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=3.55x1022). 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.

Improving early detection of developmental dysplasia of the hip through general practitioner assessment and surveillance

“…3,4,17 Late diagnosis may occur as a result of screening failures, 3 inappropriate swaddling 22,23 or progression of pathology; efforts to minimise late cases may be hampered by lack of consensus in screening guidelines. 31 While future developments in our understanding of the genetic component may lead to targeted investigations of individuals who are at risk, 18 currently we must search for hip pathology in all children.…”

“…17 Associated gene defects occur in the transforming growth factor beta superfamily, necessary for normal bone and joint development. 18 The highest DDH risk is in female breech babies (absolute risk 120/1000), followed by females with a family history (44/1000), then male breech babies (26/1000). 17 The estimated risk for males with a family history (9.4/1000) is lower than females in general (19/1000).…”

Update on the management of infant and toddler developmental dysplasia of the hip

“…Neonatal hip instability is laxity limited to the hip joint capsule and is influenced by hormonal and genetic factors. [7][8][9][10] This laxity has a natural tendency to correct itself, with 95.3% of hips returning to normal morphology by 12 weeks of age. 11 The spectrum continues to more severe forms of dysplasia with worsening hip instability, to the established hip subluxation with significant hip dysplasia, some of which may then progress to frank hip dislocation.…”

La displasia del desarrollo de la cadera puede predisponer a osteoartritis: de la inflamación a la destrucción. Revisión de la literatura

“…En este sentido, se ha reportado que las mutaciones en el gen GDF5 están asociadas a varios tipos de displasias y sinostosis, así como a la susceptibilidad del individuo a padecer OA. 1,[5][6][7] La prevalencia de la OA de cadera oscila entre 0,37% y 27%, dependiendo de la edad, el sexo, el lugar de procedencia y el grado de afectación. Al respecto, la prevalencia de OA de cadera más alta se ha descrito en los norteamericanos y la más baja en los latinoamericanos (Tabla 1).…”