Novel Complex Interactions between Mitochondrial and Nuclear DNA in Schizophrenia and Bipolar Disorder

Abstract

Mitochondrial dysfunction has been associated with schizophrenia (SZ) and bipolar disorder (BD). This review examines recent publications and novel associations between mitochondrial genes and SZ and BD. Associations of nuclear-encoded mitochondrial variants with SZ were found using gene- and pathway-based approaches. Two control region mitochondrial DNA (mtDNA) SNPs, T16519C and T195C, both showed an association with SZ and BD. A review of 4 studies of A15218G located in the cytochrome B oxidase gene (CYTB, SZ = 11,311, control = 35,735) shows a moderate association with SZ (p = 2.15E-03). Another mtDNA allele A12308G was nominally associated with psychosis in BD type I subjects and SZ. The first published study testing the epistatic interaction between nuclear-encoded and mitochondria-encoded genes demonstrated evidence for potential interactions between mtDNA and the nuclear genome for BD. A similar analysis for the risk of SZ revealed significant joint effects (34 nuclear-mitochondria SNP pairs with joint effect p ≤ 5E-07) and significant enrichment of projection neurons. The mitochondria-encoded gene CYTB was found in both the epistatic interactions for SZ and BD and the single SNP association of SZ. Future efforts considering population stratification and polygenic risk scores will test the role of mitochondrial variants in psychiatric disorders.

Oxidative-Antioxidant Imbalance and Impaired Glucose Metabolism in Schizophrenia

“…The first phase (although different in both genders in terms of anatomical differences in the white matter of the brain) is similar in most patients and is characterized by prodromal symptoms: Anxiety, irritability, social withdrawal, and depressed mood [15,16]. Recent evidence-based data also indicate a strong association between schizophrenia and bipolar disorder (BD) through a clear relationship between mitochondrial genes in both diseases [17]. Patients may also experience positive symptoms, i.e., hallucinations and delusions [18].…”

The First Complete Zoroastrian-Parsi Mitochondrial Reference Genome and genetic signatures of an endogamous non-smoking population

“…A total of 87 variants, including 6 unique variants, were observed in the D-loop region across all 25 sub-haplogroups (n=100 subjects, Table 2 ). 74/100 Parsis in our study, were found to have the polymorphism m.16519 T>C that is associated with chronic kidney disease 43 , an increased risk for Huntingtons disease, migraine headache, and cyclic vomiting syndrome 44 and schizophrenia and bipolar disorder 48 a. While six subjects of the M52 sub-haplogroup were found to have m.16525 A>G. The rest of the variants were found at m.16390 G>A (n=4 subjects) and m.16399 A>G, m.16401 C>T, and m.16497 A>G (all with n=1 subject each).…”

“…The tRNA disease-association analysis in our study showed that these genes were implicated in the onset of neurodegenerative conditions, such as AD; PD; cancers of colorectal and prostate origin; metabolic diseases, such as type 2 diabetes; and rare diseases, such as LHON (CYTB and ND2). The D-loop SNP analysis showed the prevalence (74/100 subjects) of the m.16519 T>C polymorphism, which has been implicated in chronic kidney disease 43 , an increased risk of Huntington's disease, cyclic vomiting syndrome 44 , schizophrenia, and bipolar disorder 45 . Taken together, these results warrant a deeper investigation into the tRNA and the D-loop variants in the Parsi community.…”

Correlation between GRIK2 rs6922753, rs2227283 polymorphism and aggressive behaviors with Bipolar Mania in the Chinese Han population

“…Some studies have found that a small group of molecules associated with the GRIK2 gene play an important role in the mechanism of controlling manic symptoms (Beneyto, Kristiansen, Oni-Orisan, McCullumsmith, & Meador-Woodruff, 2007;Kato, Kubota, & Kasahara, 2007). These molecules include ERK1 (Frey et al, 2013;Sodersten et al, 2014), GSK-3b (Kim, Won, & Yoon, 2019), mtDNA polymerase (Schulmann et al, 2019), and CLOCK (Etain, Milhiet, Bellivier, & Leboyer, 2011). Whether these molecules act independently or together to control behaviors associated with manic symptoms requires further confirmation.…”