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

Authors:
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 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 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

Nature 2015 Oct 14;526(7571):112-7. Epub 2015 Sep 14.

Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montréal H3A 1A2, Canada.

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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http://dx.doi.org/10.1038/nature14878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755714PMC
October 2015
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