Aim: Genome-wide association studies (GWAS) analyses have revealed genetic evidence of bipolar disorder (BD), but little is known about the genetic structure of BD subtypes. We aimed to investigate the genetic overlap and distinction of bipolar type I (BD I) & type II (BD II) by conducting integrative post-GWAS analyses.

Methods: We utilized single nucleotide polymorphism (SNP)–level approaches to uncover correlated and distinct genetic loci. Transcriptome-wide association analyses (TWAS) were then approached to pinpoint functional genes expressed in specific brain tissues and blood. Next, we performed cross-phenotype analysis, including exploring the potential causal associations between two BD subtypes and lithium responses and comparing the difference in genetic structures among four different psychiatric traits.

Results: SNP-level evidence revealed three genomic loci, SLC25A17, ZNF184, and RPL10AP3, shared by BD I and II, and one locus (MAD1L1) and significant gene sets involved in calcium channel activity, neural and synapsed signals that distinguished two subtypes. TWAS data implicated different genes affecting BD I and II through expression in specific brain regions (nucleus accumbens for BD I). Cross-phenotype analyses indicated that BD I and II share continuous genetic structures with schizophrenia and major depressive disorder, which help fill the gaps left by the dichotomy of mental disorders.

Conclusion: These combined evidences illustrate genetic convergence and divergence between BD I and II and provide an underlying biological and trans-diagnostic insight into major psychiatric disorders.

目标：全基因组关联研究 (GWAS) 分析揭示了双相情感障碍 (BD) 的遗传证据，但对 BD 亚型的遗传结构知之甚少。我们旨在通过进行综合后 GWAS 分析来研究双极 I 型 (BD I) 和 II 型 (BD II) 的遗传重叠和区别。

方法：我们利用单核苷酸多态性 (SNP) 水平的方法来发现相关和不同的遗传基因座。然后进行全转录组关联分析 (TWAS) 以查明在特定脑组织和血液中表达的功能基因。接下来，我们进行了交叉表型分析，包括探索两种 BD 亚型与锂反应之间的潜在因果关系，并比较四种不同精神特征之间遗传结构的差异。

结果：SNP 水平的证据揭示了三个基因组位点，SLC25A17、ZNF184， 和RPL10AP3，由 BD I 和 II 共享，一个基因座 (MAD1L1) 以及与钙通道活动有关的重要基因组，区分两种亚型的神经和突触信号。TWAS 数据涉及通过在特定脑区（BD I 的伏隔核）中表达影响 BD I 和 II 的不同基因。交叉表型分析表明，BD I 和 II 与精神分裂症和重度抑郁症具有连续的遗传结构，这有助于填补精神障碍二分法留下的空白。

结论：这些综合证据说明了 BD I 和 II 之间的遗传趋同和分歧，并提供了对主要精神疾病的潜在生物学和跨诊断洞察力。