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Biol Psychiatry. 2018 May 1;83(9):780-789. doi: 10.1016/j.biopsych.2018.02.1175. Epub 2018 Mar 15.

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

Author information

1
Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Neuroscience Section, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. Electronic address: Vanessa.Goncalves@camh.ca.
2
Department of Psychiatry, School of Medicine, University of São Paulo, São Paulo, Brazil.
3
Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
4
Department of Psychiatry and Human Behavior, University of California, Irvine, California.
5
Department of Statistical Sciences, Faculty of Arts and Science, University of Toronto, Toronto, Ontario, Canada.
6
Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Neuroscience Section, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
7
Department of Genetics, University of North Carolina, Chapel Hill, North Carolina; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
8
Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark; Department of Biomedical Science, University of Copenhagen, Copenhagen, Denmark.
9
Department of Statistical Sciences, Faculty of Arts and Science, University of Toronto, Toronto, Ontario, Canada; Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.

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.

KEYWORDS:

GWAS-HD; Gene-gene interaction; MAGMA; Mitochondria; Oxidative phosphorylation; Schizophrenia; Stratified FDR

PMID:
29628042
DOI:
10.1016/j.biopsych.2018.02.1175
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