Joint disease-specificity at the regulatory base-pair level

Given the pleiotropic nature of coding sequences and that many loci exhibit multiple disease associations, it is within non-coding sequence that disease-specificity likely exists. Here, we focus on joint disorders, finding among replicated loci, that GDF5 exhibits over twenty distinct associations, and we identify causal variants for two of its strongest associations, hip dysplasia and knee osteoarthritis. By mapping regulatory regions in joint chondrocytes, we pinpoint two variants (rs4911178; rs6060369), on the same risk haplotype, which reside in anatomical site-specific enhancers. We show that both variants have clinical relevance, impacting disease by altering morphology. By modeling each variant in humanized mice, we observe joint-specific response, correlating with GDF5 expression. Thus, we uncouple separate regulatory variants on a common risk haplotype that cause joint-specific disease. By broadening our perspective, we finally find that patterns of modularity at GDF5 are also found at over three-quarters of loci with multiple GWAS disease associations. While many genetic loci have been found to be associated with disease, not many have had their causal variants and mechanisms investigated. Here, the authors experimentally dissect two loci near GDF5 which are associated with two different joint disorders and which map to independent regulatory elements.

Automated summary

Non-coding sequences may hold disease-specificity, with loci such as GDF5 showing multiple associations in joint disorders. By identifying causal variants for hip dysplasia and knee osteoarthritis, researchers pinpointed variants residing in site-specific enhancers. The study also found modularity patterns at GDF5 and other loci with multiple GWAS disease associations, suggesting common regulatory mechanisms for joint-specific diseases.