Massive Blood RNA Atlas Maps Molecular Fingerprints of 98 Human Diseases

Every drop of blood carries a molecular diary. The cells circulating through our veins constantly switch genes on and off in response to infection, inflammation, metabolic stress, and dozens of other physiological pressures, and those shifting patterns of gene expression leave a readable signature in the RNA extracted from a routine blood sample. A team of researchers led by scientists at Science for Life Laboratory and KTH Royal Institute of Technology in Stockholm, together with a large clinical consortium centered at Atatürk University in Erzurum, Turkey, has now assembled one of the most comprehensive maps of those signatures ever attempted. In a study published in Nature Communications, the group presents what it calls the WBT Atlas, a whole blood transcriptomics resource built from 4,444 blood samples spanning 98 distinct health conditions, ranging from acute infections and inflammatory disorders to metabolic, cardiovascular, oncological, and surgical diseases.

The scale and clinical breadth of the underlying cohort is what sets the resource apart. Most transcriptomic studies focus on one disease at a time, comparing patients against a small control group, which makes it difficult to know whether a gene signature is truly specific to a condition or merely reflects generic illness. By collecting whole blood RNA profiles across 98 different health states within a coordinated framework, the researchers could ask, for the first time at this scale, which molecular changes are shared across many diseases and which are genuinely distinctive. The atlas characterizes each condition at multiple levels of biological organization: individual genes, co-expressed gene modules, and entire biological pathways, with particular attention to immune cell composition, metabolic activity, and cell-type-specific signals that can be inferred from bulk blood measurements.

Technically, whole blood transcriptomics presents a deconvolution problem. A blood sample is a mixture of red cells, platelets, and a diverse population of leukocytes, including neutrophils, monocytes, lymphocytes, and dendritic cells, each with its own expression program. When a disease shifts the proportions of these cell types, the bulk RNA profile changes even if no individual cell alters its internal state. The atlas addresses this by explicitly modeling immune and cell-type-specific features alongside gene and pathway-level signals, allowing the authors to separate changes driven by cellular composition from changes driven by transcriptional regulation within cells. This layered characterization means that a researcher probing, say, a suspected autoimmune condition can distinguish whether the dominant signal is an expansion of neutrophil-associated transcripts or a genuine upregulation of interferon-response genes inside lymphocytes.

A second major component of the study extends the atlas beyond RNA. For 1,280 participants representing 28 of the health conditions, the team generated matched plasma proteomics data, measuring the circulating protein landscape in the same individuals whose blood RNA had been profiled. This pairing allowed a systematic assessment of the relationship between messenger RNA abundance in blood cells and protein concentration in plasma, a relationship that is notoriously imperfect. Many transcripts are translated at low efficiency, many proteins are secreted by tissues far from the bloodstream, and many blood proteins have half-lives that decouple them from the transient RNA signals that produced them. By quantifying these RNA-protein relationships across dozens of conditions, the researchers demonstrated that the two molecular layers carry complementary rather than redundant information, each capturing aspects of disease biology the other misses.

That complementarity became the foundation for the study’s most translational result: multi-class classification models that integrate RNA and protein signatures to distinguish among a wide range of health conditions. Where most diagnostic machine learning studies tackle a binary question, diseased versus healthy, the atlas models were trained to assign samples to the correct condition among many alternatives, a substantially harder task that mirrors real clinical differential diagnosis. The integrated multi-omics models consistently outperformed classifiers built on RNA data alone or protein data alone, confirming quantitatively that the information content of the combined signatures exceeds the sum achievable with either layer by itself. The authors validated the identified RNA and protein signatures across ten independent whole blood transcriptomics cohorts and in the UK Biobank, providing external replication that is rare in single-center omics studies.

The validation strategy deserves emphasis because it speaks to a chronic weakness of the biomarker literature. Candidate signatures discovered in one cohort frequently fail when tested elsewhere, a phenomenon driven by differences in sequencing platforms, sample handling, population demographics, and disease prevalence. By requiring that the atlas-derived signatures hold up in ten external transcriptomics datasets and in the population-scale UK Biobank resource, used under Application Number 150710, the team provided evidence that the disease-associated patterns are robust biological signals rather than artifacts of a particular laboratory or cohort. For clinicians and translational researchers, this kind of cross-cohort reproducibility is the difference between an interesting observation and a candidate diagnostic tool.

The consortium behind the work is itself notable. Alongside the Stockholm computational team, which includes Mathias Uhlen, Saeed Shoaie, Cheng Zhang, and corresponding author Adil Mardinoglu, the author list spans dozens of clinician-researchers at Atatürk University’s Faculty of Medicine, Erzurum Regional Training and Research Hospital, and partner institutions, reflecting the enormous clinical recruitment effort required to assemble thousands of well-phenotyped patient samples across such a wide diagnostic spectrum. The work received support from the Knut and Alice Wallenberg Foundation, and the resulting atlas is being positioned as an open resource for the precision medicine community, enabling other groups to query disease-associated transcriptomic signatures without repeating the costly sample collection.

What might the atlas enable in practice? For diagnostic developers, the multi-class models suggest a route toward blood tests that do not merely flag that something is wrong but help triangulate what is wrong, potentially accelerating workups in settings where patients present with nonspecific symptoms. For drug developers, the pathway and module-level maps offer a way to see which biological processes are perturbed across disease families, highlighting shared inflammatory or metabolic axes that might be targeted therapeutically or that explain why a single drug produces effects across seemingly unrelated conditions. For basic researchers, the resource provides a reference against which new patient data can be projected, instantly contextualizing an individual expression profile within a landscape of 98 known health states.

The study also contributes a methodological lesson about the biology of blood itself. The finding that RNA and protein layers play complementary biological roles underscores that neither measurement alone can serve as a complete proxy for physiological state. Transcripts reflect what blood cells are actively doing at the moment of sampling; plasma proteins reflect secretion, clearance, and contributions from distant organs. Diseases leave different imprints on each layer depending on their mechanism, whether they act primarily through immune activation, tissue damage, or systemic metabolic change. An atlas that records both layers, in matched samples, across a broad disease spectrum, therefore functions less like a single dataset and more like a bilingual dictionary for translating between cellular activity and circulating physiology.

Published as an open-access article with extensive supplementary datasets, the WBT Atlas arrives at a moment when large-scale, multi-omic reference resources are reshaping how biomedical research is organized, echoing the impact of earlier protein and tissue atlases from the same Stockholm research environment. Its authors describe it as a genome-wide resource enabling translational discovery in precision medicine, and the external validations included in the paper suggest the description is more than aspiration. As more cohorts and conditions are added and as the community begins projecting new patient data onto the map, the atlas may well become a standard reference point, the molecular backdrop against which the next generation of blood-based diagnostics is drawn.

Subject of Research: A whole blood transcriptomics atlas characterizing disease-associated gene, module, and pathway signatures across 98 human health conditions with integrated plasma proteomics

Article Title: Whole blood transcriptomics atlas across human diseases

Article References: Whole blood transcriptomics atlas across human diseases. (n.d.). https://doi.org/10.1038/s41467-026-78440-w

Image Credits: AI Generated

DOI: 10.1038/s41467-026-78440-w

Keywords: transcriptomics, whole blood, biomarkers, multi-omics, plasma proteomics, precision medicine, machine learning, gene expression, disease classification, UK Biobank, Nature Communications, diagnostics