Kooperberg15, Aaron Kleinman16, Unnur Styrkarsdottir17, Ching-Ti Liu18, Charlotta Uggla19, Daniel S Evans20, Carrie M Nielson21,22, Klaudia Walter23, Ulrika Pettersson-Kymmer24,25, Shane McCarthy23, Joel Eriksson19,26, Tony Kwan27, Mila Jhamai6, Katerina Trajanoska6,28, Yasin Memari23, Josine Min14, Jie Huang23, Petr Danecek23, Beth Wilmot29,30, Rui Li1,2, Wen-Chi Chou3,4, Lauren E Mokry2, Alireza Moayyeri31,32, Melina Claussnitzer3,4,5,33, Chia-Ho Cheng3, Warren Cheung27,34, Carolina Medina-Gómez6,28,35, Bing Ge27, Shu-Huang Chen27, Kwangbom Choi36, Ling Oei6,28,35, James Fraser37, Robert Kraaij6,28,35, Matthew A Hibbs36,38, Celia L Gregson39, Denis Paquette37, Albert Hofman28,35, Carl Wibom40, Gregory J Tranah21,22, Mhairi Marshall9, Brooke B Gardiner9, Katie Cremin9, Paul Auer41, Li Hsu15, Sue Ring42, Joyce Y Tung16, Gudmar Thorleifsson43, Anke W Enneman6, Natasja M van Schoor44, Lisette C P G M de Groot45, Nathalie van der Velde6,46, Beatrice Melin40, John P Kemp9,14, Claus Christiansen47, Adrian Sayers39, Yanhua Zhou18, Sophie Calderari48,49, Jeroen van Rooij6,35, Chris Carlson15, Ulrike Peters15, Soizik Berlivet37, Josée Dostie37, Andre G Uitterlinden6,28,35, Stephen R Williams50, Charles Farber50, Daniel Grinberg51,52,53, Andrea Z LaCroix54, Jeff Haessler15, Daniel I Chasman4,55, Franco Giulianini55, Lynda M Rose55, Paul M Ridker4,55, John A Eisman56,57,58, Tuan V Nguyen56,58, Jacqueline R Center56,58, Xavier Nogues59,60,61, Natalia Garcia-Giralt59,60, Lenore L Launer62, Vilmunder Gudnason63,64, Dan Mellström19, Liesbeth Vandenput19, Najaf Amin65, Cornelia M van Duijn65, Magnus K Karlsson66, Östen Ljunggren67, Olle Svensson68, Göran Hallmans25, François Rousseau69,70, Sylvie Giroux70, Johanne Bussière70, Pascal P Arp6, Fjorda Koromani6,28, Richard L Prince71,72, Joshua R Lewis71,72, Bente L Langdahl73, A Pernille Hermann74, Jens-Erik B Jensen75, Stephen Kaptoge31, Kay-Tee Khaw76, Jonathan Reeve77,78, Melissa M Formosa79, Angela Xuereb-Anastasi79, Kristina Åkesson66,80, Fiona E McGuigan80, Gaurav Garg80, Jose M Olmos81,82, Maria T Zarrabeitia83, Jose A Riancho81,82, Stuart H Ralston84, Nerea Alonso84, Xi Jiang85, David Goltzman86, Tomi Pastinen27,34, Elin Grundberg27,34, Dominique Gauguier48,49, Eric S Orwoll22,87, David Karasik3,88, George Davey-Smith14, Albert V Smith63,64, Kristin Siggeirsdottir63, Tamara B Harris89, M Carola Zillikens6, Joyce B J van Meurs6,28, Unnur Thorsteinsdottir17,64, Matthew T Maurano90, Nicholas J Timpson14, Nicole Soranzo23, Richard Durbin23, Scott G Wilson32,71,91, Evangelia E Ntzani92,93, Matthew A Brown9, Kari Stefansson64,94, David A Hinds16, Tim Spector32, L Adrienne Cupples18,95, Claes Ohlsson19, Celia M T Greenwood2,34,96,97, Rebecca D Jackson98, David W Rowe85, Cynthia A Loomis99, David M Evans9,14, Cheryl L Ackert-Bicknell36, Alexandra L Joyner8, Emma L Duncan9,100, Douglas P Kiel3,4,5,33, Fernando Rivadeneira6,28,35, J Brent Richards1,2,32.
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.Entities:
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Year: 2015 PMID： 26367794 PMCID： PMC4755714 DOI： 10.1038/nature14878
Source DB: PubMed Journal: Nature ISSN： 0028-0836 Impact factor: 49.962