Pleiotropic effects of oxytocin receptor polymorphisms: influencing striatocortical connectivity in bipolar disorder

Background: Oxytocin (OXT), a neuropeptide involved in social behaviors and emotions, exhibits bidirectional effects depending upon positive or negative environments. Our previous report highlighted dysregulation of OXT on striatocortical functional connectivity (FC) in bipolar disorder (BD) patients. We hypothesized that: (1) in healthy controls (HC), carriers of a “sensitive” OXTR allele would show altered FC, particularly in association with childhood trauma; and (2) this gene–brain relationship would be fundamentally altered or reversed in BD patients, reflecting a gene–disease interaction. Method: Thirty-nine BD patients and 32 age-matched HC underwent resting-state functional MRI and blood sampling for genotyping and plasma OXT level assessment. Results: BD patients, compared to HC, demonstrated elevated plasma OXT levels and higher scores in childhood trauma. Gene–disease interactions were observed in the striatocortical circuitry with OXTR rs53576 and rs2228485, with greater robustness in rs2228485. In HC, the rs2228485 AA homozygotes showed enhanced striatocortical FC with the sensory association and limbic areas, which were correlated with the childhood trauma. Conversely, alterations in ventral striatocortical FC were reversed among BD patients, with hypo-FC in AA homozygotes and hyper-FC in G-allele carriers. Conclusions: These findings highlight a gene–disease interplay, suggesting that individuals carrying the “sensitive” allele may exhibit context-dependent alterations in salience-related brain networks. Our results identify a potential neural mechanism through which the OXTR polymorphism modulates environmental sensitivity, with distinct effects in HC and BD. Childhood trauma may shape striatocortical FC in an OXTR genotype-dependent manner.