Mental Health Center and Psychiatric Laboratory, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
Nanhu Brain-Computer Interface Institute, Hangzhou, China.
Schizophr Bull. 2024 Aug 27;50(5):1185-1196. doi: 10.1093/schbul/sbae094.
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.
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.
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.
These findings underscore a shared genetic origin for SCZ and BD-I, offering novel insights for potential therapeutic target identification.
研究精神分裂症 (SCZ) 和双相情感障碍 I 型 (BD-I) 的共享大脑蛋白和遗传成分，为了解潜在的病理生理过程并确定潜在的药物靶点提供了独特的机会。
为了确定 SCZ 和 BD-I 中重叠的易感性大脑蛋白，我们通过整合人类大脑蛋白质数量性状基因座与两种疾病的大规模全基因组关联研究，进行了蛋白质组全关联研究 (PWAS) 和孟德尔随机化 (MR)。我们利用转录组全关联研究 (TWAS) 来确定两种疾病中 mRNA-蛋白失调的一致性。我们应用多效性信息条件假发现率 (pleioFDR) 分析来确定 SCZ 和 BD-I 的常见风险遗传位点。此外，我们在人脑细胞中进行了特定细胞类型的分析，以检测在不同脑细胞类型中明显富集的风险基因。还检查了风险基因过表达对神经元树突分支和轴突长度的影响。
我们的 PWAS 确定了 42 种与 SCZ 相关的蛋白质和 14 种与 BD-I 相关的蛋白质，其中 NEK4、HARS2、SUGP1 和 DUS2 两种情况都有。TWAS 和 MR 分析验证了 NEK4 对 SCZ 和 BD-I 都是显著的风险基因。pleioFDR 分析进一步支持了与 NEK4 相关的遗传风险位点与两种情况有关。细胞类型特异性分析表明，NEK4 表达在谷氨酸能神经元的表面，其过表达增强了培养的原代神经元中的树突分支和轴突长度。
这些发现强调了 SCZ 和 BD-I 的遗传起源相同，为潜在的治疗靶点识别提供了新的见解。
