Abstract
Mitochondrial deficiencies with unknown causes have been observed in schizophrenia (SZ) and bipolar disorder (BD) in imaging and postmortem studies. Polymorphisms and somatic mutations in mitochondrial DNA (mtDNA) were investigated as potential causes with next generation sequencing of mtDNA (mtDNA-Seq) and genotyping arrays in subjects with SZ, BD, major depressive disorder (MDD), and controls. The common deletion of 4,977 bp in mtDNA was compared between SZ and controls in 11 different vulnerable brain regions and in blood samples, and in dorsolateral prefrontal cortex (DLPFC) of BD, SZ, and controls. In a separate analysis, association of mitochondria SNPs (mtSNPs) with SZ and BD in European ancestry individuals (n = 6,040) was tested using Genetic Association Information Network (GAIN) and Wellcome Trust Case Control Consortium 2 (WTCCC2) datasets. The common deletion levels were highly variable across brain regions, with a 40-fold increase in some regions (nucleus accumbens, caudate nucleus and amygdala), increased with age, and showed little change in blood samples from the same subjects. The common deletion levels were increased in the DLPFC for BD compared to controls, but not in SZ. Full mtDNA genome resequencing of 23 subjects, showed seven novel homoplasmic mutations, five were novel synonymous coding mutations. By logistic regression analysis there were no significant mtSNPs associated with BD or SZ after genome wide correction. However, nominal association of mtSNPs (p < 0.05) to SZ and BD were found in the hypervariable region of mtDNA to T195C and T16519C. The results confirm prior reports that certain brain regions accumulate somatic mutations at higher levels than blood. The study in mtDNA of common polymorphisms, somatic mutations, and rare mutations in larger populations may lead to a better understanding of the pathophysiology of psychiatric disorders.
Highlights
Mitochondria are subcellular organelles enriched in energetic tissues, such as muscle and brain, and located in the cytoplasm
The most significant individual brain regional correlations with age were observed in the nucleus accumbens (NACC), caudate nucleus (CAUN), and AMY (Figures 1A– C) for cohort 1; the additional figures for the other brain regions can be seen in Figure S1 in Supplementary Material
The regional susceptibility to accumulation of the common deletion might be in both dopamine and glutamatergic innervated brain regions, a result of excessive reactive oxygen species (ROS) due to toxic dopamine metabolites, as well as excess calcium ion flow (Ben-Shachar, 2002; Lin and Beal, 2006; Trushina and McMurray, 2007; Keating, 2008; Pivovarova and Andrews, 2010; Surmeier et al, 2011). Both dopaminergic and glutamatergic neurotransmitter systems have been consistently shown to be involved in psychiatric disorders and our findings of higher accumulation of common deletion levels in heavily dopaminergic and glutamatergic regions in bipolar disorder (BD) and major depressive disorder (MDD) supports the involvement of mitochondrial dysfunction in those disorders as previously suggested (Ben-Shachar, 2002; Rezin et al, 2009; Kato et al, 2011; Verge et al, 2011)
Summary
Mitochondria are subcellular organelles enriched in energetic tissues, such as muscle and brain, and located in the cytoplasm. Human mtDNA, which is inherited in a matrilineal pattern (Giles et al, 1980), is a double stranded circular molecule of approximately 16,569 nucleotides (Wallace, 2005) containing 37 genes that encode two ribosomal RNAs, 22 transfer RNAs, and 13 polypeptides (Wallace, 2005). Previous studies have shown that mtDNA mutations and variations can play a role of susceptibility to both BD and SZ (Rollins et al, 2009; Bertolin et al, 2011; Kato et al, 2011; Verge et al, 2011), suggesting a direct role for the mitochondrial genome in neuropsychiatric disorders (Shao et al, 2008). Researchers have previously speculated that parent-of-origin effects might reflect subtle ascertainment biases, imprinting, X-linked genetic factors, vertical transmission of infectious agents, and in utero or other early maternal influences on offspring (McMahon et al, 2000)
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