Mosaic variants of neurodevelopmental and mitochondrial genes in postmortem paraventricular thalamus in bipolar disorder detected by deep exome sequencing.

Aim: The genetic architecture of bipolar disorder (BD) remains incompletely understood despite extensive genomic studies. Postzygotic mosaic variants have emerged as promising contributors to BD; however, the landscape of such variants in the BD brain has yet to be elucidated.

Methods: We analyzed mosaic variants in the paraventricular thalamic region (PVR) from 18 Japanese BD cases and 11 controls using deep whole-exome sequencing. Candidate variants were validated via targeted amplicon sequencing. To explore their biological implications, we performed gene ontology analysis by integrating the brain-derived mosaic variants identified in this study with mosaic variants previously detected in peripheral tissues.

Results: We identified 99 exonic and 13 mitochondrial heteroplasmic variants in the PVR. There was a significant enrichment of deleterious mosaic variants in constrained genes (P = 0.0402) and of non-synonymous mosaic variants in neurodevelopmental genes, particularly those involved in the positive regulation of neuron projection development (false discovery rate = 2.32 × 10^-3). These genes also formed a significantly enriched protein-protein interaction network (P = 0.0106). Notably, we detected one mitochondrial variant known to be pathogenic for mitochondrial disease and two predicted pathogenic mitochondrial tRNA variants in BD cases, but none in controls.

Conclusion: Despite the modest sample size and potential confounding factors such as age and cancer status, our direct analysis of brain tissue supports previous findings of an enrichment of mosaic variants in neurodevelopmental and mitochondrial tRNA genes. These results advance our understanding of the genetic underpinnings of BD.