A cross-disease, pleiotropy-driven approach for therapeutic target prioritization and evaluation
Cell Reports Methods(2024)
摘要
Cross-disease genome-wide association studies (GWASs) unveil pleiotropic loci, mostly situated within the non-coding genome, each of which exerts pleiotropic effects across multiple diseases. However, the challenge “W-H-W” (namely, whether, how, and in which specific diseases pleiotropy can inform clinical therapeutics) calls for effective and integrative approaches and tools. We here introduce a pleiotropy-driven approach specifically designed for therapeutic target prioritization and evaluation from cross-disease GWAS summary data, with its validity demonstrated through applications to two systems of disorders (neuropsychiatric and inflammatory). We illustrate its improved performance in recovering clinical proof-of-concept therapeutic targets. Importantly, it identifies specific diseases where pleiotropy informs clinical therapeutics. Furthermore, we illustrate its versatility in accomplishing advanced tasks, including pathway crosstalk identification and downstream crosstalk-based analyses. To conclude, our integrated solution helps bridge the gap between pleiotropy studies and therapeutics discovery.
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关键词
Cross-disease pleiotropic association data,pleiotropy informing prioritization and evaluation,neuropsychiatric disorders,inflammatory disorders,computational medicine,therapeutic targets
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