Whole-exome sequencing of schizophrenia in an underrepresented indigenous population of Northeast India: Rare coding variant burden and clinical correlates.

Schizophrenia is a severe mental disorder, and emerging evidence suggests that neurodevelopmental and synaptic dysfunction are critical factors in the pathogenesis of the disorder. This study investigated schizophrenia-related genetic variation in the genetically distinct and endogamous Mizo population of Northeast India using whole-exome sequencing. Twenty individuals with schizophrenia and 27 healthy controls were analysed. A panel gene consisting 95 gene associated with schizophrenia was initially used for descriptive profiling and pathway dysregulation, whereas an expanded 239-gene neuropsychiatric panel was used for standardized case-control analysis, recurrent and clinically significant variants and rare damaging effects. The descriptive analysis identified 321 variants across 32 genes, with recurrent variants most frequently observed in PCLO and RELN (100%), NRG1 (95%), CACNA1B (90%), BRCA1 (85%), and APOE and PLXNA2 (80%). Pathogenicity analysis revealed recurrent variants with conflicting pathogenic classifications in CNTNAP2, VDR, APOE, CHD8, and ERBB4. In the standardized case-control analysis, patients carried a significantly higher burden of rare damaging coding SNVs than controls. The synaptic burden score was positively correlated with PANSS negative-symptom severity, whereas its association with PANSS positive symptoms was not significant. Pathway analysis highlighted significant involvement of MAPK signalling, dopaminergic synapse, neuroactive ligand-receptor interaction and GABAergic synapse pathways. Overall, this first whole-exome study of schizophrenia in the Indigenous Mizo population provides preliminary evidence of increased rare damaging coding-variant burden and negative-symptom severity, supporting the involvement of synaptic and neurodevelopmental disturbances in an underrepresented Indigenous population.