We applied the GRAIL text-mining algorithm19 to investigate connections between genes in the 55 autosomal BMD loci. This analysis revealed significant (GRAIL SNP P<0.01) connections between genes in 18 of the 55 input loci (Fig. 4 and Supplementary Table 16). The strongest connections were seen for members of three key biologic pathways: RANK-RANKL-OPG pathway (TNFRSF11A-TNFSF11-TNFRSF11B); mesenchymal stem cell differentiation (RUNX2, SP7, SOX9); and Wnt-signalling (LRP5, CTNNB1, SFRP4, WNT3, WNT4, WNT5B, WNT16, AXIN1) with the ten most frequently connecting terms being: ‘bone’, ‘catenin’, ‘signaling’, ‘differentiation’, ’rank’, ‘osteoblast’, ‘diacylglycerol’, ‘kappab’, ‘development’, and ‘osteoclast’. To assess the significance of this “biological” gene connection enrichment we applied GRAIL to 2000 random matched sets of 55 SNPs (See Supplementary note for details) and we did not observe any set with 15 or more loci with significant enriched connectivity (Supplementary Fig. 9) providing strong statistical evidence of the significant clustering of our BMD loci (P < 0.0005).
