Mitochondrial Mutations and Polymorphisms in Psychiatric Disorders

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.

A mitochondrial bioenergetic etiology of disease

“…mtDNA deletions that occur early in development can become widely disseminated throughout the body and cause spontaneous mitochondrial myopathy (24). However, mtDNA deletions (25)(26)(27)(28) and base substitutions (29,30) can arise in tissues throughout life, and their accumulation has been shown to modulate aging and longevity (31-33). Therefore, the accumulation of somatic mtDNA mutations may be the aging clock.…”

“…However, this would be predicted if neuropsychiatric disorders share a common bioenergetic pathophysiological mechanism. Mitochondrial dysfunction has been documented in psychiatric disorders (81), evidence of matrilineal bias in transmission has been reported (82,83), and mtDNA haplogroups and brain mtDNA somatic mutations have been observed in patients with psychiatric conditions (21,28).…”

Elevated Excitatory Input to the Nucleus Accumbens in Schizophrenia: A Postmortem Ultrastructural Study

“…[45][46][47][48] Few studies have considered the structure and function of mitochondria in the NAcc in SZ. [49][50][51][52] Differential alterations in the basal ganglia have been reported in SZ, including increased mitochondrial activity in the NAcc of paranoid SZ subjects that was attributed to APD effects. 51 Despite the evidence for mitochondrial pathology in dorsal striatum in SZ, our structural findings do not indicate this pathology is present in the NAcc.…”

Mitochondrial DNA SNPs associated with Schizophrenia exhibit Highly Variable Inter-allelic Haplogroup Affiliation and Nuclear Genogeographic Affinity: Bi-Genomic Linkage Disequilibrium raises Major Concerns for Link to Disease

“…This has been reported in neurological degenerative diseases such as Alzheimer's disease 9-12 and Parkinson's disease 12-14 , metabolic diseases and cancers 15 , as well as psychiatric diseases, notably schizophrenia (SZ) and bipolar disease [16][17][18] .…”

“…Using DNA-array data from the Danish iPSYCH study on 2,538 schizophrenia patients and 23,743 population controls, we show that eight mtDNA SNPs, previously associated with SZ [16][17][18]23 , exhibit considerable inter-allelic differences both with respect to mtDNA hg affiliation and nuclear GGA.…”