Whole-blood transcriptomics in a Japanese population cohort: physiological and methodological insights

Whole blood transcriptomics promises a practical readout of human physiology. However, several key gaps have limited its utility. Systematic analyses in healthy participants within prospective cohorts remain scarce. In addition, there is uncertainty about how age and sex shape whole-blood expression profiles, and no methodological consensus exists on whether globin mRNAs should be removed before analysis. Against this backdrop, Aoki and colleagues conducted a large-scale study using whole-blood RNA sequencing (RNA-seq) from 576 participants in the Tohoku Medical Megabank Project, aiming to generate foundational data for the Japanese population. By retaining globin transcripts and then applying in silico removal, they detected rare Hereditary Persistence of Fetal Hemoglobin (HPFH) cases, showed that immune-cell composition-particularly the neutrophil-to-lymphocyte ratio-drives major variance, and uncovered extensive age- and sex-dependent signatures, including pregnancy-associated NRF2 activation. Together, these results move the field toward establishing a Japanese whole-blood gene-expression reference by providing standardized, stratified baseline profiles and practical guidance on globin handling. This commentary explains why these choices matter and how the dataset will inform population-aware blood transcriptomics.