PMC

Structural equation models. (A) Mediation of the effects of age and sex on gene expression by blood cell composition in the nonstimulated control. (B) Fraction of genes displaying expression directly or indirectly affected by age across stimulation conditions. (C) Fraction of genes displaying expression directly or indirectly affected by sex across conditions. NS, nonstimulated control.

Distinct transcriptional responses to bacterial, viral, and fungal infections. (A) Number of genes presenting differential expression on immune stimulation. (B) Number of genes presenting common patterns of expression changes across stimulation conditions. Only expression patterns common to at least five genes are presented. (C) Principal component analysis of immune gene expression profiles in the nonstimulated state and on immune simulation. NS, nonstimulated control.

Stimulus-specific trans-acting eQTL at the CR1 locus. (A) Local eQTL at CR1 acting specifically in response to C. albicans stimulation. (B) rs12567990 was significantly associated, in trans, with the expression of IFNG and CLEC5A only after C. albicans stimulation. Gene expression is presented as normalized gene counts. (C) Network of the 34 genes significantly trans-regulated by the CR1 locus (P < 1.7 × 10⁻¹¹). The size of the nodes is proportional to −log10(p) of the association between rs12567990 and gene expression. Colors indicate the direction of the change in expression associated with the C allele (frequency = 0.81). NS, nonstimulated control.

Stimulus specificity of immune response eQTLs. (A) Specificity of local eQTLs across stimulation conditions. Numbers in the circle sectors (1–7) denote the numbers of stimuli for which the expression of the corresponding genes was associated with a nearby genetic variant. (B) Cases of CTSC and IFIT2 presenting local eQTLs across all seven conditions. The eQTL effect at CTSC differed between nonstimulated and stimulated conditions. (C) Cases of TRAF4, IL7R, and TLR3 presenting local response eQTLs specific to E. coli, SEB, and IAV stimulations, respectively, highlighting G × E interactions. Gene expression is presented as normalized gene counts. MAF, minor allele frequency; NS, nonstimulated control.

Expression variance explained by age, sex, genetics, and blood cell composition. (A) Mean variance, across genes, explained by age, sex, genetics, and the proportions of CD45⁺ cell populations in the absence of stimulation and in the six stimulation conditions. The sizes of the circles correspond to the number of genes affected by each factor in each condition. (B) Proportion of the expression variance explained by age, sex, genetics, and proportions of CD45⁺ cells for all genes expressed in response to E. coli stimulation. (C) Proportion of the expression variance explained by the different intrinsic and heritable factors for the genes of the type 1 IFN and TLR-MyD88 pathways. The order of stimuli on the x axis is the same as on A. The legend with color-coding applies to A–C. NS, nonstimulated control.

Local and trans-genetic factors associated with gene expression variation. The genomic position of the regulatory SNP is presented on the x axis, whereas that of the gene for which expression variation is associated with the regulatory variant is presented on the y axis. The numbers along the x and y axes are the chromosome numbers. Circles on the diagonals represent genes with expression patterns regulated by local eQTLs, whereas off-diagonal circles correspond to genes with expression patterns regulated in trans. On each panel, the eQTLs detected in the absence of stimulation were plotted first and were then overlaid with eQTLs detected in the corresponding stimulation conditions. Labels are shown only for genes regulated by local eQTLs with a P value <10⁻³². For trans-eQTLs regulating multiple genes, only the top 30 most significant genes are highlighted. Colored labels indicate genes with significant eQTLs only after stimulation; gray labels indicate the genes with significant eQTLs in both the presence and absence of stimulation. The exact position and rs numbers of both local and trans-associated SNPs are provided in Datasets S8–S21.

Effects of age and sex on the variation of gene expression. (A) Number of genes presenting age-dependent expression changes, as detected by linear regression and ANOVA, in the absence of stimulation and after stimulation. (B) Expression patterns of IFNA2 and FCGRT in response to IAV stimulation across five decades of life. (C) Specificity of age effects on gene expression across conditions. Numbers in the circle sectors (1–6) denote the numbers of stimuli for which the expression of the corresponding genes was age-dependent. The IAV condition was not considered, as it presented a nonlinear association with age. (D) Age-specific (20–69 y) expression of IL13 and IL4R for each stimuli. A significant age association was observed in response to SEB stimulation. (E) Specificity of the effect of sex on gene expression across conditions. Numbers in the circle sectors (1–7) denote the numbers of stimuli for which the expression of the corresponding genes was sex-dependent. (F) Expression differences between men and women for CD14 and ICOS, common to all conditions. Gene expression is presented as normalized gene counts. The legend with color-coding applies to C–F. F, female; M, male; NS, nonstimulated control.