A novel variant in GLIS3 is associated with osteoarthritis

Abstract

ObjectivesOsteoarthritis (OA) is a complex disease, but its genetic aetiology remains poorly characterised. To identify novel susceptibility loci for OA, we carried out a genome-wide association study (GWAS) in individuals from the largest UK-based OA collections to date.MethodsWe carried out a discovery GWAS in 5414 OA individuals with knee and/or hip total joint replacement (TJR) and 9939 population-based controls. We followed-up prioritised variants in OA subjects from the interim release of the UK Biobank resource (up to 12 658 cases and 50 898 controls) and our lead finding in operated OA subjects from the full release of UK Biobank (17 894 cases and 89 470 controls). We investigated its functional implications in methylation, gene expression and proteomics data in primary chondrocytes from 12 pairs of intact and degraded cartilage samples from patients undergoing TJR.ResultsWe detect a genome-wide significant association at rs10116772 with TJR (P=3.7×10−8; for allele A: OR (95% CI) 0.97 (0.96 to 0.98)), an intronic variant in GLIS3, which is expressed in cartilage. Variants in strong correlation with rs10116772 have been associated with elevated plasma glucose levels and diabetes.ConclusionsWe identify a novel susceptibility locus for OA that has been previously implicated in diabetes and glycaemic traits.

Prioritization of PLEC and GRINA as Osteoarthritis Risk Genes Through the Identification and Characterization of Novel Methylation Quantitative Trait Loci

“…We investigated 18 novel OA risk loci that had been reported as being associated with the disease at a significance level close to or surpassing the genome‐wide threshold of P < 5 × 10 −8 (Table ). If the OA‐associated SNP was directly genotyped on an Illumina HumanOmniExpress array, we utilized those SNP data.…”

“…We had both methylation and genotype data available for a total of 87 patients who had undergone knee or hip joint arthroplasty (57 knee OA patients, 14 hip OA patients, and 16 patients who had undergone hip replacement due to a femoral neck fracture (Supplementary Table 1 OA loci investigation and mQTL analysis. We investigated 18 novel OA risk loci that had been reported as being associated with the disease at a significance level close to or surpassing the genome-wide threshold of P < 5 × 10 −8 (13)(14)(15)(16)(17)(18)(19)(20) ( Table 1). If the OA-associated SNP was directly genotyped on an Illumina HumanOmniExpress array, we utilized those SNP data.…”

Exploration of shared genetic susceptibility loci between type 1 diabetes and rheumatoid arthritis in the Pakistani population

“…This SNP was strongly associated (p = 5.29E−05) with T1D susceptibility in the Pakistani population [27]. In addition to T1D, polymorphisms in GLIS3 have been reported to be associated with type 2 diabetes, Alzheimer’s disease and osteoarthritis [28, 29]. It is possible that genetic variation in GLIS3 may also have some role in the RA etiology, but this awaits confirmation in much larger genetic studies.…”

The Genetic Epidemiology of Joint Shape and the Development of Osteoarthritis

“…Of the nine identified variants in the primary analysis, several were associated with the minimum joint space width phenotype, but only a nominal association between an intergenic variant rs116882138 and centre-edge angle (a feature of DDH, β = − 1.1388, P = 0.03), and no association with alpha angle (a feature of cam morphology), was found. Tachmazidou et al [125], in the largest GWAS of OA published to date, including 77,052 cases and 378,169 controls in a meta-analysis examining 17.5million variants, identified 64 signals (52 novel) at MAF > 0.01 on top of 34 previously established loci [124,126,128,[130][131][132][133][134][135][136][137][138][139][140][141][142]. Pathways analysis using MAGMA, PASCAL, and DEPICT Although associations with other demographic characteristics and disease states were examined by linkage disequilibrium regression analysis using LDHub [91], specific direct associations with joint shape were not explored.…”