Multi-Omic Insight Into the Molecular Networks of Mitochondrial Dysfunction in the Pathogenesis of Schizophrenia

Abstract Background and Hypothesis Schizophrenia is a complex psychiatric disorder with potential links to mitochondrial dysfunction, but the underlying molecular mechanisms remain unclear. We aimed to investigate the relationship between genes encoding proteins involved in mitochondrial function and schizophrenia through multi-omic analyses. Study Design We analyzed blood-derived methylation, expression, and protein quantitative trait loci data integrated with schizophrenia genetic associations. We employed summary-data-based Mendelian randomization and colocalization analyses to identify potential associations. Phenome-wide association studies and molecular docking explored target druggability. Study Results We identified ACADVL, encoding very long-chain specific acyl-CoA dehydrogenase, as associated with schizophrenia across methylation, expression, and protein levels. Higher ACADVL methylation was associated with increased schizophrenia risk, while higher expression and protein levels were protective. Phenome-wide analyses showed no significant associations with other traits and molecular docking showed good binding affinity between ACADVL and bisphenol A and perfluorooctanoic acid. Drug repurposing identified cholic acid, chenodeoxycholic acid, and deoxycholic acid as potential ACADVL-targeting agents. Conclusions Our blood-based multi-omic analyses suggest ACADVL plays a role in schizophrenia pathophysiology. ACADVL represents a promising drug target for schizophrenia. Further validation and clinical trials are needed to explore ACADVL-based treatments for schizophrenia.