Large-scale analysis of temporal gene expression variation in peripheral blood
Abstract
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.
Article Details
Authors (68)
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