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

Research output: Contribution to journalLetter


title = "Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture.",
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.",
author = "Hou-Feng Zheng and Vincenzo Forgetta and Yi-Hsiang Hsu and Karol Estrada and Alberto Rosello-Diez and Leo, {Paul J} and Dahia, {Chitra L} and Park-Min, {Kyung Hyun} and Tobias, {Jonathan H} and Charles Kooperberg and Aaron Kleinman and Unnur Styrkarsdottir and Ching-Ti Liu and Charlotta Uggla and Evans, {Daniel S} and Nielson, {Carrie M} and Klaudia Walter and Ulrika Pettersson-Kymmer and Shane McCarthy and Joel Eriksson and Tony Kwan and Mila Jhamai and Katerina Trajanoska and Yasin Memari and Josine Min and Jie Huang and Petr Danecek and Beth Wilmot and Rui Li and Wen-Chi Chou and Mokry, {Lauren E} and Alireza Moayyeri and Melina Claussnitzer and Chia-Ho Cheng and Warren Cheung and Carolina Medina-G{\'o}mez and Bing Ge and Shu-Huang Chen and Kwangbom Choi and Ling Oei and James Fraser and Robert Kraaij and Hibbs, {Matthew A} and Gregson, {Celia L} and Denis Paquette and Albert Hofman and Carl Wibom and Tranah, {Gregory J} and Mhairi Marshall and Gardiner, {Brooke B} and Katie Cremin and Paul Auer and Li Hsu and Sue Ring and Tung, {Joyce Y} and Gudmar Thorleifsson and Enneman, {Anke W} and {van Schoor}, {Natasja M} and {de Groot}, {Lisette C P G M} and {van der Velde}, Nathalie and Beatrice Melin and Kemp, {John P} and Claus Christiansen and Adrian Sayers and Yanhua Zhou and Sophie Calderari and {van Rooij}, Jeroen and Chris Carlson and Ulrike Peters and Soizik Berlivet and Jos{\'e}e Dostie and Uitterlinden, {Andre G} and Williams, {Stephen R} and Charles Farber and Daniel Grinberg and LaCroix, {Andrea Z} and Jeff Haessler and Chasman, {Daniel I} and Franco Giulianini and Rose, {Lynda M} and Ridker, {Paul M} and Eisman, {John A} and Nguyen, {Tuan V} and Center, {Jacqueline R} and Xavier Nogues and Natalia Garcia-Giralt and Launer, {Lenore L} and Vilmunder Gudnason and Dan Mellstr{\"o}m and Liesbeth Vandenput and Najaf Amin and {van Duijn}, {Cornelia M} and Magnus Karlsson and {\"O}sten Ljunggren and Olle Svensson and G{\"o}ran Hallmans and Fran{\cc}ois Rousseau and Sylvie Giroux and Johanne Bussi{\`e}re and Arp, {Pascal P} and Fjorda Koromani and Prince, {Richard L} and Lewis, {Joshua R} and Langdahl, {Bente L} and {Pernille Hermann}, A and Jensen, {Jens-Erik B} and Stephen Kaptoge and Kay-Tee Khaw and Jonathan Reeve and Formosa, {Melissa M} and Angela Xuereb-Anastasi and Kristina {\AA}kesson and Fiona McGuigan and Gaurav Garg and Olmos, {Jose M} and Zarrabeitia, {Maria T} and Riancho, {Jose A} and Ralston, {Stuart H} and Nerea Alonso and Xi Jiang and David Goltzman and Tomi Pastinen and Elin Grundberg and Dominique Gauguier and Orwoll, {Eric S} and David Karasik and George Davey-Smith and Smith, {Albert V} and Kristin Siggeirsdottir and Harris, {Tamara B} and {Carola Zillikens}, M and {van Meurs}, {Joyce B J} and Unnur Thorsteinsdottir and Maurano, {Matthew T} and Timpson, {Nicholas J} and Nicole Soranzo and Richard Durbin and Wilson, {Scott G} and Ntzani, {Evangelia E} and Brown, {Matthew A} and Kari Stefansson and Hinds, {David A} and Tim Spector and {Adrienne Cupples}, L and Claes Ohlsson and Greenwood, {Celia M T} and Jackson, {Rebecca D} and Rowe, {David W} and Loomis, {Cynthia A} and Evans, {David M} and Ackert-Bicknell, {Cheryl L} and Joyner, {Alexandra L} and Duncan, {Emma L} and Kiel, {Douglas P} and Fernando Rivadeneira and Richards, {J Brent}",
year = "2015",
doi = "10.1038/nature14878",
language = "English",
volume = "526",
pages = "112--117",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7571",