A COMPREHENSIVE ANALYSIS OF NUCLEAR-ENCODED MITOCHONDRIAL GENES IN SCHIZOPHRENIA

Background Schizophrenia (SCZ) is a severe psychiatric disorder wherein the genetic risk factors are far from being fully understood. Multiple lines of evidence have suggested mitochondrial dysfunction in SCZ, but association of mitochondrial variants with SCZ has not been extensively investigated. Methods We conducted gene-based and gene-set analyses to test the hypothesis that variants in nuclear-encoded mitochondrial genes influence susceptibility to SCZ, using results from the most recent release of the Schizophrenia Psychiatric Genomics Consortium GWAS (35,476 cases and 46,839 controls). We applied the MAGMA statistical tool to three gene sets: oxidative phosphorylation genes, other nuclear-encoded mitochondrial genes, and genes involved in nucleus-mitochondria communication signaling. Results For gene-based analysis, a total of 1,187 mitochondrial genes were analyzed and 19 were significant after correction for multiple testing. We applied the method for an independent sample (iPSYCH study, 2,290 SCZ cases and 21,621 controls) and 12 genes had replication p-values Discussion Overall, our study showed evidence that mitochondria play a role in SCZ. Results from our study, combined with future availability of mitochondrial DNA data, will assist researchers to evaluate the role of mitochondrial genomics, potentially across all complex genetic disorders.