The Genetic Epidemiology of Developmental Dysplasia of the Hip: A Genome-Wide Association Study Harnessing National Clinical Audit Data

ABSTRACT Background Developmental dysplasia of the hip (DDH) is a common, heritable condition characterised by abnormal formation of the hip joint, but has a poorly understood genetic architecture due to small sample sizes. We apply a novel case-ascertainment approach using national clinical audit (NCA) data to conduct the largest DDH genome-wide association study (GWAS) to date, and replicate our findings in independent cohorts. Methods We used the English National Joint Registry (NJR) dataset to collect DNA and conducted a GWAS in 770 DDH cases and 3364 controls. We tested the variant most strongly associated with DDH in independent replication cohorts comprising 1129 patients and 4652 controls. Results The heritable component of DDH attributable to common variants was 55% and distributed similarly across autosomal and the X-chromosomes. Variation within the GDF5 gene promoter was strongly and reproducibly associated with DDH (rs143384, OR 1.44 [95% CI 1.34-1.56], p=3.55x10 −22 ). Two further replicating loci showed suggestive association with DDH near NFIB (rs4740554, OR 1.30 [95% CI 1.16-1.45], p=4.44x10 −6 ) and LOXL4 (rs4919218, 1.19 [1.10-1.28] p=4.38x10 −6 ). Through gene-based enrichment we identify GDF5, UQCC1, MMP24, RETSAT and PDRG1 association with DDH (p<1.2x10 −7 ). Using the UK Biobank and arcOGEN cohorts to generate polygenic risk scores we find that risk alleles for hip osteoarthritis explain <0.5% of the variance in DDH susceptibility. Conclusion Using the NJR as a proof-of-principle, we describe the genetic architecture of DDH and identify several candidate intervention loci and demonstrate a scalable recruitment strategy for genetic studies that is transferrable to other complex diseases. Key Messages We report the first genome-wide scan for DDH in a European population, and the first to use national clinical audit data for case-ascertainment in complex disease. The heritable component of DDH attributable to common variants is 55% and is distributed similarly across autosomal and the X-chromosomes. Variation within the GDF5 gene promoter is strongly and reproducibly associated with DDH, with fine-mapping indicating rs143384 as the likely casual variant. Enrichment analyses implicate GDF5, UQCC1, MMP24, RETSAT and PDRG1 as candidate targets for intervention in DDH. DDH shares little common genetic aetiology with idiopathic osteoarthritis of the hip, despite sharing variation within the GDF5 promoter as a common risk factor.