Background and Hypothesis Investigating the shared brain protein and genetic components of schizophrenia (SCZ) and bipolar I disorder (BD-I) presents a unique opportunity to understand the underlying pathophysiological processes and pinpoint potential drug targets. Study Design To identify overlapping susceptibility brain proteins in SCZ and BD-I, we carried out proteome-wide association studies (PWAS) and Mendelian Randomization (MR) by integrating human brain protein quantitative trait loci with large-scale genome-wide association studies for both disorders. We utilized transcriptome-wide association studies (TWAS) to determine the consistency of mRNA-protein dysregulation in both disorders. We applied pleiotropy-informed conditional false discovery rate (pleioFDR) analysis to identify common risk genetic loci for SCZ and BD-I. Additionally, we performed a cell-type-specific analysis in the human brain to detect risk genes notably enriched in distinct brain cell types. The impact of risk gene overexpression on dendritic arborization and axon length in neurons was also examined. Study Results Our PWAS identified 42 proteins associated with SCZ and 14 with BD-I, among which NEK4, HARS2, SUGP1, and DUS2 were common to both conditions. TWAS and MR analysis verified the significant risk gene NEK4 for both SCZ and BD-I. PleioFDR analysis further supported genetic risk loci associated with NEK4 for both conditions. The cell-type specificity analysis revealed that NEK4 is expressed on the surface of glutamatergic neurons, and its overexpression enhances dendritic arborization and axon length in cultured primary neurons. Conclusions These findings underscore a shared genetic origin for SCZ and BD-I, offering novel insights for potential therapeutic target identification.

中文翻译：

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揭示 NEK4 作为精神分裂症和 I 型双相情感障碍的潜在药物靶点：蛋白质组学和基因组学方法


背景和假设研究精神分裂症（SCZ）和I型双相情感障碍（BD-I）共有的脑蛋白和遗传成分为了解潜在的病理生理过程和查明潜在的药物靶点提供了独特的机会。研究设计为了识别 SCZ 和 BD-I 中重叠的易感性脑蛋白，我们通过将人脑蛋白数量性状基因座与大规模全基因组关联研究相结合，进行了全蛋白质组关联研究 (PWAS) 和孟德尔随机化 (MR)两种疾病。我们利用全转录组关联研究 (TWAS) 来确定两种疾病中 mRNA-蛋白质失调的一致性。我们应用多效性条件错误发现率 (pleioFDR) 分析来识别 SCZ 和 BD-I 的常见风险遗传位点。此外，我们在人脑中进行了细胞类型特异性分析，以检测不同脑细胞类型中显着丰富的风险基因。还检查了风险基因过度表达对神经元树突分枝和轴突长度的影响。研究结果 我们的 PWAS 鉴定出 42 种与 SCZ 相关的蛋白和 14 种与 BD-I 相关的蛋白，其中 NEK4、HARS2、SUGP1 和 DUS2 对于这两种情况都是常见的。 TWAS 和 MR 分析验证了 SCZ 和 BD-I 的显着风险基因 NEK4。 PleioFDR 分析进一步支持这两种情况下与 NEK4 相关的遗传风险位点。细胞类型特异性分析表明，NEK4在谷氨酸能神经元表面表达，其过度表达增强了培养的原代神经元的树突分枝和轴突长度。结论 这些发现强调了 SCZ 和 BD-I 的共同遗传起源，为潜在治疗靶点的识别提供了新的见解。