Ohtani Hiroki, Ichikawa Ryuya, Mori Kanako, Kato Tadafumi, Nishioka Masaki
Department of Psychiatry and Behavioral Science, Juntendo University Graduate School of Medicine, Bunkyo-Ku, Tokyo, Japan.
Seijin Hospital, Adachi-Ku, Tokyo, Japan.
Mol Psychiatry. 2025 May 29. doi: 10.1038/s41380-025-03071-4.
Bipolar disorder (BD), characterized by recurrent manic and depressive episodes, is a global medical challenge. Based on its high heritability, various genomic studies have elucidated the genetic architecture of BD. Nonetheless, the specific genomic mechanisms underpinning BD pathogenesis remain elusive. Among under-investigated genomic factors, mitochondrial variants-particularly brain heteroplasmic variants-are of particular interest, given the critical role of mitochondria in neural function and the frequent psychiatric symptoms observed in mitochondrial diseases. In this study, we analyzed 163 brain DNA samples from 54 BD patients, 54 controls, and 55 schizophrenia patients to investigate the association between BD and mitochondrial heteroplasmic variants. Duplex molecular barcoding sequencing was employed for single-molecule resolution. We found an enrichment of ultra-rare heteroplasmic variants with allele fractions exceeding 1% in BD. Among them, potentially pathogenic variants, including m.3243A>G, loss-of-function variants, and rRNA variants, were particularly enriched in BD. In contrast, single-molecule analysis did not reveal a general trend of increases in low-level heteroplasmic variants in BD, in terms of per-base mutation frequency and heteroplasmic fractions. Thus, a subset of BD patients may be stratified according to the presence of ultra-rare mitochondrial variants. Our findings provide a foundation for future research into targeted therapeutic strategies for BD, grounded in genomic stratification by mitochondrial variants.
双相情感障碍（BD）以反复出现的躁狂和抑郁发作为特征，是一项全球性的医学挑战。基于其高遗传性，各种基因组研究已经阐明了BD的遗传结构。尽管如此，BD发病机制背后的具体基因组机制仍然难以捉摸。在研究较少的基因组因素中，线粒体变异——尤其是大脑中的异质性变异——特别受关注，因为线粒体在神经功能中起关键作用，且在线粒体疾病中经常观察到精神症状。在本研究中，我们分析了来自54例BD患者、54例对照和55例精神分裂症患者的163份脑DNA样本，以研究BD与线粒体异质性变异之间的关联。采用双链分子条形码测序实现单分子分辨率。我们发现BD中存在等位基因分数超过1%的超罕见异质性变异富集现象。其中，包括m.3243A>G在内的潜在致病变异、功能丧失变异和rRNA变异在BD中尤为富集。相比之下，单分子分析未发现BD中低水平异质性变异在每碱基突变频率和异质性分数方面有普遍增加的趋势。因此，一部分BD患者可能根据超罕见线粒体变异的存在进行分层。我们的研究结果为未来基于线粒体变异进行基因组分层的BD靶向治疗策略研究奠定了基础。
