Insight impairment mediates the effect of SOX2-OT polymorphism on antipsychotic response in first-episode schizophrenia

Insight impairment is a core clinical feature of schizophrenia that predicts poor treatment adherence and unfavorable prognosis. Genetic factors have been increasingly recognized as a likely basis for inter-individual variability in insight; however, direct evidence for a complete mechanistic chain—from specific genetic variants through insight impairment to clinical outcomes—remains to be established. We enrolled 233 antipsychotic-free patients with first-episode schizophrenia. Five SNPs previously implicated in insight (SOX2-OT rs1479165 and DISC1 rs821616, rs821597, rs821633, rs6675281) were genotyped. Insight was assessed using the Birchwood Insight Scale (BIS) and treatment response was measured as PANSS reduction rate at 8 weeks. Mediation analysis, brain expression quantitative trait locus (eQTL) (GTEx v8), and STRING protein–protein interaction network were integrated to explore the pathway from genotype to clinical outcome. The SOX2-OT rs1479165 C allele was significantly associated with better insight (β = 2.03, p < 0.001). Baseline BIS score significantly predicted PANSS reduction rate (β = 3.175, p < 0.001). Mediation analysis demonstrated that the effect of SOX2-OT on treatment response was predominantly mediated by baseline insight (ACME = 6.11, 95% CI [3.93, 8.43], p < 0.001), with a mediation proportion of 78.1%. eQTL analysis revealed that the effect allele increased expression of RP11-275H4.1 (a SOX2-OT transcript) across 12 brain regions, with strongest effects in hippocampus, caudate, and prefrontal cortex. STRING network analysis further showed that SOX2-OT is embedded within a transcriptional regulatory network centered on neurodevelopmental transcription factors including SOX2, POU5F1, NANOG, KLF4, CTNNB1, and PAX6, highly enriched for pathways governing neural stem cell maintenance and cell fate commitment. Individual DISC1 SNPs exhibited inconsistent directional associations with insight, with no significant aggregated genetic effect observed. This study provides the first independent validation of the association between SOX2-OT rs1479165 and insight in a non-European individuals with schizophrenia, and provides a potential mechanistic pathway from a specific genetic variant through insight impairment to antipsychotic treatment response. The eQTL and STRING findings suggest that a putative region-specific transcriptional regulatory cascade affecting neurodevelopment and neural plasticity that may underpin the observed genetic-insight-treatment response pathway. These findings underscore insight as a clinically meaningful phenotype and a potential therapeutic target bridging genetic risk and clinical outcome in schizophrenia.