A Comprehensive Analysis of Nuclear-Encoded Mitochondrial Genes in Schizophrenia.

Abstract

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.

• Authors: 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
• Journal: Biological psychiatry (Biol Psychiatry) Vol. 83 Issue 9 Pg. 780-789 (05 01 2018) ISSN: 1873-2402 [Electronic] United States
• PMID: 29628042 (Publication Type: Journal Article, Meta-Analysis, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Topics

• Adolescent
• Adult
• Aged
• Female
• Genes, Mitochondrial
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Humans
• Male
• Middle Aged
• Schizophrenia (genetics)
• Young Adult