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.

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Osteoarthritis is a chronic disease characterised by irreversible damage to joint structures, including loss of articular cartilage, osteophyte formation, alterations in the subchondral bone and synovial inflammation. Pain, functional disability and impairment of health-related quality of life are major complaints in patients with osteoarthritis. Several compounds have been investigated for their positive effects on the relief of clinical symptoms and improvement of structural changes in osteoarthritis. It has been shown that chondroitin sulphate interferes with the progression of structural changes in joint tissues and is used in the management of patients with osteoarthritis. This review summarises data from relevant reports describing the mechanisms of action of chondroitin sulphate involved in the beneficial effects of the drug.

Two haplotypes defined by polymorphisms in the 5' flank of the COLIA1 regulate BMD in a bidirectional manner in women.

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Objective: Extragonadal estrogen biosynthesis is relevant for the regulation of bone metabolism. The aims of this paper were: (i) to examine CYP19 (aromatase) gene expression in primary cultures of osteoblasts under several hormone and cytokine treatments and (ii) to study the promoter usage of CYP19 in these cells. Methods: Primary cultures of osteoblasts were obtained from healthy donors. The effects of vitamin D and other factors on CYP19 expression were analysed by semiquantitative RT-PCR. Furthermore, CYP19 alternative promoter usage under the different treatments was characterized by RT-PCR. Results: CYP19 transcripts were detected in cultured human osteoblasts in serum-free conditions. Vitamin D, dexamethasone, 17b-estradiol and testosterone increased transcript levels of CYP19, whereas interleukin-1b or tumor necrosis factor a decreased them. Aromatase mRNA produced under treatment with vitamin D was transcribed from promoters I.4 and I.3, while stimulation with dexamethasone or dexamethasone plus vitamin D also involved promoter I.2. Testosterone activated promoters I.2 and I.4. Conclusions: Our results suggested that vitamin D, testosterone, estrogens and glucocorticoids regulate CYP19 gene expression in human primary osteoblasts and the main promoter used appears to be promoter I.4. Promoters pII and I.3 seem to be related to basal transcription and may mediate estrogen stimulation, while promoter I.2 seems to play a role in the effect of glucocorticoids. These findings indicate that vitamin D and several hormones regulate local estrogen synthesis in human osteoblasts mainly through usage of promoters I.4 and I.3.

Atypical femoral fractures (AFFs) are a rare but potentially devastating event, often but not always linked to bisphosphonate (BP) therapy. The pathogenic mechanisms underlying AFFs remain obscure, and there are no tests available that might assist in identifying those at high risk of AFF. We previously used exome sequencing to explore the genetic background of three sisters with AFFs and three additional unrelated AFF cases, all previously treated with BPs. We detected 37 rare mutations (in 34 genes) shared by the three sisters. Notably, we found a p.Asp188Tyr mutation in the enzyme geranylgeranyl pyrophosphate synthase, a component of the mevalonate pathway, which is critical to osteoclast function and is inhibited by N-BPs. In addition, the CYP1A1 gene, responsible for the hydroxylation of 17β-estradiol, estrone, and vitamin D, was also mutated in all three sisters and one unrelated patient. Here we present a detailed list of the variants found and report functional analyses of the GGPS1 p.Asp188Tyr mutation, which showed a severe reduction in enzyme activity together with oligomerization defects. Unlike BP treatment, this genetic mutation will affect all cells in the carriers. RNAi knockdown of GGPS1 in osteoblasts produced a strong mineralization reduction and a reduced expression of osteocalcin, osterix, and RANKL, whereas in osteoclasts, it led to a lower resorption activity. Taken together, the impact of the mutated GGPPS and the relevance of the downstream effects in bone cells make it a strong candidate for AFF susceptibility. We speculate that other genes such as CYP1A1 might be involved in AFF pathogenesis, which remains to be functionally proved. The identification of the genetic background for AFFs provides new insights for future development of novel risk assessment tools. © 2018 American Society for Bone and Mineral Research.