Genome wide association study of bone size yields eleven loci that also affect height, bone density, osteoarthritis and fractures
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ABSTRACT:
PROVIDER: PRJNA528321 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8758360.fastq.gz | Fastqsanger.gz | |||
| SRR8758370.fastq.gz | Fastqsanger.gz | |||
| SRR8758361.fastq.gz | Fastqsanger.gz | |||
| SRR8758371.fastq.gz | Fastqsanger.gz | |||
| SRR8758362.fastq.gz | Fastqsanger.gz |
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Project description:Bone area is one measure of bone size that is easily derived from dual-energy X-ray absorptiometry (DXA) scans, primarily performed to evaluate bone density and osteoporosis risk. Here, we report on a genome-wide association (GWA) study of DXA bone area of the hip and spine (N ≥ 28,954). We found associations of common variants at eleven loci that replicate in samples of European and East Asian descent (N = 13,608 – 21,277). We also examined association of these markers with osteoarthritis and fractures in European samples (Ncases = 3,293 – 27,321). The strongest DXA area association is with a variant in the microRNA MIR196A2 gene at the HOXC locus that associates with reduced lumbar spine area (rs11614913[T], P = 2.3 × 10-42, β = −0.090) and confers risk of hip fractures (P = 1.0 × 10-8, OR = 1.11). We demonstrate that the hip fracture risk allele [T] is less efficient in repressing miR-196a-5p target genes. We also show that the DXA area measure contributes to the risk of hip fracture independent of bone density. Eight DXA area loci associate with osteoarthritis, including rs143384 in the 5’ UTR of the GDF5 gene and a missense variant in the COL11A1 gene (rs3753841[G], NP_001177638.1:p.Pro1284Leu). We also report a complex relationship between the variants associated with DXA area measures and height and bone mineral density (BMD).
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Project description:Osteoblasts require substantial amounts of energy to synthesize bone matrix and coordinate the mineralization of the skeleton. This study analyzed the effect of mitochondrial dysfunction on bone formation in mouse limbs. The limb mesenchyme-specific Tfam knockout (Tfamf/f;Prx1-Cre: Tfam-cKO) mice were analyzed morphologically, and histologically and gene expression in the limb bones were assessed by in situ hybridization, quantitative real-time PCR and RNA sequencing. Moreover, we analyzed mitochondrial function of osteoblasts in Tfam-cKO mice by mitochondrial membrane potential assay and transmission electron microscopic (TEM) observations. We investigated the pathogenesis of spontaneous bone fractures by immunohistochemical analysis, TEM observations and biomechanical examination. The forelimbs in Tfam-cKO mice were significantly shortened from birth and occurred spontaneous fractures within the first week after birth, resulting in severe limb deformities. Histologically, bone hypoplasia with decrease of matrix mineralization was apparent, and the expressions of type Ⅰ collagen and osteocalcin were decreased in the osteoblasts of Tfam-cKO mice although Runx2 expression was unchanged. Decreased type Ⅰ collagen deposition and mineralization in the matrix of the limb bones in Tfam-cKO mice was associated with marked mitochondrial dysfunction. Biomechanical analysis showed significantly lower Young’s modulus and hardness due to poor apatite orientation in the bone tissue of Tfam-cKO mice. The mice with limb mesenchyme-specific Tfam deletion exhibited spontaneous limb bone fractures, resulting in severe limb deformities. Their bone fragility was caused by poor apatite orientation due to impaired osteoblasts differentiation and maturation.
