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


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 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 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 x 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.

Type Journal
ISBN 1476-4687 (Electronic) 0028-0836 (Linking)
Authors Zheng, H. F. ; Forgetta, V. ; Hsu, Y. H. ; Estrada, K. ; Rosello-Diez, A. ; Leo, P. J. ; Dahia, C. L. ; Park-Min, K. H. ; Tobias, J. H. ; Kooperberg, C. ; Kleinman, A. ; Styrkarsdottir, U. ; Liu, C. T. ; Uggla, C. ; Evans, D. S. ; Nielson, C. M. ; Walter, K. ; Pettersson-Kymmer, U. ; McCarthy, S. ; Eriksson, J. ; Kwan, T. ; Jhamai, M. ; Trajanoska, K. ; Memari, Y. ; Min, J.; et al.
Publisher Name NATURE
Published Date 2015-01-01
Published Volume 526
Published Issue 7571
Published Pages 112-7
Status Published in-print
URL link to publisher's version
OpenAccess link to author's accepted manuscript version