A research team led by Professors Li Ming and Xiao Xiao from the Kunming Institute of Zoology, Chinese Academy of Sciences, has published the largest genetic study of bipolar disorder (BD) across East Asian and European populations. The findings, published in Nature Neuroscience on 25 November, provide critical insights into the genetic basis and cell-type-specific mechanisms of BD.
The study integrated a Han Chinese genome-wide association study (GWAS) comprising 5,164 cases and 13,460 controls with datasets from East Asian and European consortia, culminating in a trans-ancestry meta-analysis of approximately 90,000 cases and 960,000 controls. Researchers identified 93 independent genome-wide significant loci, including 23 novel associations. Notably, the genetic correlation between East Asian and European samples was high (≈0.86), indicating substantial overlap in common variant genetic architecture.
Through fine-mapping and variant-to-gene analyses, the team prioritized 39 high-confidence BD risk genes. Cell-type enrichment analyses, leveraging single-cell transcriptomic data, revealed that BD genetic risk is predominantly enriched in fetal cortical GABAergic interneurons and, postnatally, in deep-layer excitatory neurons. Additionally, interneurons in subcortical regions, such as the amygdala and hippocampus, are closely related to BD.
Fifteen prioritized genes showed altered expression in patient-derived brain tissues, while 22 encode proteins that are either druggable or current drug targets—suggesting opportunities for therapeutic repurposing, particularly of antiepileptic drugs.
This work underscores the importance of diversifying samples in genetic studies beyond European ancestries to enhance discovery power and refine causal inferences. It marks a significant step toward precision psychiatry, offering a foundation for developing targeted interventions for bipolar disorder.
Upper: Manhattan plot for both Han Chinese GWAS and EAS GWAS; Lower: Manhattan plot for trans-ancestry GWAS with 93 GWS loci, among which 23 are novel.