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Project description:Bone area is one measure of bone size that is easily derived from dual-energy X-ray absorptiometry (DXA) scans. In a GWA study of DXA bone area of the hip and lumbar spine (N???28,954), we find thirteen independent association signals at twelve loci that replicate in samples of European and East Asian descent (N?=?13,608 - 21,277). Eight DXA area loci associate with osteoarthritis, including rs143384 in GDF5 and a missense variant in COL11A1 (rs3753841). The strongest DXA area association is with rs11614913[T] in the microRNA MIR196A2 gene that associates with lumbar spine area (P?=?2.3?×?10-42, ??=?-0.090) and confers risk of hip fracture (P?=?1.0?×?10-8, OR?=?1.11). We demonstrate that the risk allele is less efficient in repressing miR-196a-5p target genes. We also show that the DXA area measure contributes to the risk of hip fracture independent of bone density.
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Project description:Stress fractures are microcracks in bone caused by repetitive loading and these microcracks can increase the risk of developing catastrophic fractures. Early detection of stress fractures can be difficult due to the necessity of accurate clinical detection. MicroRNAs could be used as potential diagnostic and prognostic biomarkers due to their size, abundance, tissue specificity and stability in body fluids. Global profiling of circulating plasma small RNA-sequencing between lame horses (stress fractures and non-stress fractures) and non-lame control horses and the effects and role of selected stress fracture-related miRNAs on equine bone marrow derived mesenchymal stem cells (BMMSCs) were investigated. The miRNA profiles of stress fracture cases and non-lame stress fracture cases were similar. No miRNA was identified for potential usage as a biomarker for differentiating stress fracture from lame cases. However, the miRNA profiles of lame cases and non-lame control horses were significantly different. RNA-sequencing showed three miRNAs (eca-miR-486-5p, eca-miR-26a and eca-miR-23a) were most significantly differentially expressed (p value <0.05) between lame cases and non-lame controls, which was validated by qPCR. Of these, eca-miR-486-5p demonstrated the most abundant and significant increased miRNA in the lame cases compared to non-lame control cases. Cell transfection experiments using the miR-486-5p mimic treatment in equine BMMSCs showed upregulation of the osteogenic transcription factor, Runt-related transcription factor 2 (RUNX2) and insulin-like growth factor type 1 (IGF1). A significant decrease of miR-133a in the miR-486-5p mimic treated cells was also demonstrated. Since RUNX2 is the known target of miR-133a, miR 486-5p together with miR-133a would suggest the biological importance of bone turnover and osteogenesis in equine BMMSCs, but further investigation of role of miR-486-5p and miR-133a in equine bone biology is warranted.
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Project description:Osteoporosis is the consequence of altered bone metabolism resulting in the systemic reduction of bone strength and increased risk of fragility fractures. MicroRNAs (miRNAs) regulate gene expression on a post-transcriptional level are known to take part in the control of bone formation and bone resorption. Recently, targeted secretion of miRNAs from cells originating from various tissues has been described, which allows for their minimal-invasive detection in serum/plasma and use as biomarkers for presence and progression of pathological conditions. One pilot study has reported circulating miRNAs in serum and tissue of fracture patients. However, further studies are required to explore whether a dysbalance in bone homeostasis of fracture patients can reliably be reflected by specific circulating miRNAs, and whether these miRNAs might serve as drugable targets. Here, we report results from a comprehensive multiplex study of 175 miRNAs in serum samples obtained from 7 patients with osteoporotic fractures at the femoral neck, and 7 age-matched controls. Following elaborate quality control statistical analysis of this exploratory dataset identified 9 microRNAs with altered serum levels in response to fracture (adjusted p-value < 0.1). Of these, hsa-miR-10a/b gave excellent discrimination of both groups (AUC = 1.0), and clustering of samples based on the top10 miRNAs confirmed the high discriminatory power of circulating microRNAs for osteoporotic fractures. In the next step 3 miRNAs with unknown roles in osteogenic differentiation and 4 miRNA from a previous study were tested for their effects on osteogenic differentiation. Of these, 3 miRNAs showed robust effects on osteogenic differentiation. Overall, these data provide important insights into changes in serum miRNA in post-traumatic patients. Future studies will show, whether this knowledge can be used to improve current diagnostic methodologies to predict fracture risk and design novel treatment strategies for osteoporosis patients.
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