Format

Send to

Choose Destination
PLoS One. 2015 May 26;10(5):e0127280. doi: 10.1371/journal.pone.0127280. eCollection 2015.

Mitochondrial mutations in subjects with psychiatric disorders.

Author information

1
Functional Genomics Laboratory, Department of Psychiatry & Human Behavior, University of California Irvine, Irvine, California, United States of America.
2
School of Information and Computer Sciences (ICS), Institute for Genomics and Bioinformatics (IGB), University of California Irvine, Irvine, California, United States of America.
3
Department of Forensic Molecular Biology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
4
HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, United States of America.
5
Department of Psychiatry, Weill Cornell Medical College, New York, New York, United States of America.
6
Department of Psychiatry & Behavioral Sciences, Stanford University, Palo Alto, California, United States of America.
7
Molecular and Behavioral Neurosciences Institute, University of Michigan, Ann Arbor, Michigan, United States of America.
8
Department of Psychiatry & Human Behavior, University of California Irvine, Irvine, California, United States of America.

Abstract

A considerable body of evidence supports the role of mitochondrial dysfunction in psychiatric disorders and mitochondrial DNA (mtDNA) mutations are known to alter brain energy metabolism, neurotransmission, and cause neurodegenerative disorders. Genetic studies focusing on common nuclear genome variants associated with these disorders have produced genome wide significant results but those studies have not directly studied mtDNA variants. The purpose of this study is to investigate, using next generation sequencing, the involvement of mtDNA variation in bipolar disorder, schizophrenia, major depressive disorder, and methamphetamine use. MtDNA extracted from multiple brain regions and blood were sequenced (121 mtDNA samples with an average of 8,800x coverage) and compared to an electronic database containing 26,850 mtDNA genomes. We confirmed novel and rare variants, and confirmed next generation sequencing error hotspots by traditional sequencing and genotyping methods. We observed a significant increase of non-synonymous mutations found in individuals with schizophrenia. Novel and rare non-synonymous mutations were found in psychiatric cases in mtDNA genes: ND6, ATP6, CYTB, and ND2. We also observed mtDNA heteroplasmy in brain at a locus previously associated with schizophrenia (T16519C). Large differences in heteroplasmy levels across brain regions within subjects suggest that somatic mutations accumulate differentially in brain regions. Finally, multiplasmy, a heteroplasmic measure of repeat length, was observed in brain from selective cases at a higher frequency than controls. These results offer support for increased rates of mtDNA substitutions in schizophrenia shown in our prior results. The variable levels of heteroplasmic/multiplasmic somatic mutations that occur in brain may be indicators of genetic instability in mtDNA.

PMID:
26011537
PMCID:
PMC4444211
DOI:
10.1371/journal.pone.0127280
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substance, Secondary source ID, Grant support

Publication types

MeSH terms

Substance

Secondary source ID

Grant support

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center