Protein Disulfide Isomerase A3, a Stress Response Gene, Is Associated with Cognitive Impairment in Schizophrenia and Linked to Inflammatory Activation

Abstract Background and Hypothesis Protein disulfide isomerase A3 (PDIA3), a critical regulator of endoplasmic reticulum stress, was identified as a risk gene in schizophrenia (SZ). This implies the role of PDIA3 in SZ-associated immune dysregulation. Study Design We integrated Psychiatric Genomics Consortium and PsychENCODE expression quantitative trait loci data, employing summary data-based Mendelian randomization analyses to investigate PDIA3-SZ associations. Clinical characterization and C-reactive protein (CRP)-based inflammatory profiling were analyzed in people with SZ categorized by PDIA3 genotypes. Plasma PDIA3 levels were quantified and correlated with clinical profiles, CRP concentrations, and white matter density. Hierarchical linear regression with mediation modeling characterized PDIA3-CRP-cognitive interactions. Finally, LOC14 (a PDIA3 inhibitor) was administered in mice to elucidate its role in SZ-related pathobiology. Study Results PDIA3 was identified as a robust SZ risk factor, and people with SZ carrying the risk A allele of rs7174732 in PDIA3 gene exhibit more severe cognitive impairment and a trend toward higher plasma CRP levels. Plasma PDIA3 in people with SZ was positively correlated with cognition and white matter density of the hippocampus, and negatively correlated with CRP levels. Furthermore, decreased plasma PDIA3 level in people with SZ was a significant predictor of worse working memory, and CRP acted as a mediator with an 16.2% effect. Inhibition of PDIA3 in mice was associated with increased anxiety, impaired cognition, and increased power in low-frequency signals in vivo, alongside activated inflammatory responses and regulated SZ-related biological pathways. Conclusions We established a PDIA3-CRP-cognitive interaction network in SZ.