Whole-genome sequencing of mixed OCD–schizophrenia pedigrees characterizes shared and divergent rare-variant architectures

Psychiatric disorders often co-occur and share liability, yet why distinct diagnoses arise under a largely shared familial genetic background remains poorly understood. We assembled 21 Han Chinese mixed pedigrees co-ascertained for obsessive–compulsive disorder (OCD) and schizophrenia (SCZ) (21 OCD, 21 SCZ, and 38 unaffected first-degree relatives) and performed deep (60×) whole-genome sequencing. Leveraging within-family structure as an internal control, we integrated rare coding and regulatory variation across co-segregating and disorder-biased loci and evaluated diagnostic separation using stratified group cross-validation to prevent relatedness-driven leakage. Mutation-burden models distinguished OCD from controls (AUC 0.839), SCZ from controls (AUC 0.749), and affected individuals from controls (AUC 0.792), whereas OCD–SCZ discrimination remained modest (AUC 0.631), consistent with partial genetic sharing. Burden decomposition suggested that coding-region signals accounted for most of the discriminative performance, while non-coding burden provided limited incremental contribution under current annotations. Developmental network mapping nominated temporally stratified prenatal-to-postnatal modules, including a late-pregnancy angiogenesis-related module shared across disorders and SCZ-biased astrocyte/calcium-related programs. Together, these results illustrate how mixed-pedigree WGS can help disentangle convergent versus divergent rare-variant architectures across OCD and SCZ and provide family-grounded, interpretable signatures for future disorder-specific stratification.