Diagnosis- and Cell Type-Specific Mitochondrial Functional Pathway Signatures in Schizophrenia and Bipolar Disorder

Abstract

Objective: The shared risk factors and clinical features in schizophrenia and bipolar disorder may be linked via mitochondrial dysfunction. However, the severity of mitochondrial dysfunction, and/or the specific mitochondrial functional pathways affected, may differ between diagnoses, especially at the level of individual cell types.

Methods: Transcriptomic profiling data for a gene set indexing mitochondrial functional pathways were obtained for dorsolateral prefrontal cortex (DLPFC) gray matter and layer 3 and layer 5 pyramidal neurons of subjects with schizophrenia or bipolar disorder. Analyses were conducted using a dual strategy: identification of differentially expressed genes (DEGs) and their functional pathway enrichment, and application of weighted gene coexpression network analysis. These analyses were repeated in monkeys chronically exposed to antipsychotic drugs to determine their effect on mitochondrial-related gene expression.

Results: In DLPFC gray matter, 41% of mitochondrial-related genes were differentially expressed in the schizophrenia group, whereas 8% were differentially expressed in the bipolar group. In the schizophrenia group, 83% of DEGs showed lower expression, and these were significantly enriched for three functional pathways, each indexing energy production. DEGs in the bipolar disorder group were not enriched for functional pathways. This disease-related pattern of findings was also identified in pyramidal neurons. None of the gene expression alterations disrupted coexpression modules, and DEGs were not attributable to antipsychotic medications.

Conclusions: Schizophrenia and bipolar disorder do not appear to share similar mitochondrial alterations in the DLPFC. The selective and coordinated down-regulation of energy production genes in schizophrenia is consistent with the effects of chronic reductions in pyramidal neuron firing, and enhancement of this activity may serve as a therapeutic target.

Keywords: Bipolar Disorder; Genetics; Mitochondrial Function; Schizophrenia.

Figure 1.

Differential expression, WGCNA and module preservation and enrichment of GOMito genes in DLPFC gray matter of schizophrenia and bipolar disorder subjects. A. Volcano plots of gene expression illustrating for each GOMito gene detected by RNASeq the mean log2 fold difference in schizophrenia and bipolar disorder subjects relative to unaffected subjects and the −log10 p-value. Dashed horizontal line denotes statistical significance at q = 0.05, with data points above the line indicating DEGs. Inset shows the number of shared and unique GOMito genes differentially-expressed in schizophrenia and bipolar disorder subjects. B. Scatter plot illustrating the positive correlation between schizophrenia and bipolar disorder subjects of GOMito differential-expression test-statistics. C. WGCNA identified five GOMito gene co-expression modules in unaffected subjects. Colored bars on the top and left sides of the heat maps indicate each identified module. Heat map shows pair-wise correlation strength in unaffected subjects for each GOMito gene. For each module, the table (bottom) provides the number of genes present in each module, the number that were differentially-expressed, and the percent that were under-expressed in schizophrenia or bipolar disorder subjects relative to unaffected subjects. D. Module preservation Zsummary scores illustrating strong (Zsummary>10) preservation of brown, yellow and green modules, and moderate (2<Zsummary<10) preservation of purple and black modules in schizophrenia and bipolar disorder subjects. E. IPA showed significant mitochondrial dysfunction, OXPHOS and sirtuin signaling pathway enrichment within the brown module. For each pathway, DEGs were significantly enriched in schizophrenia subjects, but none of these pathway genes were differentially-expressed in bipolar disorder subjects.

Figure 2.

Differential expression, WGCNA and module preservation and enrichment of GOMito genes in DLPFC L3PNs and L5PNs of schizophrenia subjects. A. Volcano plots of gene expression illustrating for each GOMito gene detected by microarray the mean log2 fold difference in schizophrenia subjects relative to unaffected and the −log10 p-value. Dashed horizontal line denotes statistical significance at q=0.05, with data points above the line indicating DEGs. Inset shows the number of shared and unique DEGs in L3PNs and L5PNs. B. Scatter plot illustrating the correlation between L3PNs and L5PNs of GOMito differential-expression test-statistics in schizophrenia subjects. C. WGCNA of GOMito gene expression identified three co-expression modules in unaffected subjects in L3PNs and five co-expression modules in L5PNs. Colored bars on the top and left sides of the heat maps indicate each identified module. Heat map shows pair-wise correlation strength in unaffected subjects for each GOMito gene. For each module, the tables (bottom) provide the number of genes present in each module, the number differentially-expressed, and the percent that were under-expressed in L3PNs and L5PNs in schizophrenia relative to unaffected subjects. D. Module preservation Zsummary scores illustrating for L3PNs, strong (Zsummary>10) preservation of turquoise module, and moderate (2<Zsummary<10) preservation of magenta and dark green modules. For L5PNs, strong (Zsummary>10) module preservation is present for plum and lavender modules, moderate (2<Zsummary<10) preservation for gold and salmon modules, and no (Zsummary<10) preservation of orange module. E. IPA in L3PNs showed significant mitochondrial dysfunction, OXPHOS and sirtuin signaling pathway enrichment within the magenta module and sirtuin signaling pathway enrichment in the turquoise model. F. IPA in L5PNs showed significant mitochondrial dysfunction and OXPHOS pathway enrichment within the lavender module and OXPHOS pathway enrichment in the salmon module.

Figure 3.

Comparison of differential-expression test-statistics in L3PNs and L5PNs of schizophrenia and bipolar disorder subjects. A. Scatter plot illustrating the correlation within L3PNs (left) and L5PNs (right) of GOMito differential-expression test-statistics between schizophrenia and bipolar disorder subjects. B. Scatter plot illustrating the correlation between L3PNs (left) and L5PNs (right) of GOMito differential-expression test-statistics in the two studies including schizophrenia subjects.

Figure 4.

Comparison of differential-expression test-statistics in gray matter and L3PNs and L5PNs of schizophrenia subjects and monkeys chronically exposed to antipsychotic drugs. A. Scatter plots illustrating the test-statistic correlation in gray matter of schizophrenia subjects and monkeys administered haloperidol (top) or clozapine (bottom). B. Scatter plots illustrating the test-statistic correlation in L3PNs and L5PNs of schizophrenia subjects and monkeys administered haloperidol (top) or olanzapine (bottom).