A Comprehensive Analysis of Nuclear-Encoded Mitochondrial Genes in Schizophrenia

BACKGROUND: The genetic risk factors of schizophrenia (SCZ), a severe psychiatric disorder, are not yet fully understood. Multiple lines of evidence suggest mitochondrial dysfunction may play a role in SCZ, but comprehensive association studies are lacking. We hypothesized that variants in nuclear-encoded mitochondrial genes influence susceptibility to SCZ. METHODS: We conducted gene-based and gene-set analyses using summary association results from the Schizophrenia Psychiatric Genomics Consortium GWAS (PGC-SCZ2) comprising 35,476 cases and 46,839 controls. We applied the MAGMA method to three sets of nuclear-encoded mitochondrial genes: oxidative phosphorylation genes, other nuclear-encoded mitochondrial genes, and genes involved in nucleus-mitochondria crosstalk. Furthermore, we conducted a replication study using the iPSYCH SCZ sample of 2,290 cases and 21,621 controls. RESULTS: In the PGC-SCZ2 sample, 1,186 mitochondrial genes were analyzed among which 159 had p-values