bioRxiv2017
BackgroundDevelopmental 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.\n\nMethodsWe 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.\n\nResultsThe 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.\n\nConclusionUsing 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.\n\nKey MessagesO_LIWe 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.\nC_LIO_LIThe heritable component of DDH attributable to common variants is 55% and is distributed similarly across autosomal and the X-chromosomes.\nC_LIO_LIVariation within the GDF5 gene promoter is strongly and reproducibly associated with DDH, with fine-mapping indicating rs143384 as the likely casual variant.\nC_LIO_LIEnrichment analyses implicate GDF5, UQCC1, MMP24, RETSAT and PDRG1 as candidate targets for intervention in DDH.\nC_LIO_LIDDH shares little common genetic aetiology with idiopathic osteoarthritis of the hip, despite sharing variation within the GDF5 promoter as a common risk factor.\nC_LI