Fig. 4

PBMC gene expression signatures resembling the ALS transcriptome. a Top 12 ALS-matching PBMC signatures. 422 PBMC gene expression signatures were screened to identify those with elevated expression of ALS-increased DEGs and decreased expression of ALS-decreased DEGs. Expression shifts in each signature were quantified using signed log₁₀-transformed p-values (Log10P; positive values: increased expression; negative values: decreased expression). Round symbols represent the median Log10P for the 100 genes most strongly elevated in ALS patients (red), and the median Log10P for the 100 genes most strongly decreased in ALS patients (blue). Whiskers outline the middle 50% of Log10P values (25th to 75th percentile). b High altitude versus ALS scatterplot (9130 genes). FC estimates are shown from the comparison of blood samples obtained at high altitude versus sea level (vertical axis), and from the comparison of samples from ALS versus control subjects (horizontal axis). The yellow ellipse outlines the middle 50% of genes closest to the bivariate median (Mahalanobis distance). The spearman rank correlation coefficient is shown (upper-left). The percentage of genes in each quadrant is indicated (top margin; red font: P < 0.05, Fisher’s exact test). The color-coded vertical bar (right margin) reflects the proportion of genes in each quadrant. c High altitude GSEA analysis (ALS-increased DEGs). d High altitude GSEA analysis (ALS-decreased DEGs). In c, d, genes were ranked according to their expression change in the comparison between subjects at high altitude and sea level (horizontal axis), and cumulative overlap between the ranked gene list and ALS DEGs is shown (vertical axis; p-values: Wilcoxon rank sum test). e Venn diagrams. Top: Overlap between ALS-increased and altitude-increased DEGs (FDR < 0.10). Bottom: Overlap between ALS-decreased and altitude-decreased DEGs (FDR < 0.10). f Genes increased in ALS patients and high altitude subjects. g Genes decreased in ALS patients and high altitude subjects. In f, g, FC estimates obtained from the comparison between high altitude and sea level subjects is shown in parentheses (bottom margin). h Gene ontology biological process terms enriched among 144 genes with increased expression in ALS patients and high altitude subjects (FDR < 0.10, FC > 1.25). i Gene ontology biological process terms enriched among 34 genes with decreased expression in ALS patients and high altitude subjects (FDR < 0.10, FC < 0.83)