Abstract
Osteoporosis is characterized by increased bone loss and deterioration of bone microarchitecture, which will lead to reduced bone strength and increased risk of fragility fractures. Previous studies have identified many genetic loci associated with osteoporosis, but functional mechanisms underlying the associations have rarely been explored. In order to explore the potential molecular functional mechanisms underlying the associations for osteoporosis, we performed integrative analyses by using the publically available datasets and resources. We searched 128 identified osteoporosis associated SNPs (P<10−6), and 8 SNPs exert cis-regulation effects on 11 eQTL target genes. Among the 8 SNPs, 2 SNPs (RPL31 rs2278729 and LRP5 rs3736228) were confirmed to impact the expression of 3 genes (RPL31, CPT1A and MTL5) that were differentially expressed between human subjects of high BMD group and low BMD group. All of the functional evidence suggested the important functional mechanisms underlying the associations of the 2 SNPs (rs2278729 and rs3736228) and 3 genes (RPL31, CPT1A and MTL5) with osteoporosis. This study may provide novel insights into the functional mechanisms underlying the osteoporosis associated genetic variants, which will help us to comprehend the potential mechanisms underlying the genetic association for osteoporosis.
Highlights
Osteoporosis is a skeletal disease characterized by low bone mineral density (BMD) and microarchitectural deterioration of bone tissue, leading to decreased bone strength and increased the risk of fracture[1]
We detected 88 genes for the 128 SNPs by Gene Relationships Across Implicated Loci (GRAIL) analysis: 31 genes can be detected by Phenotype-Genotype Integrator (PheGenI) and 57 newly detected genes were
Among the 128 unique SNPs, we found that 8 SNPs have potential eQTL effects on a total of eleven eQTL target genes (Table 1) in LCLS or monocytes[28,29,30] which are two type of cells closely related with bone metabolism and all of them act as cis-effect regulators
Summary
Osteoporosis is a skeletal disease characterized by low bone mineral density (BMD) and microarchitectural deterioration of bone tissue, leading to decreased bone strength and increased the risk of fracture[1]. Osteoporosis endangers the health and life quality of patients, and brings huge economic burden to the global health. More than 2 million Americans suffered osteoporotic fractures in 2005 with treatment costs more than $17 billion [2]. Due to the aging of the population in the United States, it is expected that osteoporotic fractures rates will reach more than 3 million patients and $25.3 billion treatment costs over the 25 years [3].
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