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dc.contributor.authorFormosa, Melissa Marie-
dc.contributor.authorXuereb-Anastasi, Angela-
dc.date.accessioned2017-04-27T12:41:57Z-
dc.date.available2017-04-27T12:41:57Z-
dc.date.issued2015-
dc.identifier.citationFormosa, M. M., & Xuereb-Anastasi, A. (2015). Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature, 526 (7571), 112-117.en_GB
dc.identifier.urihttps://www.um.edu.mt/library/oar//handle/123456789/18700-
dc.descriptionA full list of authors and affiliations appears on page 5 of this article.en_GB
dc.description.abstractThe 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 En1cre/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.en_GB
dc.language.isoenen_GB
dc.publisherMacmillan Publishers Ltd.en_GB
dc.rightsinfo:eu-repo/semantics/openAccessen_GB
dc.subjectOsteoporosisen_GB
dc.subjectBones -- Diseases -- Diagnosisen_GB
dc.subjectOsteoporosis -- Genetic aspectsen_GB
dc.titleWhole-genome sequencing identifies EN1 as a determinant of bone density and fractureen_GB
dc.typearticleen_GB
dc.rights.holderThe copyright of this work belongs to the author(s)/publisher. The rights of this work are as defined by the appropriate Copyright Legislation or as modified by any successive legislation. Users may access this work and can make use of the information contained in accordance with the Copyright Legislation provided that the author must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the prior permission of the copyright holder.en_GB
dc.description.reviewedpeer-revieweden_GB
dc.identifier.doi10.1038/nature14878-
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