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.
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.
Finite element analysis of computed tomography (CT) scans provides non-invasive estimates of bone strength at the spine and hip. To further validate such estimates clinically, we performed a five-year case-control study of 1110 women and men over age 65 from the AGES-Reykjavik cohort (case = incident spine or hip fracture; control = no incident spine or hip fracture, respectively). From the baseline CT scans, we measured femoral and vertebral strength, as well as bone mineral density (BMD) at the hip (areal BMD only) and lumbar spine (trabecular volumetric BMD only). We found that, for incident radiographically-confirmed spine fractures (n=167), the age-adjusted odds ratio for vertebral strength was significant for women (2.8, 95% CI: 1.8–4.3) and men (2.2, 95% CI: 1.5–3.2), and for men, remained significant (p=0.01) independent of vertebral trabecular volumetric BMD. For incident hip fractures (n=171), the age-adjusted odds ratio for femoral strength was significant for women (4.2, 95% CI: 2.6–6.9) and men (3.5, 95% CI: 2.3–5.3) and remained significant after adjusting for femoral neck areal BMD in women and for total hip areal BMD in both sexes; fracture classification improved for women by combining femoral strength with femoral neck areal BMD (p=0.002). For both sexes, the probabilities of spine and hip fractures were similarly high at the BMD-based interventional thresholds for osteoporosis and at corresponding pre-established thresholds for “fragile bone strength” (spine: women ≤ 4,500 N, men ≤ 6,500 N; hip: women ≤ 3,000 N, men ≤ 3,500 N). Since it is well established that individuals over age 65 who have osteoporosis at the hip or spine by BMD criteria should be considered at high risk of fracture, these results indicate that individuals who have “fragile bone strength” at the hip or spine should also be considered at high risk of fracture.
Objectives-A history of fracture is a strong risk factor for future fractures. The aim of the present study was to determine whether the predictive value of a past major osteoporotic fracture (MOF) for future MOF changed with time.Methods-The study was based on a population-based cohort of 18,872 men and women born between 1907 and 1935. Fractures were documented over 510,265 person-years. An extension of Poisson regression was used to investigate the relationship between the first MOF and the second. All associations were adjusted for age and time since baseline.Results-5039 individuals sustained one or more MOF, of whom 1919 experienced a second MOF. The risk of a second MOF after a first increased by 4% for each year of age (95 % CI: 1.02-1.06) and was 41% higher for women than men (95% CI: 1.25-1.59). The risk of a second MOF was highest immediately after the first fracture and thereafter decreased with time though remained higher than the population risk throughout follow-up. For example, 1 year after the first MOF the risk of a second fracture was 2.7 (2.4-3.0) fold higher than the population risk. After 10 years this risk ratio was and 1.4 (1.2-1.6). The effect was more marked with increasing age.Conclusions-The risk of MOF after a first MOF is increased over the whole follow up but the imminent risk is even higher. If the acute increment in risk in the few years following MOF is amenable to therapeutic intervention, then immediate short-term treatments may provide worthwhile clinical dividends in a very cost-effective manner, particularly in the elderly.
Higher marrow fat correlated with lower trabecular, but not cortical, BMD in older women but not men. Higher marrow fat was associated with prevalent vertebral fracture in men, even after adjustment for BMD.
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