Zonulin as an endophenotype for schizophrenia: A study in patients and unaffected siblings

Zonulin, a key regulator of epithelial tight junctions, is implicated in intestinal and blood-brain barrier permeability and neuroinflammation. Although elevated zonulin is reported in schizophrenia, its expression in unaffected siblings and status as an endophenotype remain unclear. We compared serum zonulin levels among patients with schizophrenia, unaffected siblings and healthy controls, investigating association with symptom severity and cognitive function.

This cross-sectional study included 43 patients with schizophrenia (SZ), 43 unaffected siblings (UAS), and 43 healthy controls (HC). Serum zonulin was measured via sandwich enzyme-linked immunosorbent assay (ELISA). Clinical symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS) and cognition with the Cognitive Assessment Interview-Turkish Version (CAI-TR). Group differences were examined using ANOVA/ANCOVA (adjusting for age, sex, BMI and smoking), and associations via Spearman correlations.

Unadjusted serum zonulin levels (ng/mL) were higher in SZ (146.8 ± 11.5) and UAS (145.6 ± 9.7) compared with HC (140.1 ± 6.4). After adjustment for confounders, the SZ-HC difference remained significant, while the UAS-HC difference was no longer statistically significant. Correlations between zonulin and PANSS domains were null after FDR correction. Zonulin was not significantly associated with CAI-TR domains or total scores in patients or siblings (all p > 0.05).

Elevated zonulin in schizophrenia, together with its unadjusted elevation in unaffected siblings and lack of robust association with symptom severity or cognition, suggests that zonulin may represent a candidate trait-related marker of gut-brain barrier dysfunction within an endophenotypic framework. However, the sibling finding was attenuated after adjustment for confounders and should be interpreted cautiously.