Mitochondrial Mutations in Subjects with Psychiatric Disorders

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 vari...

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Veröffentlicht in:PloS one Jg. 10; H. 5; S. e0127280
Hauptverfasser: Sequeira, Adolfo, Rollins, Brandi, Magnan, Christophe, van Oven, Mannis, Baldi, Pierre, Myers, Richard M., Barchas, Jack D., Schatzberg, Alan F., Watson, Stanley J., Akil, Huda, Bunney, William E., Vawter, Marquis P.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Public Library of Science 26.05.2015
Public Library of Science (PLoS)
Schlagworte:
Adult
Bipolar disorder
Brain
Case-Control Studies
Deoxyribonucleic acid
Disorders
DNA
DNA Mutational Analysis
DNA, Mitochondrial - genetics
Electrophoresis, Agar Gel
Energy metabolism
Female
Gene sequencing
Genes
Genetic aspects
Genetic Loci
Genomes
Genomic instability
Genomics
Genotyping
Heteroplasmy
Humans
Male
Mental depression
Mental disorders
Mental Disorders - blood
Mental Disorders - genetics
Metabolism
Methamphetamine
Middle Aged
Mitochondrial DNA
Molecular Sequence Data
Mutation
Mutation - genetics
Neurodegenerative diseases
Neurotransmission
Physiological aspects
Prefrontal Cortex - pathology
Schizophrenia
Stability
Studies
ISSN:1932-6203, 1932-6203
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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.
AbstractList 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.
Audience Academic
Author Sequeira, Adolfo
Barchas, Jack D.
Rollins, Brandi
Baldi, Pierre
Schatzberg, Alan F.
van Oven, Mannis
Vawter, Marquis P.
Akil, Huda
Bunney, William E.
Watson, Stanley J.
Magnan, Christophe
Myers, Richard M.
AuthorAffiliation 4 HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, United States of America
1 Functional Genomics Laboratory, Department of Psychiatry & Human Behavior, University of California Irvine, Irvine, California, United States of America
6 Department of Psychiatry & Behavioral Sciences, Stanford University, Palo Alto, California, United States of America
8 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
7 Molecular and Behavioral Neurosciences Institute, University of Michigan, Ann Arbor, Michigan, United States of America
3 Department of Forensic Molecular Biology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
5 Department of Psychiatry, Weill Cornell Medical College, New York, New York, United States of Ame
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– name: 8 Department of Psychiatry & Human Behavior, University of California Irvine, Irvine, California, United States of America
– name: 5 Department of Psychiatry, Weill Cornell Medical College, New York, New York, United States of America
– name: 1 Functional Genomics Laboratory, Department of Psychiatry & Human Behavior, University of California Irvine, Irvine, California, United States of America
– name: 3 Department of Forensic Molecular Biology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
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  givenname: Marquis P.
  surname: Vawter
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/26011537$$D View this record in MEDLINE/PubMed
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ContentType Journal Article
Copyright COPYRIGHT 2015 Public Library of Science
2015 Sequeira et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
2015 Sequeira et al 2015 Sequeira et al
Copyright_xml – notice: COPYRIGHT 2015 Public Library of Science
– notice: 2015 Sequeira et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
– notice: 2015 Sequeira et al 2015 Sequeira et al
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Competing Interests: The authors have declared that no competing interests exist.
Conceived and designed the experiments: AS BR CM MVO PB RMM JDB AFS SJW HA WEB MPV. Performed the experiments: AS BR CM MVO MPV. Analyzed the data: AS BR CM MVO PB MPV. Wrote the paper: AS BR CM MVO PB RMM JDB AFS SJW HA WEB MPV.
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Snippet A considerable body of evidence supports the role of mitochondrial dysfunction in psychiatric disorders and mitochondrial DNA (mtDNA) mutations are known to...
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StartPage e0127280
SubjectTerms Adult
Bipolar disorder
Brain
Case-Control Studies
Deoxyribonucleic acid
Disorders
DNA
DNA Mutational Analysis
DNA, Mitochondrial - genetics
Electrophoresis, Agar Gel
Energy metabolism
Female
Gene sequencing
Genes
Genetic aspects
Genetic Loci
Genomes
Genomic instability
Genomics
Genotyping
Heteroplasmy
Humans
Male
Mental depression
Mental disorders
Mental Disorders - blood
Mental Disorders - genetics
Metabolism
Methamphetamine
Middle Aged
Mitochondrial DNA
Molecular Sequence Data
Mutation
Mutation - genetics
Neurodegenerative diseases
Neurotransmission
Physiological aspects
Prefrontal Cortex - pathology
Schizophrenia
Stability
Studies
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Title Mitochondrial Mutations in Subjects with Psychiatric Disorders
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