Discovery of Disease Relationships via Transcriptomic Signature Analysis Powered by Agentic AI

TL;DR

This paper presents a transcriptomics-based framework using agentic AI to uncover disease relationships, revealing known and novel links, and suggesting mechanisms and therapeutic opportunities across diseases.

Contribution

Introduces GenoMAS, an agentic AI system for large-scale transcriptomic analysis, and develops a pathway-based similarity framework to discover and interpret disease relationships.

Findings

Revealed known and novel disease connections.

Identified molecular mechanisms underlying disease links.

Suggested therapeutic repurposing opportunities.

Abstract

Modern disease classification often overlooks molecular commonalities hidden beneath divergent clinical presentations. This study introduces a transcriptomics-driven framework for discovering disease relationships by analyzing over 1300 disease-condition pairs using GenoMAS, a fully automated agentic AI system. Beyond identifying robust gene-level overlaps, we develop a novel pathway-based similarity framework that integrates multi-database enrichment analysis to quantify functional convergence across diseases. The resulting disease similarity network reveals both known comorbidities and previously undocumented cross-category links. By examining shared biological pathways, we explore potential molecular mechanisms underlying these connections-offering functional hypotheses that go beyond symptom-based taxonomies. We further show how background conditions such as obesity and hypertension modulate transcriptomic similarity, and identify therapeutic repurposing opportunities for rare diseases like autism spectrum disorder based on their molecular proximity to better-characterized conditions. In addition, this work demonstrates how biologically grounded agentic AI can scale transcriptomic analysis while enabling mechanistic interpretation across complex disease landscapes. All results are publicly accessible at github.com/KeeeeChen/Pathway_Similarity_Network.