Fig. 4. CircRNAs are linked to neuropsychiatric disease.
a Histogram summarizing the number of filtered (grey bars) and validated (red bars) circRNAs (y-axis) supported by increasing numbers of back-spliced reads (x-axis). Pie charts show the proportion of PD-risk genes (green), AD-risk genes (cyan), and synaptic genes (orange) expressing validated circRNAs. Percentages for filtered circRNAs were 88.1% and 80.2% for AD- and PD-associated genes, respectively. Examples of circRNAs for each of these three categories (colored dots) are highlighted. b The AD GWAS locus PICALM produced 16 circRNAs in pyramidal neurons, 17 in dopamine neurons, and 12 in non-neuronal cells. GWAS P values on the y-axis of upper panel are derived from the AD GWAS study32. c Genes for addiction-associated traits (magenta font) preferentially produced circRNAs in dopamine neurons, autism-and bipolar-disease-associated genes (cyan font) preferentially in pyramidal neurons, and cancer loci (bold black font) preferentially in non-neuronal cells. Dot sizes correspond to the gene count in the query set, with color shade corresponding to the P values from Fisher’s exact test. P values below the Bonferroni-corrected significance threshold of 1.08 × 10−5 (e.g., 0.05 divided by the total number of 4368 unique disease sets tested) are considered statistically significant and highlighted in red. d–f Examples of circRNAs expressed from the PD- and intellectual disability-associated gene KANSL1 (d), from the addiction-associated gene PDE4B (e), and from the cancer-associated gene ATM (f). Normalized lcRNAseq density tracks in each cell type (DA: dopamine neuron; PY: pyramidal neurons; NN: non-neuronal cells) are shown below the gene model. circRNAs in each locus were identified using the healthy control samples (n = 109) g Functionally, expression of circDNAJC6 and several other synapse-related circRNAs (labeled with orange dots) was reduced at the earliest, prodromal Parkinson’s disease stages with brainstem-confined Lewy body neuropathology (P = 0.014, two-sided Wald test). By contrast, expression of the linear mRNA DNAJC6 was not altered (P = 0.99, two-sided Wald test). Volcano plot indicates circRNAs differentially expressed in dopamine neurons from brains of individuals with prodromal PD-associated Lewy body neuropathology in the brainstem consistent with Lewy body Braak Stages 1–3 (ILB: n = 27) compared to controls (HC: n = 59). Circular RNAs were analyzed at the gene level, as indicated by their host gene symbol in the plot. The horizontal dashed line represents P = 0.05 and the vertical dashed lines (light grey) represent fold-changes of 0.5 and 2.