To prioritize causal-candidate genes and regulatory variants in ankylosing spondylitis (AS) using a comprehensive multi-omics approach, highlighting its significance in understanding the disease.
Key Findings:
Identified 30 genome-wide significant loci with 26,178 significant variants, underscoring the genetic complexity of AS.
Prioritized 64 causal-candidate genes with gene expression explaining 19.5% of AS heritability, indicating a substantial genetic contribution.
Seven genes showed convergent evidence from cTWAS and colocalization, suggesting strong candidates for further investigation.
Cross-trait LDSC revealed positive genetic correlations with inflammatory bowel disease and psoriasis, indicating shared pathways.
Interpretation:
The study provides a framework for prioritizing AS candidate genes and regulatory variants, distinguishing between statistical prioritization and experimental support, and suggesting avenues for future research.
Limitations:
The study primarily focuses on European-ancestry cohorts, which may limit generalizability to other populations.
The total heritability explained by known variants remains below the estimated 90% heritability of AS, indicating that many risk factors remain unidentified.
Conclusion:
The findings nominate immune and regulatory hypotheses for further investigation rather than definitive therapeutic targets, emphasizing the need for continued research in this area.
In a UK cohort, patients with osteoarthritis who initiated centrally acting analgesics had a higher hazard of knee or hip replacement than those who initiated SSRIs, though residual confounding by pain severity remains a key limitation.
