Genome-wide association studies (GWAS) analyses have revealed genetic evidence of bipolar disorder (BD), but little is known about genetic structure of BD subtypes. We aimed to investigate genetic overlap and distinction of bipolar type I (BDI) & type II (BDII) by conducting integrative post-GWAS analyses. This study 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 BDI & II and drug responses and comparing the difference of genetic structures among four different psychiatric traits. Our results find SNP-level evidence revealed three genomic loci, SLC25A17, ZNF184 and RPL10AP3 shared by BDI & II, while one locus (i.e., MAD1L1) and significant gene sets involved in calcium channel activity, neural and synapsed signals that distinguished two subtypes. TWAS data implicated different genes effecting BDI & II through expression in specific brain regions (e.g., nucleus accumbens for BDI). Cross-phenotype analyses indicated that BDI & II share continuous genetic structures with schizophrenia (SCZ) and major depression disorder (MDD), which help fill the gaps left by the dichotomy of mental disorder. These combined evidences illustrate genetic convergence and divergence between BDI & II and provide an underlying biological and trans-diagnostic insight into major psychiatric disorders.

中文翻译：

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双相情感障碍 I 型和 II 型之间的趋同和发散模式：来自综合基因组分析的证据

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 分析来研究双相 I 型 (BDI) 和 II 型 (BDII) 的遗传重叠和区别。该研究利用单核苷酸多态性 (SNP) 级别的方法来揭示相关和不同的遗传位点。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 BDI 和 II 与药物反应之间的潜在因果关系，并比较四种不同精神特征之间的遗传结构差异。SLC25A17、ZNF184和RPL10AP3由 BDI 和 II 共享，而一个位点（即MAD1L1）和重要的基因集涉及钙通道活性、神经和突触信号，可区分两种亚型。TWAS 数据表明，不同的基因通过在特定大脑区域（例如 BDI 的伏隔核）中的表达来影响 BDI 和 II。交叉表型分析表明，BDI 和 II 与精神分裂症 (SCZ) 和重度抑郁症 (MDD) 共享连续的遗传结构，这有助于填补精神障碍二分法留下的空白。这些综合证据说明了 BDI 和 II 之间的遗传趋同和差异，并提供了对主要精神疾病的潜在生物学和跨诊断洞察力。