GRIA Gene Expression in Schizophrenia: A Participant-Level Meta-Analysis

Schizophrenia is a complex mental disorder with an estimated heritability of 80%, yet its underlying pathophysiology remains poorly understood. Emerging evidence implicates the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) glutamate receptor-a key player in fast excitatory synaptic transmission, encoded by Glutamate Ionotropic Receptor AMPA Type Subunits 1-4 (GRIA1-4)-in the disorder's pathophysiology. However, findings from postmortem brain samples regarding GRIA1-4 expression have been inconsistent. This study aimed to systematically evaluate the differential expression of GRIA1-4 genes in schizophrenia by integrating transcriptomic data from postmortem brain tissue and patient-derived cerebral organoids.

We conducted a participant-level meta-analysis of seven postmortem brain sample datasets (n = 295; 151 schizophrenia, 144 controls) and analyzed an independent organoid dataset (n = 16). Expression differences between schizophrenia and control samples were quantified using Hedges' g under a random-effects model, with heterogeneity assessed using the I² statistic.

Our analysis revealed significant downregulation of all four GRIA genes (GRIA1-4) in postmortem brain tissue from individuals with schizophrenia, with the effect concentrated in a subgroup of patients. No substantial heterogeneity was attributable to differences in brain regions or measurement platforms. Consistent downregulation of GRIA1-3 was observed in patient-derived cerebral organoids, which model early neurodevelopmental stages.

Our findings highlight AMPA receptor dysfunction as a potential contributor to schizophrenia pathophysiology in a subgroup of patients, consistent with the broader role of glutamatergic signaling disruption in this disorder. The convergent evidence from postmortem brain tissue and developmental models underscores the need for further investigation of GRIA genes as potential biomarkers for patient stratification and as therapeutic targets. While further study is needed to understand the functional consequences of our findings, such insights may inform the development of personalized treatment strategies targeting glutamatergic dysfunction in schizophrenia.