Fig. 6: Enrichment of sex-diversified MP subcluster genes in human GRNs.

a, Dot plot showing 18 top-ranked arterial wall GRNs (x axis) according to their enrichments in genes of sex-specified MP subclusters in the carotid plaques. The y axis shows −log₁₀(10% FDR) (highlighted). Dot size indicates the number of genes overlapping between MP subclusters and GRNs. b, Horizontal bar graph showing the statistical enrichments (x axis, −log₁₀(P value)) of genes associated with SYNTAX scores of the arterial-wall-specific GRNs above −log(10% FDR) in a. c, Horizontal bar graph showing the statistical enrichments (x axis, −log₁₀(P value)) of genes associated with Duke scores in the arterial-wall-specific GRNs above −log(10% FDR) in a. d, Horizontal bar graph showing the enrichment significances (x axis, −log₁₀(P value)) of DEGs in indicated MP subclusters between symptomatic and asymptomatic carotid plaques in the arterial wall GRNs above −log(10% FDR) in a. e, Horizontal bar graph showing the enrichment significances (x axis, −log₁₀(P value)) in indicated MP subclusters of DEGs in Athero-Express scRNA-seq carotid plaque data⁵⁵ between 20 females and 26 males in the arterial-wall GRNs above −log(10% FDR) in a. f, Pie chart showing the relative cell type specificity of genes in GRN33 (top) and GRN174 (bottom) according to the scRNA-seq data (Methods). Below the pie chart are abbreviations of GRN33 (top) and GRN174 (bottom) GWAS CAD candidate genes. g, GRN33 (top) and GRN174 (bottom) color coded according to cell type specificity. Bigger-sized nodes are the key driver genes. h, Box plots (left) showing sex-specific expression of top-ranked key drivers isolated from female (n = 7) and male (n = 8) carotid plaques and (right) corresponding expression patterns during the progression of atherosclerosis in female (n = 18) or male (n = 28) Ldlr^−/−Apob^100/100 mice (Methods). mMP, mouse MP clusters in Ldlr^−/−Apob^100/100 mice. Top or rank, the key driver’s hierarchical ranking in the GRN. H², broad sense heritability contributions of GRN33 (top) and GRN174 (bottom) (%). The golden center line denotes the median value (50th percentile), and the golden box contains the 25th to 75th percentiles of the dataset. The golden whiskers mark the 5th and 95th percentiles. i, Radar plot showing the statistical significance of key cardiometabolic phenotype associations with GRN33 (top) and GRN174 (bottom). The significance of GRN–phenotype associations (−log₁₀; P = 0–100) was calculated by aggregating GRN gene-level phenotype associations (Pearson correlation two-tailed t-test) corrected for the total number of STARNET GRNs (n = 135) and the number of genes in each GRN using the Benjamini–Hochberg procedure.

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