Genome-wide association study identifies variants at CSF1, OPTN and TNFRSF11A as genetic risk factors for Paget's disease of bone

Abstract

Paget's disease of bone (PDB) is a common disorder with a strong genetic component characterized by focal increases in bone turnover, which in some cases is caused by mutations in SQSTM1. To identify additional susceptibility genes, we performed a genome-wide association study in 750 individuals with PDB (cases) without SQSTM1 mutations and 1,002 controls and identified three candidate disease loci, which were then replicated in an independent set of 500 cases and 535 controls. The strongest signal was with rs484959 on 1p13 near the CSF1 gene (P = 5.38 x 10(-24)). Significant associations were also observed with rs1561570 on 10p13 within the OPTN gene (P = 6.09 x 10(-13)) and with rs3018362 on 18q21 near the TNFRSF11A gene (P = 5.27 x 10(-13)). These studies provide new insights into the pathogenesis of PDB and identify OPTN, CSF1 and TNFRSF11A as candidate genes for disease susceptibility.

Figure 1. Loci for susceptibility to PDB detected by genome wide association study

Manhattan plot of association test results from the discovery cohort showing chromosomal positions of the 294,633 SNPs passing quality control plotted against genomic-control adjusted −log₁₀​ P. Association with Paget’s disease was tested using stratified Cochran-Mantel-Haenszel test. The red horizontal line indicates the threshold for genome wide significance (P < 1.7 × 10⁻⁷).

Figure 2. Details of loci associated with Paget’s disease

Association and linkage disequilibrium (LD) plots of regions showing genome wide significant association with Paget’s disease located on (a) chr 1p13, (b) chr 10p13 and (c) 18q21. The chromosomal position (based on NCBI human genome Build 36) of SNPs is plotted against genomic-control adjusted −log₁₀​ P. Genotyped SNPs are shown as red triangles and imputed SNPs as blue diamonds. The estimated recombination rates (cM/Mb) from HapMap CEU release 22 are shown as grey lines and the red horizontal line indicates genome wide significance threshold (P < 1.7 × 10⁻⁷). Genotyped SNPs were tested using stratified Cochran-Mantel-Haenszel test and imputed SNPs were tested using regression analysis based on imputed allelic dosage and adjusting for population clusters. SNPs reaching genome wide significance are shown with red text. LD plots for the indicated regions are based on HapMap CEU release 22 showing LD blocks depicted for alleles with MAF > 0.05 using the r² colouring scheme of Haploview. The blue arrows indicate known genes in the region and possible recombination hotspots (> 20 cM/Mb) are shown as green arrows on the LD plots.