TY - JOUR
T1 - Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture
AU - Zheng, H.
AU - Forgetta, V.
AU - Hsu, Y.H.
AU - Estrada, K.
AU - Rosello-Diez, A.
AU - de Groot, C.P.G.M.
PY - 2015
Y1 - 2015
N2 - 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, 2, 3, 4, 5, 6, 7, 8, as well as rare, population-specific, coding variants9. 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 BMD8 (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.
AB - 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, 2, 3, 4, 5, 6, 7, 8, as well as rare, population-specific, coding variants9. 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 BMD8 (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.
U2 - 10.1038/nature14878
DO - 10.1038/nature14878
M3 - Article
SN - 0028-0836
VL - 526
SP - 112
EP - 117
JO - Nature
JF - Nature
ER -