Whole-blood transcriptomic traces of organ pathology and their causal triage

Whole blood offers a non-invasive window into organ health, yet it remains unclear which organ pathologies leave a detectable trace in the blood transcriptome, and whether such traces are causal or reactive. Progress has been limited because paired whole-blood profiles and pathologist-graded organ pathology are rarely available together. Here we assembled a pathology-linked benchmark of 59 pathologies across 20 organs in 803 GTEx v10 donors with matched whole-blood RNA-seq and postmortem histology. Because a postmortem cohort's blood is strongly shaped by age, sex, and the circumstances of death, our framework, TRACE, counts a signal only when blood expression predicts a pathology beyond these donor factors. Four pathologies passed, with liver cirrhosis by far the strongest (AUC 0.79). The cirrhosis signature replicated in an independent cohort of living patients (AUC 0.80) and remained specific against severe systemic illness. To separate candidate drivers from reactive markers, we used human genetics: Mendelian randomization linking plasma proteins to liver disease, which recovered established fibrosis drivers, including PAI-1 (SERPINE1), tenascin-C, thrombospondin-2 and nominated further candidates. Together, TRACE provides a resource and a confounder-aware framework for learning which organ pathologies the blood transcriptome can, and cannot, detect, and which of those signals are likely causal.