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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 : 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 ,
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WP1107: Mitochondrial LC-Fatty Acid Beta-Oxidation
WP1226: Mitochondrial LC-Fatty Acid Beta-Oxidation
WP1263: Mitochondrial Gene Expression
WP1301: Mitochondrial Gene Expression
WP1368: Mitochondrial Gene Expression
WP1502: Mitochondrial biogenesis
WP1905: RNA Polymerase I, RNA Polymerase III, and Mitochondrial Transcription
WP296: TCA Cycle - biocyc
WP368: Mitochondrial LC-Fatty Acid Beta-Oxidation
WP391: Mitochondrial Gene Expression
WP401: Mitochondrial LC-Fatty Acid Beta-Oxidation
WP406: Mitochondrial LC-Fatty Acid Beta-Oxidation
WP419: Mitochondrial LC-Fatty Acid Beta-Oxidation
WP448: Mitochondrial LC-Fatty Acid Beta-Oxidation
WP498: Mitochondrial LC-Fatty Acid Beta-Oxidation
WP525: Mitochondrial Unfolded-Protein Response
WP62: Mitochondrial tRNA Synthetases
WP763: Mitochondrial LC-Fatty Acid Beta-Oxidation
WP871: Mitochondrial LC-Fatty Acid Beta-Oxidation
WP928: Mitochondrial Gene Expression
WP989: Mitochondrial LC-Fatty Acid Beta-Oxidation
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