Phenotype-Genotype analysis of caucasian patients with high risk of osteoarthritis

Background: Osteoarthritis (OA) is a common cause of disability and pain around the world. Epidemiologic studies of family history have revealed evidence of genetic influence on OA. Although many efforts have been devoted to exploring genetic biomarkers, the mechanism behind this complex disease remains unclear. The identified genetic risk variants only explain a small proportion of the disease phenotype. Traditional genome-wide association study (GWAS) focuses on radiographic evidence of OA and excludes sex chromosome information in the analysis. However, gender differences in OA are multifactorial, with a higher frequency in women, indicating that the chromosome X plays an essential role in OA pathology. Furthermore, the prevalence of comorbidities among patients with OA is high, indicating multiple diseases share a similar genetic susceptibility to OA. Methods: In this study, we performed GWAS of OA and OA-associated key comorbidities on 3366 OA patient data obtained from the Osteoarthritis Initiative (OAI). We performed Mendelian randomization to identify the possible causal relationship between OA and OA-related clinical features. Results: One significant OA-associated locus rs2305570 was identified through sex-specific genome-wide association. By calculating the LD score, we found OA is positively correlated with heart disease and stroke. A strong genetic correlation was observed between knee OA and inflammatory disease, including eczema, multiple sclerosis, and Crohn’s disease. Our study also found that knee alignment is one of the major risk factors in OA development, and we surprisingly found knee pain is not a causative factor of OA, although it was the most common symptom of OA. Conclusion: We investigated several significant positive/negative genetic correlations between OA and common chronic diseases, suggesting substantial genetic overlaps between OA and these traits. The sex-specific association analysis supports the critical role of chromosome X in OA development in females.