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

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• dc.contributor.author Zheng, Hou-Fengca
• dc.contributor.author Calderari, Sophieca
• dc.contributor.author Grinberg, Danielca
• dc.contributor.author Gauguier, Dominiqueca
• dc.contributor.author Richards, J. Brentca
• dc.date.accessioned 2016-02-01T09:26:01Z
• dc.date.available 2016-04-30T02:00:04Z
• dc.date.issued 2015
• dc.description.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.ca
• dc.format.mimetype application/pdfca
• dc.identifier.citation Zheng HF, Forgetta V, Hsu YH, Estrada K, Rosello-Diez A, Leo PJ. et al. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature. 2015 Oct 1;526(7571):112-7. DOI: 10.1038/nature14878.ca
• dc.identifier.doi http://dx.doi.org/10.1038/nature14878
• dc.identifier.issn 0028-0836
• dc.identifier.uri http://hdl.handle.net/10230/25703
• dc.language.iso engca
• dc.publisher Nature Publishing Groupca
• dc.relation.ispartof Nature. 2015 Oct 1;526(7571):112-7
• dc.rights © Nature Publishing Group http://dx.doi.org/10.1038/nature14878ca
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.other Ossos -- Malalties -- Aspectes genèticsca
• dc.subject.other Fracturesca
• dc.title Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture.ca
• dc.type info:eu-repo/semantics/articleca
• dc.type.version info:eu-repo/semantics/acceptedVersionca