Single-molecule DNA analysis implicates brain mitochondria pathology in bipolar disorder

Area of Science:

• Genetics
• Neuroscience
• Mitochondrial Biology

Background:

• Bipolar disorder (BD) is a complex psychiatric condition with high heritability, but its precise genetic mechanisms remain unclear.
• Mitochondria are crucial for neural function, and their dysfunction is linked to psychiatric symptoms, making mitochondrial variants a key area of investigation for BD.

Purpose of the Study:

• To investigate the association between mitochondrial heteroplasmic variants and bipolar disorder.
• To explore the role of brain heteroplasmic variants in the pathogenesis of BD.

Main Methods:

• Analysis of 163 brain DNA samples from bipolar disorder patients, schizophrenia patients, and controls.
• Utilized duplex molecular barcoding sequencing for single-molecule resolution of mitochondrial variants.

Main Results:

• Found an enrichment of ultra-rare mitochondrial heteroplasmic variants (allele fraction >1%) in bipolar disorder brains.
• Identified enrichment of potentially pathogenic variants, including m.3243A>G, loss-of-function, and rRNA variants, in BD patients.
• Did not observe a general increase in low-level heteroplasmic variants in BD patients.

Conclusions:

• A subset of bipolar disorder patients may be identifiable through the presence of ultra-rare mitochondrial variants.
• Findings support genomic stratification based on mitochondrial variants for future research and targeted therapeutic strategies in BD.