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 variants1–8, as well as rare, populationspecific, coding variants9. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal553,236) and fracture (ntotal5508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n52,882 fromUK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n 53,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n526,534), and de novo replication genotyping (n 520,271). 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 BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., Pmeta52310214), which was also associated with a decreased risk of fracture (odds ratio50.85; P52310211; ncases598,742 and ncontrols5409,511). 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 lowfrequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF51.2%, replication effect size5 10.41 s.d., Pmeta51310211). 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.

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