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Title: | Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture |
Authors: | Formosa, Melissa Marie Xuereb-Anastasi, Angela |
Keywords: | Osteoporosis Bones -- Diseases -- Diagnosis Osteoporosis -- Genetic aspects |
Issue Date: | 2015 |
Publisher: | Macmillan Publishers Ltd. |
Citation: | Formosa, M. M., & Xuereb-Anastasi, A. (2015). Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature, 526 (7571), 112-117. |
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 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. |
Description: | A full list of authors and affiliations appears on page 5 of this article. |
URI: | https://www.um.edu.mt/library/oar//handle/123456789/18700 |
Appears in Collections: | Scholarly Works - FacHScABS |
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Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture.pdf | 10.07 MB | Adobe PDF | View/Open |
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