Large-scale analysis of temporal gene expression variation in peripheral blood
Year: 2026
Type: article
Study design: Observational Study
Abstract: Transcriptomic profiling of peripheral blood offers a promising, non-invasive approach for disease diagnosis and monitoring. However, its clinical translation is hindered by limited knowledge of the natural temporal variation. Here, we present a comprehensive reference map of longitudinal transcriptomic variability, based on RNA-sequencing of 333 healthy individuals sampled at three time points over six months. We find that 85% of genes and 99% of transcripts exhibit greater intra-individual than inter-individual variation, primarily driven by dynamic regulation of housekeeping pathways. In contrast, immune-related transcripts -particularly those linked to T and B cell activity- are strikingly stable over time. Gene expression levels drive inter-individual differences, while splicing variation contributes more to intra-individual fluctuation. In an independent twin cohort (148 monozygotic, 166 dizygotic), genes with high inter-individual variability show greater heritability, suggesting genetic control of steady-state expression. By integrating extensive clinical and environmental data, we trace temporal expression changes to genetic, compositional, and external factors, and identify robust seasonal and sex-specific signatures. These findings were validated in a third, cross-sectional cohort of 3,480 individuals. The observed temporal variation patterns have important implications for cohort-based transcriptomic analyses, as they may limit discovery and reproducibility of expression quantitative trait loci and increase the risk of spurious associations in cross-sectional studies. This resource provides a critical baseline for distinguishing disease-associated transcriptomic changes from normal physiological variation, advancing the reliability of blood-based biomarkers in clinical practice.
Source: Nature Communications
Authors: Neha Mishra, Franziska Kimmig, Doris Vandeputte, Valentina Talevi, Lindsey De Commer, Chloe Verspecht, Arnau Vich Vila, Julia S. El-Sayed Moustafa, Lukasz Kreft, Alexander Botzki, Youssef El Darzi, Sebastian Proost, Lindsay Devolder, Dongmeng Wang, Joana P. Bernardes, N. Ahmad Aziz, Konrad Aden, Vibeke Andersen, Aggelos Banos, George Bertsias, Marc Beyer, Johanna I. Blase, Dimitrios Boumpas, Paraskevi Christofidou, Axel Finckh, Gilles Gasparoni, Michel Georges, Wei Gu, Robert Häsler, Stephan Huthmacher, Mohamad Jawhara, Amy Kenyon, Christina Kratsch, Roland Krause, Gordan Lauc, Paul A. Lyons, Massimo Mangino, Eoin F. McKinney, Gioacchino Natoli, Karl Nordström, Marek Ostaszewski, Silja H. Overgaard, Marija Pezer, Souad Rahmouni, Benedikt Reiz, Elisa Rosati, Despina Sanoudou, Venkata Satagopam, Reinhard Schneider, Jonas Schulte-Schrepping, Prodromos Sidiropoulos, Kenneth G. C. Smith, Signe B. Sørensen, Timothy Spector, Aleksandar Vojta, Jörn Walter, Stefanie Warnat-Herresthal, Vlatka Zoldoš, Andre Franke, Stefan Schreiber, Emmanouil T. Dermitzakis, Sara Vieira-Silva, Gwen Falony, Kerrin S. Small, Monique M. B. Breteler, Joachim L. Schultze, Jeroen Raes, Philip Rosenstiel
Institutions: Christian-Albrechts-Universität zu Kiel, University Hospital Schleswig-Holstein, Vrije Universiteit Brussel, Rega Institute for Medical Research, Ghent University, VIB-KU Leuven Center for Microbiology, KU Leuven, German Center for Neurodegenerative Diseases, King's College London, Vlaams Instituut voor Biotechnologie, University of Bonn, University Hospital Bonn, Institut für Medizinische Biometrie, Informatik und Epidemiologie, University of Southern Denmark, Academy of Athens, Biomedical Research Foundation of the Academy of Athens, FORTH Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas, Queen Mary University of London, University Hospital of Geneva, Saarland University, University of Liège, University of Luxembourg, Luxembourg Centre for Systems Biomedicine, European Institute of Oncology, University of Cambridge, University of Zagreb, University of Geneva, SIB Swiss Institute of Bioinformatics, Institute of Genetics and Genomics in Geneva, Johannes Gutenberg University Mainz, University Medical Center of the Johannes Gutenberg University Mainz, Institute of Molecular Biology, Wageningen University & Research
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: Wellcome Trust, National Institute for Health and Care Research, King's College London, European Commission, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Fonds Wetenschappelijk Onderzoek, KU Leuven, China Scholarship Council, Deutsches Zentrum für Neurodegenerative Erkrankungen, Versus Arthritis, HORIZON EUROPE Framework Programme, Medical Research Council, Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council
Awards: Personalized disease prediction and prevention in chronic inflammatory disorders, G1285364889, G165400314, G1786533719, SFB 1454: Metaflammation und Zelluläre Programmierung, G2079995099, G2783498043, G3288281479, G3456425215, G3535823272, G3620252990, EXC 2167: Präzisionsmedizin für Chronische Entzündungserkrankungen (PMI), G4015387183, Identification of the Molecular Mechanisms of non-response to Treatments, Relapses and Remission in Autoimmune, Inflammatory, and Allergic Conditions, G4549622993, A systems based approach to integrating genetic and longitudinal omics data to support diagnosis and prediction of common chronic disease, G5097674540, CHARM: CHAracterization and ReMediation of a dysbiotic colon microbiota configuration, G5459882233, Better control and treatment of immune-mediated diseases by exploring the universe of microenvironment imposed tissue signatures and their correlates in liquid biopsies, A Systems medicine approach to chronic inflammatory disease, G7172262573, G7456496496, G7919834827, G8093076636, G8340574297, G8456596083, EXC 2151: ImmunoSensation2 the immune sensory system, G8803244803, PreBeDem - Mit Prävention und Behandlung gegen Demenz, G8888865168
OpenAlex ID: W7162769259
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