Bone mineral density (BMD) is the most important predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and East Asian ancestry. We tested the top-associated BMD markers for replication in 50,933 independent subjects and for risk of low-trauma fracture in 31,016 cases and 102,444 controls. We identified 56 loci (32 novel)associated with BMD atgenome-wide significant level (P<5×10−8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal-stem-cell differentiation, endochondral ossification and the Wnt signalling pathways. However, we also discovered loci containing genes not known to play a role in bone biology. Fourteen BMD loci were also associated with fracture risk (P<5×10−4, Bonferroni corrected), of which six reached P<5×10−8 including: 18p11.21 (C18orf19), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

No abstract

Bone density achieved in early adulthood is the major determinant of risk of osteoporotic fracture. Up to 60% of women suffer osteoporotic fractures as a result of low bone density, which is under strong genetic control acting through effects on bone turnover. Here we show that common allelic variants in the gene encoding the vitamin D receptor can be used to predict differences in bone density, accounting for up to 75% of the total genetic effect on bone density in healthy individuals. The genotype associated with lower bone density was overrepresented in postmenopausal women with bone densities more than 2 standard deviations below values in young normal women. The molecular mechanisms by which bone density is regulated by the vitamin D receptor gene are not certain, although allelic differences in the 3' untranslated region may alter messenger RNA levels. These findings could open new avenues to the development and targeting of prophylactic interventions. It follows that other pathophysiological processes considered to be subject to complex multifactorial genetic regulation may also be modulated by a single gene with pleiotropic transcriptional actions.

Context There are few data on long-term mortality following osteoporotic fracture and fewer following subsequent fracture.Objectives To examine long-term mortality risk in women and men following all osteoporotic fractures and to assess the association of subsequent fracture with that risk. Design, Setting, and ParticipantsProspective cohort from the Dubbo Osteoporosis Epidemiology Study of community-dwelling women and men aged 60 years and older from Dubbo, Australia, who sustained a fracture between April 1989 and May 2007.Main Outcome Measures Age-and sex-specific standardized mortality ratios (SMRs) compared with the overall Dubbo population for hip, vertebral, major, and minor fractures. ResultsIn women, there were 952 low-trauma fractures followed by 461 deaths, and in men, 343 fractures were followed by 197 deaths. Age-adjusted SMRs were increased following hip fractures (SMRs, 2.43 [95% confidence interval [CI], 2.02-2.93] and 3.51 [95% CI, 2.65-4.66]), vertebral fractures (SMRs, 1.82 [95% CI, 1.52-2.17] and 2.12 [95% CI, 1.66-2.72]), major fractures (SMRs, 1.65 [95% CI, 1.31-2.08] and 1.70 [95% CI, 1.23-2.36]), and minor fractures (SMRs, 1.42 [95% CI, 1.19-1.70] and 1.33 [95% CI, 0.99-1.80]) for both women and men, respectively.Mortality was increased for all ages for all fractures except minor fractures for which increased mortality was only apparent for those older than 75 years. Increased mortality risk persisted for 5 years for all fractures and up to 10 years for hip fractures. Increases in absolute mortality that were above expected, for 5 years after fracture, ranged from 1.3 to 13.2 per 100 person-years in women and from 2.7 to 22.3 per 100 person-years in men, depending on fracture type. Subsequent fracture was associated with an increased mortality hazard ratio of 1.91 (95% CI, 1.54-2.37) in women and 2.99 (95% CI, 2.11-4.24) in men. Mortality risk following a subsequent fracture then declined but beyond 5 years still remained higher than in the general population (SMR, 1.41 [95% CI, 1.01-1.97] and SMR, 1.78 [95% CI, 0.96-3.31] for women and men, respectively). Predictors of mortality after any fragility fracture for both men and women included age, quadriceps weakness, and subsequent fracture but not comorbidities. Low bone mineral density, having smoked, and sway were also predictors for women and less physical activity for men. ConclusionsIn a sample of older women and men, all low-trauma fractures were associated with increased mortality risk for 5 to 10 years. Subsequent fracture was associated with increased mortality risk for an additional 5 years.

We have discovered common sequence variants that are consistently associated with bone mineral density and with low-trauma fractures in three populations of European descent. Although these variants alone are not clinically useful in the prediction of risk to the individual person, they provide insight into the biochemical pathways underlying osteoporosis.

SUMMARY 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 largely unknown. Bone mineral density (BMD) is highly heritable, is a major predictor of osteoporotic fractures and has been previously associated with common genetic variants1–8, and 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), whole-exome sequencing (n= 3,549), deep imputation of genotyped samples using a combined UK10K/1000Genomes 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 4-fold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564[T], MAF = 1.7%, replication effect size = +0.20 standard deviations [SD], Pmeta = 2×10−14), which was also associated with a decreased risk of fracture (OR = 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, likely as a consequence of high bone turn-over. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817[T], MAF = 1.1%, replication effect size = +0.39 SD, 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.

No abstract

Objectives To determine whether earlier clinical intervention by a medical emergency team prompted by clinical instability in a patient could reduce the incidence of and mortality from unexpected cardiac arrest in hospital.