scholarly journals Mendelian Randomization analysis reveals a causal influence of circulating sclerostin levels on bone mineral density and fractures

2018 ◽  
Author(s):  
Jie Zheng ◽  
Winfried Maerz ◽  
Ingrid Gergei ◽  
Marcus Kleber ◽  
Christiane Drechsler ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Femoral Neck ◽  
Fracture Risk ◽  
Bone Mineral ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Mendelian Randomisation ◽  
Adaptive Responses ◽  
Mineral Density ◽  
A Genome

ABSTRACTIn bone, sclerostin is mainly osteocyte-derived and plays an important local role in adaptive responses to mechanical loading. Whether circulating levels of sclerostin also play a functional role is currently unclear, which we aimed to examine by two sample Mendelian Randomisation (MR). A genetic instrument for circulating sclerostin, derived from a genome wide association study (GWAS) meta-analysis of serum sclerostin in 10,584 European-descent individuals, was examined in relation to femoral neck bone mineral density (BMD; n= 32,744) in GEFOS, and estimated BMD by heel ultrasound (eBMD; n=426,824), and fracture risk (n=426,795), in UK Biobank. Our GWAS identified two novel serum sclerostin loci, B4GALNT3 (standard deviation (SD)) change in sclerostin per A allele (β=0.20, P=4.6×10−49), and GALNT1 (β=0.11 per G allele, P=4.4×10−11). B4GALNT3 is an N-acetyl-galactosaminyltransferase, adding a terminal LacdiNAc disaccharide to target glycocoproteins, found to be predominantly expressed in kidney, whereas GALNT1 is an enzyme causing mucin-type O-linked glycosylation. Using these two SNPs as genetic instruments, MR revealed an inverse causal relationship between serum sclerostin and femoral neck BMD (β= −0.12, 95%CI= −0.20 to −0.05) and eBMD (β= −0.12, 95%CI= −0.14 to −0.10), and a positive relationship with fracture risk (β= 0.11, 95%CI= 0.01 to 0.21). Colocalization analysis demonstrated common genetic signals within the B4GALNT3 locus for higher sclerostin, lower eBMD, and greater B4GALNT3 expression in arterial tissue (Probability>99%). Our findings suggest that higher sclerostin levels are causally related to lower BMD and greater fracture risk. Hence, strategies for reducing circulating sclerostin, for example by targeting glycosylation enzymes as suggested by our GWAS results, may prove valuable in treating osteoporosis.

scholarly journals PTHandIL21RMay Underlie Variation of Femoral Neck Bone Mineral Density as Revealed by a Genome-Wide Association Study

2009 ◽  
pp. 091029141139034-32 ◽  
Author(s):  
Yan Guo ◽  
Li-Shu Zhang ◽  
Tie-Lin Yang ◽  
Qing Tian ◽  
Dong-Hai Xiong ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Femoral Neck ◽  
Association Study ◽  
Bone Mineral ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Mineral Density ◽  
Genome Wide ◽  
A Genome

Radiographic bone texture analysis is correlated with 3D microarchitecture in the femoral head, and improves the estimation of the femoral neck fracture risk when combined with bone mineral density

2013 ◽  
Vol 82 (9) ◽  
pp. 1494-1498 ◽  
Author(s):  
Matthieu Ollivier ◽  
Thomas Le Corroller ◽  
Guillaume Blanc ◽  
Sébastien Parratte ◽  
Pierre Champsaur ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Femoral Head ◽  
Femoral Neck ◽  
Fracture Risk ◽  
Femoral Neck Fracture ◽  
Texture Analysis ◽  
Bone Mineral ◽  
Mineral Density ◽  
Neck Fracture ◽  
Bone Texture Analysis

People with HIV infection had lower bone mineral density and increased fracture risk: a meta-analysis

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Chao-Jui Chang ◽  
Yi-Lin Chan ◽  
Iqbal Pramukti ◽  
Nai-Ying Ko ◽  
Ta-Wei Tai
Keyword(s):  
Bone Mineral Density ◽  
Hiv Infection ◽  
Fracture Risk ◽  
Bone Mineral ◽  
Meta Analysis ◽  
Lower Bone Mineral Density ◽  
Mineral Density

