Protein-centric omics integration analysis identifies candidate plasma proteins for multiple autoimmune diseases

Area of Science:

• Genetics and Immunology
• Systems Biology
• Pharmacogenomics

Background:

• Translating genome-wide association studies (GWAS) findings into therapeutic targets for autoimmune diseases (AIDs) remains challenging due to unknown mechanisms of risk variants.
• Current immunomodulatory drugs for AIDs lack disease specificity, necessitating the identification of precise therapeutic targets.

Purpose of the Study:

• To identify autoimmune disease (AID)-associated plasma proteins by integrating protein quantitative trait loci (pQTL) data with large-scale GWAS summary statistics.
• To uncover potential causal relationships between plasma proteins and AIDs and prioritize novel therapeutic targets.

Main Methods:

• Performed a comprehensive protein-centric omics integration analysis, including proteome-wide association study (PWAS), enrichment analysis, Mendelian randomization (MR), and colocalization analysis.
• Integrated pQTL data from 1348 proteins and 7213 individuals with GWAS data from ten large-scale AID studies.

Main Results:

• Identified 174 protein-AID associations via PWAS, with significant enrichment in immune-related pathways like inflammatory response.
• Discovered 97 protein-AID pairs with potential causal relationships through MR, of which 21 were strongly supported by colocalization analysis, including 10 novel associations.
• Identified four proteins with existing drugs and 17 with druggability, suggesting potential therapeutic avenues.

Conclusions:

• The study successfully identified novel plasma proteins associated with AIDs and their potential causal links.
• These findings enhance the understanding of AID pathogenesis and highlight promising protein targets for developing specific immunomodulatory therapies.