Temporal expression signatures of rare variant-harboring genes linked to autism, bipolar disorder, schizophrenia and epilepsy across neurodevelopment

Autism spectrum disorder (ASD), bipolar disorder (BPD), schizophrenia (SCZ), and epilepsy (EPI) are distinct clinical syndromes, but share genetic overlaps, brain processes, clinical features, and pharmacological treatments, suggesting a broad transdiagnostic structure. However, spatiotemporal transcriptomic profiles of the associated genes have not been examined in a transdiagnostic manner. Genes harboring rare variants identified through whole exome-sequencing are particularly valuable for investigating disease pathobiology, as they impact gene and protein function. We compiled gene-level exome-wide association data of ASD, BPD, SCZ, and EPI from the Autism Sequencing, BipEx, SCHEMA, and EPI25 consortia, respectively. Then, we examined this data in conjunction with the BrainSpan Atlas transcriptomic data from 26 brain regions, spanning fetal stages to adulthood, using clustering and enrichment analyses. Temporal clustering showed specific signatures with BPD genes expressed from early infancy to adulthood and ASD genes in early prenatal stages. Spatial clustering revealed enrichment of BPD genes in visual, somatosensory, and motor cortical regions, and ASD genes in fetal ganglionic eminence. While genome-wide association studies have highlighted an overlap between BPD and SCZ, our analysis revealed SCZ converging with ASD, and EPI aligning with BPD, suggesting a core substrate of shared biology, that is also reflected in their pharmacological overlaps. BPD and ASD clusters were enriched for trans-synaptic signaling and chromatin modification, respectively. This study suggests a neurodevelopmental continuum underlying these syndromes, bridging rare variants with developmental windows and neural substrates for therapy, and gene networks and cell types suitable for experimental research in patient-derived cell lines and animal models.