Joint disease-specificity at the regulatory base-pair level

Pushpanathan Muthuirulan, Dewei Zhao, Mariel Young, Daniel Richard, Zun Liu, Alireza Emami, Gabriela Portilla, Shayan Hosseinzadeh, Jiaxue Cao, David Maridas, Mary Sedlak, Danilo Menghini, Liangliang Cheng, Lu Li, Xinjia Ding, Yan Ding, Vicki Rosen, Ata M Kiapour, Terence D Capellini.
Nat Commun. 2021-07-06;12(1):4161.
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.
Consortium data used in this publication
All the raw data used in this paper are included in Figs. (2–5), Supplementary figures (1– 9), supplementary Data (1–6), as well as supplementary tables (1–15). All developmental human ATAC-seq sequencing data (raw sequencing FASTQ files and processed peak bed files) have been deposited on NCBI GEO under accession code GSE153260. All adult knee OA data from Liu et al.57 can be found on NCBI Geo under accession code GSE108301. All OAI datasets can be found at