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Protein-Centric Omics Integration Analysis Highlights the Heterogeneity Among Multiple Autoimmune Diseases
21 Pages Posted: 10 May 2023
More...Abstract
Background: It remains challenging to translate the findings from genome-wide association studies (GWAS) of Autoimmune diseases (AIDs) into interventional targets, presumably due to the lack of knowledge on how the GWAS risk variants contribute to AIDs. In addition, current immunomodulatory drugs for AIDs are broad in action, often with side effects such as infection and malignancy.
Methods: We performed comprehensive protein-centric omics integration analysis to identify AIDs-associated plasma proteins through integrating protein quantitative trait loci datasets of plasma protein (1348 proteins and 7213 individuals) and totally ten large-scale GWAS summary statistics of AIDs under a cutting-edge systematic analytic framework. Specifically, we initially screened out the protein-AIDs associations using proteome-wide association study (PWAS), followed by enrichment analysis to reveal the underlying biological processes and pathways. Then, we performed both Mendelian randomization (MR) and colocalization analyses to further identify protein-AIDs pairs with putatively causal relationships. We finally prioritized the potential drug targets for AIDs.
Findings: A total of 174 protein-AIDs associations were identified by PWAS. Enrichment analysis illustrated that AIDs-associated plasma proteins were significantly enriched immune related biological process and pathways, such as inflammatory response (P = 3.96 × 10-10), indicating the homogeneity among these multiple AIDs at the pathway level. MR analysis further identified 99 protein-AIDs pairs with potential causal relationships, among which 20 pairs were highly supported by colocalization analysis (PP.H4 > 0.75). Notably, the 20 proteins are distributed on 20 approximately independent LD blocks across the whole genome and are more likely to be biologically plausible, indicating the heterogeneity among these AIDs at the protein level. Further explorations showed that four proteins (TLR3, FCGR2A, IL23R, TCN1) have corresponding drugs, and 17 proteins have druggability.
Interpretation: Our results provided biological insights into the pathogenesis of different AIDs and indicated multiple AIDs are homogeneous at the pathway level but heterogeneous at the protein level, suggesting that the drug development for AIDs could be developed in a disease-specific manner.
Funding: This study has been supported by grants from the National Natural Science Foundation of China (82173624 and 81872712), the Natural Science Foundation of Shandong Province (ZR2019ZD02), the Taishan Scholar Project of Shandong Province, and Cheeloo Young Talent Program of Shandong University.
Declaration of Interest: The authors declare no competing interests.
Keywords: Autoimmune disease, Plasma protein, Proteome-wide association study, Mendelian randomization, Colocalization, Therapeutic target
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