Whole-genome sequencing identifiesEN1as a... : Nature (original) (raw)

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

Nature

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October 1, 2015

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| DOI: 10.1038/nature14878

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 ( n total = 53,236) and fracture ( n total = 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. ); 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., P meta = 2 × 10−14), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10−11; n cases = 98,742 and n controls = 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., P meta = 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.