title: Mitochondrial mutations in subjects with psychiatric disorders.
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.
authors.affiliation: Functional Genomics Laboratory, Department of Psychiatry & Human Behavior, University of California Irvine, Irvine, California, United States of America.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Sequeira
authors.affiliation: Functional Genomics Laboratory, Department of Psychiatry & Human Behavior, University of California Irvine, Irvine, California, United States of America.
authors.forename: Brandi
authors.initials: B
authors.lastname: Rollins
authors.affiliation: School of Information and Computer Sciences (ICS), Institute for Genomics and Bioinformatics (IGB), University of California Irvine, Irvine, California, United States of America.
authors.forename: Christophe
authors.initials: C
authors.lastname: Magnan
authors.affiliation: Department of Forensic Molecular Biology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Mannis
authors.initials: M
authors.lastname: van Oven
authors.affiliation: School of Information and Computer Sciences (ICS), Institute for Genomics and Bioinformatics (IGB), University of California Irvine, Irvine, California, United States of America.
authors.forename: Pierre
authors.initials: P
authors.lastname: Baldi
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, United States of America.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Myers
authors.affiliation: Department of Psychiatry, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Jack D
authors.initials: JD
authors.lastname: Barchas
authors.affiliation: Department of Psychiatry & Behavioral Sciences, Stanford University, Palo Alto, California, United States of America.
authors.forename: Alan F
authors.initials: AF
authors.lastname: Schatzberg
authors.affiliation: Molecular and Behavioral Neurosciences Institute, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Watson
authors.affiliation: Molecular and Behavioral Neurosciences Institute, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Huda
authors.initials: H
authors.lastname: Akil
authors.affiliation: Department of Psychiatry & Human Behavior, University of California Irvine, Irvine, California, United States of America.
authors.forename: William E
authors.initials: WE
authors.lastname: Bunney
authors.affiliation: Functional Genomics Laboratory, Department of Psychiatry & Human Behavior, University of California Irvine, Irvine, California, United States of America.
authors.forename: Marquis P
authors.initials: MP
authors.lastname: Vawter
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D004587:Electrophoresis, Agar Gel; D005260:Female; D056426:Genetic Loci; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000097:blood / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D017397:Prefrontal Cortex / Q000473:pathology
chemical_list: D004272:DNA, Mitochondrial