Abstract
Paget’s disease of bone (PDB) is characterised by focal abnormalities of bone remodelling, with increased osteoclastic resorption the primary feature of the disease. Genetic factors have been shown to play an important role in PDB, and genome-wide association studies (GWAS) have identified 7 genetic loci as associated with PDB at the genome-wide level. Expression quantitative trait locus (eQTL) studies using cell types that are directly relevant to the disease of interest are increasingly being used to identify putative effector genes for GWAS loci. We have recently constructed a unique osteoclast-specific eQTL resource using cells differentiated in vitro from 158 subjects for study of the genetics of bone disease. Considering the major role osteoclasts have in PDB, we used this resource to investigate potential genetic regulatory effects for the 7 PDB genome-wide significant loci on genes located within 500 kb of each locus. After correction for multiple testing, we observed statistically significant associations for rs4294134 with expression of the gene STMP1, and rs2458413 with expression of the genes DPYS and DCSTAMP. The eQTL associations observed for rs4294134 with STMP1, and rs2458413 with DCSTAMP were further supported by eQTL data from other tissue types. The product of the STMP1 gene has not been extensively studied, however the DCSTAMP gene has an established role in osteoclast differentiation and the associations seen between rs2458413 and PDB are likely mediated through regulatory effects on this gene. This study highlights the value of eQTL data in determining which genes are relevant to GWAS loci.
Highlights
Paget’s disease of bone (PDB), first described by Sir James Paget in 1876, is characterised by focal abnormalities of bone remodelling
Genetic factors have been shown to play an important role in the pathogenesis of PDB and are generally considered to be the primary risk-factor for developing the disease, with relatives of an affected individual having around 7-fold greater risk of developing PDB than the general population[5]
The G allele at rs4294134, which is associated with an increased risk of PDB12, was found to be associated with increased expression of STMP1 in our osteoclast Expression quantitative trait locus (eQTL) dataset, consistent with the allelic effect observed in the GTEx tissues
Summary
Paget’s disease of bone (PDB), first described by Sir James Paget in 1876, is characterised by focal abnormalities of bone remodelling It is the most common metabolic bone disease after osteoporosis, affecting around 2% of European individuals aged 55 years and over[1], both the incidence and severity of newly diagnosed cases is falling[2,3]. The genetic architecture of the disease is complex, with contributions from rare mutations in the SQSTM1 gene as well as common variants with small effects located in other genes. The most recent of these, performed by Albagha et al.[12] in a study cohort of 2,215 PDB cases without SQSTM1 mutations and 4,370 controls, identified 7 loci as associated with PDB at the genome-wide significance level. Considering the major role osteoclasts have in PDB, we sought to use this resource to investigate potential genetic regulatory effects for the 7 genome-wide significant loci for PDB
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