Association of 3q13.32 variants with hip trochanter and intertrochanter bone mineral density identified by a genome-wide association study

2016 ◽  
Vol 27 (11) ◽  
pp. 3343-3354 ◽  
Author(s):  
Y.-F. Pei ◽  
Z.-G. Xie ◽  
X.-Y. Wang ◽  
W.-Z. Hu ◽  
L.-B. Li ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Association Study ◽  
Bone Mineral ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Mineral Density ◽  
Genome Wide ◽  
A Genome

scholarly journals Genetic predisposition to increased serum calcium, bone mineral density, and fracture risk in individuals with normal calcium levels: mendelian randomisation study

BMJ ◽  
2019 ◽  
pp. l4410 ◽  
Author(s):  
Agustin Cerani ◽  
Sirui Zhou ◽  
Vincenzo Forgetta ◽  
John A Morris ◽  
Katerina Trajanoska ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Bone Mineral ◽  
Serum Calcium ◽  
Genetic Predisposition ◽  
Calcium Supplementation ◽  
Meta Analysis ◽  
Mendelian Randomisation ◽  
Uk Biobank ◽  
Mineral Density ◽  
The Uk

Abstract Objective To determine if genetically increased serum calcium levels are associated with improved bone mineral density and a reduction in osteoporotic fractures. Design Mendelian randomisation study. Setting Cohorts used included: the UK Biobank cohort, providing genotypic and estimated bone mineral density data; 25 cohorts from UK, USA, Europe, and China, providing genotypic and fracture data; and 17 cohorts from Europe, providing genotypic and serum calcium data (summary level statistics). Participants A genome-wide association meta-analysis of serum calcium levels in up to 61 079 individuals was used to identify genetic determinants of serum calcium levels. The UK Biobank study was used to assess the association of genetic predisposition to increased serum calcium with estimated bone mineral density derived from heel ultrasound in 426 824 individuals who had, on average, calcium levels in the normal range. A fracture genome-wide association meta-analysis comprising 24 cohorts and the UK Biobank including a total of 76 549 cases and 470 164 controls, who, on average, also had calcium levels in the normal range was then performed. Results A standard deviation increase in genetically derived serum calcium (0.13 mmol/L or 0.51 mg/dL) was not associated with increased estimated bone mineral density (0.003 g/cm 2 , 95% confidence interval −0.059 to 0.066; P=0.92) or a reduced risk of fractures (odds ratio 1.01, 95% confidence interval 0.89 to 1.15; P=0.85) in inverse-variance weighted mendelian randomisation analyses. Sensitivity analyses did not provide evidence of pleiotropic effects. Conclusions Genetic predisposition to increased serum calcium levels in individuals with normal calcium levels is not associated with an increase in estimated bone mineral density and does not provide clinically relevant protection against fracture. Whether such predisposition mimics the effect of short term calcium supplementation is not known. Given that the same genetically derived increase in serum calcium is associated with an increased risk of coronary artery disease, widespread calcium supplementation in the general population could provide more risk than benefit.

scholarly journals Authors’ Reply: Veganism, vegetarianism, bone mineral density, and fracture risk: a systematic review and meta-analysis

2019 ◽  
Vol 77 (6) ◽  
pp. 452-453
Author(s):  
Isabel Iguacel ◽  
María L Miguel-Berges ◽  
Alejandro Gómez-Bruton ◽  
Luis A Moreno ◽  
Cristina Julian
Keyword(s):  
Bone Mineral Density ◽  
Systematic Review ◽  
Fracture Risk ◽  
Bone Mineral ◽  
Meta Analysis ◽  
Mineral Density

Fracture risk and bone mineral density levels in patients with systemic lupus erythematosus: a systematic review and meta-analysis

2016 ◽  
Vol 27 (4) ◽  
pp. 1413-1423 ◽  
Author(s):  
X. Wang ◽  
S. Yan ◽  
C. Liu ◽  
Y. Xu ◽  
L. Wan ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Systematic Review ◽  
Systemic Lupus Erythematosus ◽  
Fracture Risk ◽  
Bone Mineral ◽  
Lupus Erythematosus ◽  
Meta Analysis ◽  
Mineral Density ◽  
Systemic Lupus

scholarly journals Meta-Analysis of Genome-Wide Association Studies Identifies Novel Functional CpG-SNPs Associated with Bone Mineral Density at Lumbar Spine

