Figure 4. CircRNAs are linked to neuropsychiatric disease.

a. Histogram summarizing the number of 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 circRNAs. 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. 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. 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 $(\mathrm{n}=109)$ 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 ($P=0.014$, Wald test). By contrast, expression of the linear mRNA DNAJC6 was not altered ($P=0.99$, 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: $\mathrm{n}=27$) compared to controls (HC: $\mathrm{n}=59$). 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.