Osteonecrosis of the femoral head (ONFH) is an ischemic disorder that causes bone and bone marrow necrosis. In spite of many studies, the primary cause of ischemia is still unknown. The purpose of this study is to identify the susceptibility genes in ONFH. We performed a genome-wide association study (GWAS) in 1,602 ONFH cases and 60,000 controls. Stratified GWASs based on the 3 subgroups of ONFH (corticosteroids, alcohol, idiopathic) were also performed. We then evaluated the candidate gene in silico using public databases. Two loci in 12q24.11–12 and 20q12 showed significant association with ONFH. A stratified analysis suggested that the 12q24 locus was associated with ONFH through the drinking capacity. In the 20q12 locus, LINC01370 was the only gene, which functions were related to the plausible biological pathway for the development of ONFH. A novel ONFH locus was identified at chromosome 20q12, and LINC01370 was the best candidate gene in this locus

Introduction. Aseptic loosening, the clinical endpoint of osteolysis, remains the leading cause of total hip arthroplasty (THA) failure, and is caused by a host response to wear debris that varies between individuals. Although several candidate gene studies have identified loci associated with osteolysis susceptibility, there have been no systematic studies at genome-wide level. We aimed to identify risk loci associated with osteolysis by conducting a genome-wide association study. Methods. 3,706 Caucasian European patients following THA were studied. The discovery cohort comprising 894 patients (317 with osteolysis) were genotyped using the Illumina-610 beadchip followed by 1000 Genome-based imputation covering 10 million single nucleotide polymorphisms (SNPs). Phenotypes were transformed to normality where required, regressed on important covariates and z-standardised. Following quality control, osteolysis case-control analysis and a quantitative trait association analysis for time to prosthesis failure were undertaken. Index SNPs p<9×10. −4. were taken forward for replication in a second cohort comprising 2,812 subjects (834 osteolysis cases) recruited from the Norwegian arthroplasty registry. Genotyping was undertaken using Sequenom MassARRAY iPLEX Gold assay and association analyses undertaken using logistic and linear regression. Summary statistics were combined in a fixed-effects meta-analysis framework. Results. The strongest signal associated with time to prosthesis failure lay within DEFB129 gene. The signal index SNP, rs6105394, approached genome wide significance at p=5.75×10. −7. Two signals in the susceptibility analysis also approached genome-wide significance, 1 within CAMK4 (rs306105, OR 0.41, p=6.54×10. −7. ) and 1 upstream of PLNXA2 (rs11119057, OR 0.96, p=6.44×10. −7. ). Following meta-analysis, the strongest signal in the susceptibility analysis remained that within CAMK4 (rs306105, p=3.79×10. −4. ). The strongest signal associated with time to failure was just upstream of CNTN3 (rs1374879, p=2.15×10. −5. ). Discussion. We have identified promising loci associated with osteolysis and time to prosthesis failure although not at genome-wide significance (p<5×10. −8. ). In order to further validate these loci, larger genome wide association analysis is required

Introduction. Periprosthetic osteolysis resulting in aseptic loosening is a leading cause for total hip arthroplasty (THA) failure. Individuals vary in their susceptibility to osteolysis, and it is thought that heritable factors contribute to this variation. We conducted two genome-wide association studies to identify genetic risk loci associated with osteolysis and genetic risk loci associated with time to prosthesis failure due to osteolysis. Patients/Materials & Methods. The Norway cohort comprised 2,624 subjects after THA recruited from the Norwegian Arthroplasty Registry, 779 with revision surgery for osteolysis. The UK cohort comprised 890 subjects recruited from hospitals in the north of England, 317 with radiographic evidence or revision surgery for osteolysis. All subjects had received a fully cemented or hybrid THA using small-diameter metal or ceramic-on-conventional polyethylene bearing. Osteolysis susceptibility case-control analyses and quantitative trait analyses for time to prosthesis failure were undertaken after genome-wide genotyping. Finally, a meta-analysis of the discovery datasets was undertaken. Results. Genome-wide association analysis identified 4 and 11 independent suggestive genetic signals for osteolysis susceptibility at P≤5×10. −6. in the Norwegian and UK cohorts, respectively. Following meta-analysis, 5 independent genetic signals showed suggestive association with osteolysis at P≤5×10. −6. , with the strongest comprising 18 correlated variants on chromosome 7 (lead signal rs850092, Figure 1, p=1.13×10. −6. ). Genome-wide quantitative trait analysis in cases only showed a total of 5 and 9 independent genetic signals for time to prosthesis failure at P≤5×10. −6. , respectively. Following meta-analysis, 11 independent genetic signals showed suggestive evidence of association with time to failure at P≤5×10. −6. , with the largest association block comprising 174 correlated variants in chromosome 15 (lead signal rs10507055, Figure 2, p=1.40×10. −7. ). Discussion. These studies provide the first genome-wide insights into the heritable biology of osteolysis, a major complication of joint replacement surgery. Although there were no dominant signals of genome-wide significance, we find replicating evidence for several independent genetic loci both for osteolysis susceptibility and time to prosthesis failure at P≤5×10. −6. , consistent with the complex aetiology of the disease. Conclusion. The heritable contribution to osteolysis is modest. The identified genetic loci may however provide novel avenues for therapy development in this condition. For any figures and tables, please contact the authors directly

Introduction. Although DDH is one of the most common skeletal dysplasias (incidence 1.5 cases per 1000 births), it remains slow and costly to recruit large-scale patient cohorts for powerful genetic association studies. In this work we have successfully used the NJR as a platform to generate a DDH biobank of 907 individuals, upon which we have conducted the first ever genome-wide association study (GWAS) for DDH. Methods. 5411 patients recorded as having a hip replacement for ‘hip dysplasia’ between March 2003 and December 2013 were approached to participate in the study. Following filtering by questionnaire for non-DDH cases and non-European Caucasians, 907 patients returned a completed saliva sample. A randomly selected sample of individuals participating on the UK Household Longitudinal Study that had been previously genotyped using the same platform were used as controls at a case:control ratio of 1:4. A further data set consisting of 332 cases, 1375 controls and 26 variants was used to replicate the top signals. Results. Of 256833 variants that passed QC, 11 variants reached genome-wide significance. All these variants came from the same signal, with rs143384 as the index SNP (allele A, allele frequency 0.60, OR [95% CI] 1.58[1.40–1.77], P=1.1×10. −14. ). Twenty-six independent variants were prioritized to follow up through de novo replication. Variant rs143384 was found to be significantly associated with DDH after meta-analysing discovery and replication datasets (allele A, allele frequency 0.60, OR [95% CI] 1.50[1.36–1.66], P=2.81×10. −16. ). Discussion. Using eHR case-ascertainment and distance recruitment strategies we conducted the first GWAS for DDH and confirmed association of the GDF5 variant rs143384 with DDH (P=2.81×10. −16. ). We establish the first genome-wide significant locus for DDH, discovered through linking EHRs with genomics as a proof of principle in enabling powerful genetic association studies of relatively rare but complex diseases