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

Nature
Authors
Keywords
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
Journal
Nature
Volume
526
Issue
7571
Pages
112-7
Date Published
2015 Oct 01
ISSN
1476-4687
URL
DOI
10.1038/nature14878
PubMed ID
26367794
PubMed Central ID
PMC4755714
Links
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