LAUSR

Background Mitochondrial dysfunction has been well documented in patients with Bipolar Disorder (BD). Studies demonstrated that alternations in mtDNA copy number have been associated with mitochondrial dysfunction and increased oxidative stress. However, association between mtDNA copy number and BD compared to controls has been inconclusive so far. In this study, we aimed to assess whether mtDNA copy number is altered in BD type I (BDI) compared to controls. We also explored whether the total number of heteroplasmic Single Nucleotide Variants (SNVs) for a given subject, another marker for oxidative stress, is altered in BDI. Methods One hundred BDI patients were selected for Whole Genome Sequencing (WGS) experiment using leukocyte DNA from the Mayo Clinic Bipolar Disorder Biobank. In addition, 1000 patients from the Mayo Clinic Biobank, a control biobank, were also selected for the experiment. After applying basic quality control filtering (e.g., low sequencing coverage and sample contamination) to nuclear DNA sequencing data, this study used 99 BD1 patients and 961 controls. MtDNA copy number was defined as the relative quantity of mtDNA compared to nuclear DNA. For each SNV, likelihood functions were estimated under two models (heteroplasmy and homoplasmy) taking into account sequencing error, and log-likelihood ratio (LLR) was calculated. The total number of heteroplasmic SNVs for a given subject was calculated by counting the sites with LLR ≥ 5. Adjusting for age and sex, regression models were used to test the association between BD status and mtDNA copy number and the total number of heteroplasmic SNVs after log-transformation. Results BDI patients were younger compared to controls (median age at the biobank enrollment: 45 in BDI vs 61 in controls) with more females in cases (60% vs 50%). Overall, older age and male sex were associated with lower mtDNA copy number (P Discussion This small study potentially supports recent findings on a slight decrease in mtDNA copies among BDI and more copies in females. This study also shows that mtDNA copy number decreases with age, while the degree of heteroplasmy increases. Although the underlying mechanism for this observation is not clear, it may reflect mitochondrial DNA replication and degradation due to mitochondrial dysfunction and premature cellular senescence in BD.