A Comprehensive Analysis of Nuclear-Encoded Mitochondrial Genes in Schizophrenia

Vanessa F. Gonçalves, Carolina Cappi, Christian M. Hagen, Adolfo Sequeira, Marquis P. Vawter, Andriy Derkach, Clement C. Zai, Paula L. Hedley, Jonas Bybjerg-Grauholm, Jennie G. Pouget, Ari B. Cuperfain, Patrick F. Sullivan, Michael Christiansen, James L. Kennedy, Lei Sun

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


Background: The genetic risk factors of schizophrenia (SCZ), a severe psychiatric disorder, are not yet fully understood. Multiple lines of evidence suggest that 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 Psychiatric Genomics Consortium Schizophrenia Phase 2 (PGC-SCZ2) genome-wide association study comprising 35,476 cases and 46,839 control subjects. 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 2290 cases and 21,621 control subjects. Results: In the PGC-SCZ2 sample, 1186 mitochondrial genes were analyzed, among which 159 had p values <.05 and 19 remained significant after multiple testing correction. A meta-analysis of 818 genes combining the PGC-SCZ2 and iPSYCH samples resulted in 104 nominally significant and nine significant genes, suggesting a polygenic model for the nuclear-encoded mitochondrial genes. Gene-set analysis, however, did not show significant results. In an in silico protein-protein interaction network analysis, 14 mitochondrial genes interacted directly with 158 SCZ risk genes identified in PGC-SCZ2 (permutation p =.02), and aldosterone signaling in epithelial cells and mitochondrial dysfunction pathways appeared to be overrepresented in this network of mitochondrial and SCZ risk genes. Conclusions: This study provides evidence that specific aspects of mitochondrial function may play a role in SCZ, but we did not observe its broad involvement even using a large sample.

Original languageEnglish
Pages (from-to)780-789
Number of pages10
JournalBiological Psychiatry
Issue number9
StatePublished - 1 May 2018
Externally publishedYes


  • Gene-gene interaction
  • Mitochondria
  • Oxidative phosphorylation
  • Schizophrenia
  • Stratified FDR


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