Figure 1.

GWAS results demonstrate association between GDF5 and DDH. A and B. Manhattan plot of the DDH genome-wide association scan in A) European population and B) Chinese population. A. The dashed line indicates the genome-wide significance threshold (P =5.0 × 10-8). Green dots represent variants for which P-values reached the genome-wide significance threshold. Chromosomes X and pseudo-autosomal regions on the chromosome X are represented by number 23 and 24, respectively. B. No loci in Chinese GWAS reached genome-wide significance threshold and potential signals were defined as loci for which P-values were under 1 x 10-4 (dash line). C. A meta-analysis incorporating two functional nearing SNPs (rs143383 & rs143384) of GDF5 in osteoarthritis were derived from GWAS results, a replication study in Chinese population with 218 patients and 360 controls and achieved a significant signal in replication. (OR=0.66, 95% CI: 0.60-0.73, p=8.02E-30 for rs143384; OR=0.68, 95% CI: 0.62-0.75, p=2.68E-23 for rs143383). D. The genomic region linked to DDH susceptibility in human spans the regulatory enhancer architecture of GDF5 in the present study with DDH in cases vs controls. Y-axis is the -log P-value of the trait association for SNPs across the interval derived from two separate GWAS. X-axes show genomic megabase locations (bottom axis) of human sequences orthologous to reported G1, R1, R2, R3, R4, and R5 elements (red color in top axis). The highest scoring variant tested in the human study, rs143383 and rs143384 (red circle), is located in GDF5 5'UTR, immediately downstream of the R2 region. Note that significant association extends over a broad region and Some loci in the present study locate in or near the separable enhancers. E. Chromatin conformation capture data was acquired from human cell types to gain an understanding of the regulatory neighborhood containing GDF5 loci. Across cell types and species, we found conservation in the topologically associated domain (TAD) structure of the loci.