Genome-wide association study of developmental dysplasia of the hip identifies an association with GDF5

Developmental dysplasia of the hip (DDH) is the most common skeletal developmental disease. However, its genetic architecture is poorly understood. We conduct the largest DDH genome-wide association study to date and replicate our findings in independent cohorts. We find the heritable component of DDH attributable to common genetic variants to be 55% and distributed equally across the autosomal and X-chromosomes. We identify replicating evidence for association between GDF5 promoter variation and DDH (rs143384, effect allele A, odds ratio 1.44, 95% confidence interval 1.34–1.56, P = 3.55 × 10(−22)). Gene-based analysis implicates GDF5 (P = 9.24 × 10(−12)), UQCC1 (P = 1.86 × 10(−)(10)), MMP24 (P = 3.18 × 10(−9)), RETSAT (P = 3.70 × 10(−)(8)) and PDRG1 (P = 1.06 × 10(−)(7)) in DDH susceptibility. We find shared genetic architecture between DDH and hip osteoarthritis, but no predictive power of osteoarthritis polygenic risk score on DDH status, underscoring the complex nature of the two traits. We report a scalable, time-efficient recruitment strategy and establish for the first time to our knowledge a robust DDH genetic association locus at GDF5.