Insights into the genetic architecture of osteoarthritis from stage 1 of the arcOGEN study

Abstract

Objectives: The genetic aetiology of osteoarthritis has not yet been elucidated. To enable a well-powered genome-wide association study (GWAS) for osteoarthritis, the authors have formed the arcOGEN Consortium, a UK-wide collaborative effort aiming to scan genome-wide over 7500 osteoarthritis cases in a two-stage genome-wide association scan. Here the authors report the findings of the stage 1 interim analysis.

Methods: The authors have performed a genome-wide association scan for knee and hip osteoarthritis in 3177 cases and 4894 population-based controls from the UK. Replication of promising signals was carried out in silico in five further scans (44,449 individuals), and de novo in 14 534 independent samples, all of European descent.

Results: None of the association signals the authors identified reach genome-wide levels of statistical significance, therefore stressing the need for corroboration in sample sets of a larger size. Application of analytical approaches to examine the allelic architecture of disease to the stage 1 genome-wide association scan data suggests that osteoarthritis is a highly polygenic disease with multiple risk variants conferring small effects.

Conclusions: Identifying loci conferring susceptibility to osteoarthritis will require large-scale sample sizes and well-defined phenotypes to minimise heterogeneity.

Figure 1

Summary of polygene analysis results evaluating the genetic architecture of osteoarthritis. Lines in red (real data) and blue (permuted data) show mean±1 SD of the Nagelkerke's pseudo r² statistic, which indicates the proportion of case–control status accounted for by score alleles in the single-nucleotide polymorphism (SNP) sets. The blue line represents expectation under the null hypothesis of no genetic component to the disease. The red line represents stage 1 genome-wide association study data and shows that SNP at the tail of the p value distribution (up to p<0.25, but primarily p<0.10) have a significantly higher case–control discriminatory capacity.