Abstract
Postmortem studies, as well as genetic association studies, have implicated mitochondrial dysfunction in schizophrenia (SZ). We conducted multistaged analysis to assess the involvement of mitochondrial DNA (mtDNA) variations in SZ. Initially, the entire mtDNA genome was sequenced in pools of DNA from SZ cases and controls (n = 180 in each group, set 1). Two polymorphisms localized to the NADH dehydrogenase subunit 5 (ND5) gene demonstrated suggestive case control allele frequency differences (mtDNA 13368 G/A, p = .019 and mtDNA 13708G/A, p = .043). Hence, the ND5 gene was sequenced in individual samples from the initial panel of cases and controls. Additional subjects from another independent set of cases and controls (set 2, cases, n = 244, controls n = 508) were also sequenced individually. No significant differences in allele frequencies for mtDNA 13368 G/A, and mtDNA 13708G/A were observed. However, we identified 216 other rare variants, 53 of which were reported earlier in association studies of other mitochondrial disorders. We compared the distribution of polymorphisms in both sets of cases and controls. No significant case-control differences were observed in the smaller, first set. In the second set, cases had more variants overall (p = 0.014), as well as synonymous variants (p = 0.02), but the difference for nonsynonymous variants was not significant (p = 0.19). Screening available first-degree relatives (n = 10) revealed 10 maternally inherited variations, suggesting that not all the variants are somatic mutations. Further investigations are warranted.
Highlights
Mitochondria are vital for cells especially that have constant high-energy demands, like muscle and brain cells
We observed a significant case-control difference for 2 variants in the NADH dehydrogenase subunit 5 (ND5) gene. We followed up this result by comprehensively sequencing the ND5 gene in all subjects
We confirmed the presence of homoplasmic variations at both positions showing case-control differences in the pooled analyses, but the significant allele frequency difference observed in the pooled DNA analysis was not reflected in the analyses of individual traces
Summary
Mitochondria are vital for cells especially that have constant high-energy demands, like muscle and brain cells. Several disorders can result from mitochondrial dysfunction. The prototypic mitochondrial diseases are Leber hereditary optic neuropathy (LHON), myoclonus epilepsy with ragged red fibers, and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS).[1] Mitochondrial DNA (mtDNA) mutations may confer risk for common polygenic diseases, such as Parkinson disease, Alzheimer disease, and bipolar disorder.[2,3,4,5,6]. Some case studies have documented SZ and other psychotic disorders in patients exhibiting MELAS.[7,8,9] Earlier studies of postmortem SZ brains revealed altered gene expression in the mitochondrial oxidative phosphorylation pathway.[10,11] There is additional evidence from postmortem brain studies for oxidative stress–induced cellular damage.[12] This damage can be attributed to mitochondrial dysfunction because mitochondria are major sites for the reactive oxygen species generation.[13,14]
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