Genetic Determinants of the Association between Osteoarthritis and Psychiatric Disorders

Abstract

Background. The associations between hip/knee osteoarthritis (OA) and various psychiatry disorders, as well as the underlying genetic determinants, remain unclear. Methods. Based on the community-based prospective data of UK Biobank, we constructed two matched cohorts to assess the bidirectional associations between OA and five common psychiatry disorders. Then, we further examined the existence of overall genetic association for those disease pairs with demonstrated phenotypic association through polygenic risk score (PRS) prediction using individual-level genotyping data of UK Biobank and LD score regression (LDSC) analysis utilizing publicly available GWAS summary statistics. Last, also based on GWAS summary statistics, we performed enrichment analyses to pinpoint specific genetic determinants that might contribute to the observed overall genetic shares. Results. The phenotypic analyses revealed an elevated risk of hip/knee OA among individuals with any psychiatric disorders, compared to their matched unexposed individuals (hazard $\text{ratio}\left(\text{HR}\right)=1.62$ , 95% confidence interval (CI): 1.57-1.68), and vice versa (HR =1.93, 95% CI: 1.83-2.04). We further observed positive associations of knee OA with depression and stress-related disorder in the PRS analyses, which corroborated with the results of LDSC analyses ( $r$ for $\text{genetic}=0.20$ (95% CI: 0.15-0.25) and $r$ for $\text{genetic}=0.29$ (95% CI: 0.19-0.40), respectively). Using GWAS summary statistics, we identified several shared genes and pathways, particularly the biological process related to HDAC histones, between knee OA and depression/stress-related disorder. Conclusions. Our study demonstrated a bidirectional association between OA and multiple psychiatric disorders, and the findings of shared genetic architectures between knee OA and depression/stress-related disorder provided possible targets for further mechanistic exploration and intervention development.