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Chuan Qiu ◽  
Hui Shen ◽  
Xiaoying Fu ◽  
Chao Xu ◽  
Hongwen Deng
Keyword(s):  
Bone Mineral Density ◽  
Dna Methylation ◽  
Lumbar Spine ◽  
Bone Mineral ◽  
Meta Analysis ◽  
Mineral Density ◽  
Significance Level ◽  
Genome Wide ◽  
A Genome ◽  
Genome Wide Significance

Osteoporosis is a serious public health issue, which is mostly characterized by low bone mineral density (BMD). To search for additional genetic susceptibility loci underlying BMD variation, an effective strategy is to focus on testing of specific variants with high potential of functional effects. Single nucleotide polymorphisms (SNPs) that introduce or disrupt CpG dinucleotides (CpG-SNPs) may alter DNA methylation levels and thus represent strong candidate functional variants. Here, we performed a targeted GWAS for 63,627 potential functional CpG-SNPs that may affect DNA methylation in bone-related cells, in five independent cohorts (n=5905). By meta-analysis, 9 CpG-SNPs achieved a genome-wide significance level (p<7.86×10−7) for association with lumbar spine BMD and additional 15 CpG-SNPs showed suggestive significant (p<5.00×10−5) association, of which 2 novel SNPs rs7231498 (NFATC1) and rs7455028 (ESR1) also reached a genome-wide significance level in the joint analysis. Several identified CpG-SNPs were mapped to genes that have not been reported for association with BMD in previous GWAS, such as NEK3 and NFATC1 genes, highlighting the enhanced power of targeted association analysis for identification of novel associations that were missed by traditional GWAS. Interestingly, several genomic regions, such as NEK3 and LRP5 regions, contained multiple significant/suggestive CpG-SNPs for lumbar spine BMD, suggesting that multiple neighboring CpG-SNPs may synergistically mediate the DNA methylation level and gene expression pattern of target genes. Furthermore, functional annotation analyses suggested a strong regulatory potential of the identified BMD-associated CpG-SNPs and a significant enrichment in biological processes associated with protein localization and protein signal transduction. Our results provided novel insights into the genetic basis of BMD variation and highlighted the close connections between genetic and epigenetic mechanisms of complex disease.

scholarly journals Regulatory SNP of RREB1 is Associated With Bone Mineral Density in Chinese Postmenopausal Osteoporosis Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Shuo Feng ◽  
Han Wang ◽  
Yumeng Yan ◽  
Xin Su ◽  
Jintao Ao ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Postmenopausal Osteoporosis ◽  
Bone Mineral ◽  
Quantitative Trait ◽  
Genome Wide Association Study ◽  
Chinese Women ◽  
Tissue Expression ◽  
Mineral Density ◽  
T Score ◽  
A Genome

Postmenopausal osteoporosis (PMO) is the most common bone disorder in elderly Chinese women. Although genetic factors have been shown to have a pivotal role in PMO, studies on genetic loci associated with PMO in Chinese individuals are still lacking. We aimed to identify SNPs that contribute to PMO in Chinese individuals by conducting a genome-wide association study (GWAS). Bone mineral density (BMD) of postmenopausal Chinese women was assessed. Participants with T-score &lt; −2.5 standard deviations (n = 341) were recruited and divided into a discovery group (n = 150) and a replication group (n = 191). GWAS was performed, with T-score as the quantitative trait, using linear regression. Our results revealed that an SNP cluster upstream of RREB1 showed a trend of association with BMD in Chinese PMO patients. The leading SNP of the cluster was rs475011 (pcombined = 1.15 × 10−6, beta = 0.51), which is a splicing quantitative trait locus (sQTL) of RREB1. This association was further supported by data from the UK Biobank (UKBB; p = 9.56 × 10−12). The high BMD-associated allele G of rs475011 is related to a high intron excision ratio. This SNP may increase BMD by upregulating mature RREB1 mRNA, based on data from the Genotype-Tissue Expression (GTEx) database. We identified BMD-associated SNPs that regulate RREB1 in Chinese PMO patients. Future functional experiments are needed to further link rs475011, RREB1, and PMO in Chinese individuals.

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