Abstract：
For bipolar disorder (BD), the inconsistency of treatment guidelines and the long phases of pharmacological adjustment remain major challenges. BD is known to be comorbid with many medical and psychiatric conditions and they may share inflammatory and stress-related aetiologies, which could give rise to this association. The integrated stress response (ISR) responds to various stress conditions that lead to alterations in cellular homeostasis. However, as a causative mechanism underlying cognitive deficits and neurodegeneration in a broad range of brain disorders, the impact of ISR on BD is understudied. Mendelian randomization has been widely used to repurpose licensed drugs and discover novel therapeutic targets. Thus, we aimed to identify novel therapeutic targets for BD and analyze their pathophysiological mechanisms, using the summary data-based Mendelian Randomization (SMR) and Bayesian colocalization (COLOC) methods to integrate the summary-level data of the GWAS on BD and the expression quantitative trait locus (eQTL) study in blood. We utilized the GWAS data including 41,917 BD cases and 371,549 controls from the Psychiatric Genomics Consortium and the eQTL data from 31,684 participants of predominantly European ancestry from the eQTLGen consortium. The SMR analysis identified the EIF2B5 gene that was associated with BD due to no linkage but pleiotropy or causality. The COLOC analysis strongly suggested that EIF2B5 and the trait of BD were affected by shared causal variants, and thus were colocalized. Utilizing data in EpiGraphDB we find other putative causal BD genes (EIF2AK4 and GSK3B) to prioritize potential alternative drug targets.
摘要：
对于双相情感障碍（BD），治疗指南的不一致和药物调整的长期阶段仍然是一个主要挑战.已知BD与许多医疗和精神疾病并存，它们可能共享炎症和压力相关的病因。这可能会导致这种联系。整合应激反应(ISR)对导致细胞稳态改变的各种应激反应条件作出反应。然而,作为广泛的脑部疾病中认知缺陷和神经变性的致病机制，ISR对BD的影响研究不足。孟德尔随机化已被广泛用于重新使用许可药物并发现新的治疗靶标。因此，我们旨在确定BD的新治疗靶点并分析其病理生理机制，使用基于汇总数据的孟德尔随机化（SMR）和贝叶斯共定位（COLOC）方法整合BD上GWAS的汇总数据和血液中表达数量性状基因座（eQTL）研究。我们利用了GWAS数据，包括来自精神病学基因组学联盟的41,917例BD病例和371,549例对照，以及来自eQTLGen联盟主要欧洲血统的31,684名参与者的eQTL数据。SMR分析鉴定了与BD相关的EIF2B5基因，因为没有连锁，但具有多效性或因果关系。COLOC分析强烈表明，EIF2B5和BD的性状受到共同因果变异的影响，因此被共同定位。利用EpiGraphDB中的数据，我们发现了其他推定的因果BD基因（EIF2AK4和GSK3B）来优先考虑潜在的替代药物靶标。
