Fig. 5: Enrichment of sex-diversified SMC subcluster genes in human GRNs.

a, Dot plot showing 11 top-ranked arterial wall GRNs (x axis) according to their enrichments in genes of sex-specified SMC subclusters in the carotid plaques. The y axis shows −log₁₀(10% FDR) (highlighted). Dot size indicates the number of genes overlapping between the SMC subclusters and GRNs. M, male; F, female. b, Horizontal bar graph showing the statistical enrichments (x axis, −log₁₀(P value)) of genes associated with SYNTAX scores in 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 SMC subclusters between symptomatic (Sy) and asymptomatic (Asy) 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 SMC 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 GRN177 according to the scRNA-seq data (Methods). Below the pie chart are abbreviations of GRN177 GWAS CAD candidate genes. g, GRN177 color coded according to the cell type specificity. Bigger-sized nodes are key driver genes. h, Box plot (left) showing sex-specific expression of top-ranked key driver genes isolated from female (n = 7) and male (n = 8) carotid plaques and (right) corresponding expression pattern during the progression of atherosclerosis in female (n = 18) or male (n = 28) Ldlr^−/−Apob^100/100 mice (Methods). ND, not determined; KDR: key driver; mSMC: mouse SMC clusters in Ldlr^−/−Apob^100/100 mice. Top or rank, the key driver’s hierarchical ranking in the GRN. H², broad sense heritability contribution of GRN177 (%). The red center line denotes the median value (50th percentile), and the red box contains the 25th to 75th percentiles of the dataset. The red whiskers mark the 5th and 95th percentiles. i, Radar plot showing the statistical significance of key cardiometabolic phenotype associations with GRN177. 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. fP.HDL.Chol, fasting plasma high-density lipoprotein cholesterol levels; fP.LDL.Chol, fasting plasma low-density lipoprotein cholesterol levels; fP.TG, fasting plasma triglyceride levels; HbA1c, hemoglobin A1C/glycated hemoglobin; P.Chol, plasma cholesterol levels.

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