Identification of ASD-associated circRNA-miRNA-mRNA regulatory interactions based on the 73 cortex samples overlapped with the samples examined in a previous miRNA study (Wu et al. 2016). (A) Schematic diagram representing the ASD-associated circRNA-miRNA-mRNA axes that satisfied our criteria (see the text). “−” represents the negative correlation between the expression of circRNAs and miRNAs and between the expression of miRNAs and mRNAs. “+” represents the positive correlation between the expression of circRNAs and mRNAs. The correlations are performed by Spearman's correlation tests. (B,C) Enrichment analyses of phenotype ontology (B) and 14 groups of gene list (C) among the target genes of the identified ASD-associated circRNA-miRNA-mRNA axes. The red dashed lines represent FDR Bonferroni-corrected P-values for enrichments with FDR < 0.05. For C, the P-values of gene enrichment analyses are determined using two-tailed Fisher's exact test (left) and empirical gene enrichment analysis (right), respectively. Top SFARI genes represent the genes with top ASD genetic risk factors from the SFARI database (score = 1–3 and syndromic). For the left panel, the enrichment odds ratios with FDR < 0.05 are provided in parentheses. For the right panel, the arrow represents FDR Bonferroni-corrected P-values for enrichments with FDR < 0.05. (D) The four categories of up-regulated (top) and down-regulated (bottom) circRNA-involved ASD-associated circRNA-miRNA-mRNA interactions. The Venn diagrams represent the overlap between the four categories of interactions, on which the numbers represent the numbers of target genes and the numbers of the corresponding circRNA-miRNA-mRNA interactions are shown in parentheses. A summary table representing the total number of interactions for each category is also provided (bottom right). (E) The 356 up-regulated circRNA-involved circRNA-miRNA-mRNA interactions plotted by the Cytoscape package.
