Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture.
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| 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. |
| Year of Publication | 2015
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| Journal | Nature
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| Volume | 526
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| Issue | 7571
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| Pages | 112-7
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| Date Published | 2015 Oct 01
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| ISSN | 1476-4687
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| URL | |
| DOI | 10.1038/nature14878
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| PubMed ID | 26367794
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| PubMed Central ID | PMC4755714
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| Grant list | R00 AR061430 / AR / NIAMS NIH HHS / United States
MC_UU_12013/3 / Medical Research Council / United Kingdom
P30 CA015704 / CA / NCI NIH HHS / United States
R01 AR035583 / AR / NIAMS NIH HHS / United States
RG/08/014/24067 / British Heart Foundation / United Kingdom
G1000143 / Medical Research Council / United Kingdom
MR/L003120/1 / Medical Research Council / United Kingdom
R01 AG027576 / AG / NIA NIH HHS / United States
U01 AR045614 / AR / NIAMS NIH HHS / United States
102215 / Wellcome Trust / United Kingdom
U01 AR045654 / AR / NIAMS NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
119462-1 / Canadian Institutes of Health Research / Canada
R01 AG005407 / AG / NIA NIH HHS / United States
MC_PC_15018 / Medical Research Council / United Kingdom
G0401527 / Medical Research Council / United Kingdom
MC_UU_12013/1 / Medical Research Council / United Kingdom
U01 AR045583 / AR / NIAMS NIH HHS / United States
U01 AG042140 / AG / NIA NIH HHS / United States
MC_UU_12013/4 / Medical Research Council / United Kingdom
UM1 CA182913 / CA / NCI NIH HHS / United States
K01 AR062655 / AR / NIAMS NIH HHS / United States
U01 AR045647 / AR / NIAMS NIH HHS / United States
RC2 AR058973 / AR / NIAMS NIH HHS / United States
R01 AR035582 / AR / NIAMS NIH HHS / United States
P30 AR057235 / AR / NIAMS NIH HHS / United States
R01 AG005394 / AG / NIA NIH HHS / United States
R01 AR063702 / AR / NIAMS NIH HHS / United States
20000 / Arthritis Research UK / United Kingdom
U01 AG042143 / AG / NIA NIH HHS / United States
U01 AR045580 / AR / NIAMS NIH HHS / United States
R01 AG027574 / AG / NIA NIH HHS / United States
U01 AG018197 / AG / NIA NIH HHS / United States
U01 AR066160 / AR / NIAMS NIH HHS / United States
U01 AR045632 / AR / NIAMS NIH HHS / United States
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