Blood-Informative Transcripts Define Nine Common Axes of Peripheral Blood Gene Expression

We describe a novel approach to capturing the covariance structure of peripheral blood gene expression that relies on the identification of highly conserved Axes of variation. Starting with a comparison of microarray transcriptome profiles for a new dataset of 189 healthy adult participants in the Emory-Georgia Tech Center for Health Discovery and Well-Being (CHDWB) cohort, with a previously published study of 208 adult Moroccans, we identify nine Axes each with between 99 and 1,028 strongly co-regulated transcripts in common. Each axis is enriched for gene ontology categories related to sub-classes of blood and immune function, including T-cell and B-cell physiology and innate, adaptive, and anti-viral responses. Conservation of the Axes is demonstrated in each of five additional population-based gene expression profiling studies, one of which is robustly associated with Body Mass Index in the CHDWB as well as Finnish and Australian cohorts. Furthermore, ten tightly co-regulated genes can be used to define each Axis as “Blood Informative Transcripts” (BITs), generating scores that define an individual with respect to the represented immune activity and blood physiology. We show that environmental factors, including lifestyle differences in Morocco and infection leading to active or latent tuberculosis, significantly impact specific axes, but that there is also significant heritability for the Axis scores. In the context of personalized medicine, reanalysis of the longitudinal profile of one individual during and after infection with two respiratory viruses demonstrates that specific axes also characterize clinical incidents. This mode of analysis suggests the view that, rather than unique subsets of genes marking each class of disease, differential expression reflects movement along the major normal Axes in response to environmental and genetic stimuli. Author Summary: Gene expression profiling of human tissues typically reveals a complex structure of co-regulation of gene expression that has yet to be explored with regard to the genetic and environmental sources of covariance or its implications for quantitative and clinical traits. Here we show that peripheral blood samples from multiple studies can be described by nine common axes of variation that collectively explain up to one half of all transcriptional variance in blood. Specific axes diverge according to environmental variables such as lifestyle and infectious disease exposure, but a strong genetic component to axis regulation is also inferred. As few as 10 “blood-informative transcripts” (BITs) can be used to define each axis and potentially classify individuals with respect to multiple aspects of their blood and immune function. The analysis of longitudinal profiles of one individual shows how these change relative to clinical shifts in metabolic profile following viral infection. The notion that gene expression diverges along genetic paths of least resistance defined by these axes has important implications for interpreting differential expression in case-control studies of disease.