Enrichment of deleterious variants of mitochondrial DNA polymerase gene (POLG1) in bipolar disorder

Abstract

Aim Rare missense variants, which likely account for a substantial portion of the genetic ‘dark matter’ for a common complex disease, are challenging because the impacts of variants on disease development are difficult to substantiate. This study aimed to examine the impacts of amino acid substitution variants in the POLG1 found in bipolar disorder, as an example and proof of concept, in three different modalities of assessment: in silico predictions, in vitro biochemical assays, and clinical evaluation. We then tested whether deleterious variants in POLG1 contributed to the genetics of bipolar disorder. Methods We searched for variants in the POLG1 gene in 796 Japanese patients with bipolar disorder and 767 controls and comprehensively investigated all 23 identified variants in the three modalities of assessment. POLG1 encodes mitochondrial DNA polymerase and is one of the causative genes for a Mendelian‐inheritance mitochondrial disease, which is occasionally accompanied by mood disorders. The healthy control data from the Tohoku Medical Megabank Organization were also employed. Results Although the frequency of carriers of deleterious variants varied from one method to another, every assessment achieved the same conclusion that deleterious POLG1 variants were significantly enriched in the variants identified in patients with bipolar disorder compared to those in controls. Conclusion Together with mitochondrial dysfunction in bipolar disorder, the present results suggested deleterious POLG1 variants as a credible risk for the multifactorial disease.

Altered ethanolamine plasmalogen and phosphatidylethanolamine levels in blood plasma of patients with bipolar disorder

“…Therefore, ethanolamine phospholipids levels are more associated to BP I than to BP II related pathological processes. Associations of BP and genetic variants of mitochondrial functions [44][45][46][47] and ER stress [48][49][50] have been reported, and the links between mitochondrial dysfunction, ER stress, and inflammatory status may be more relevant to the pathophysiology of BP subtype I. The interaction of genetic variation of B-cell CLL/lymphoma 2 (BCL-2) and its expression was shown in BP I patients specifically 51 ; BCL-2 is located in both mitochondria and ER and has various roles including anti-apoptosis and intracellular calcium homeostasis.…”

Ant1 mutant mice bridge the mitochondrial and serotonergic dysfunctions in bipolar disorder

“…Mitochondrial dysfunction has been implicated in bipolar disorder based on several lines of evidence [ 2 ] including altered energy metabolism detected by magnetic resonance spectroscopy [ 38 ], comorbidity with mitochondrial diseases [ 4 , 7 ], and findings in postmortem brains including an accumulation of ΔmtDNAs [ 39 , 40 ], altered gene expression of mitochondria-related genes [ 41 ], altered morphology of mitochondria [ 42 ], and decreased activity of mitochondrial complex I [ 43 ]. On the other hand, serotonergic dysfunction in bipolar disorder has been implicated by evidence including the mania-inducing effect of antidepressants that inhibits the serotonin transporter and thereby activates serotonin [ 44 ], the efficacy of atypical antipsychotics that inhibits serotonergic neurotransmission [ 45 ], altered mRNA expression levels of serotonergic receptors in postmortem brain [ 46 ], altered DNA methylation of serotonin transporter gene [ 47 ], altered serotonin transporter binding in the brain by positron emission tomography [ 48 ], and levels of cerebrospinal fluid metabolites, among others [ 14 ].…”

“…However, the relationship between these apparently unrelated metabolic signaling systems has not been elucidated [ 3 ]. Clinical studies showed that around 20% of patients with mitochondrial disease have comorbid bipolar disorder [ 4 – 6 ], whereas 0.38% of patients with bipolar disorder had mutations of POLG (polymerase γ) causative for mitochondrial disease [ 7 ]. In a family of bipolar disorder and autosomal dominantly inherited chronic external ophthalmoplegia (CPEO), the L98P mutation of ANT1 (adenine nucleotide translocator 1, SLC25A4 ) was identified [ 8 , 9 ].…”

Differential mitochondrial DNA copy number in three mood states of bipolar disorder

“…MtDNA polymerase gamma (POLG) is the only one polymerase responsible for the mtDNA replication. POLG is prone to oxidative damage,and its deleterious variants were suggested as a risk for BD [ 33 ]. Munkholm et al revealed downregulation of POLG expression in BD across mania, hypomania, depression or mixed states in peripheral leukocyte [ 34 ].…”