揭示NEK4作为精神分裂症和双相情感障碍I期的潜在药物靶点:蛋白质组和基因组方法。

IF 5.3 1区 医学 Q1 PSYCHIATRY Schizophrenia Bulletin Pub Date : 2024-08-27 DOI:10.1093/schbul/sbae094
Chengcheng Zhang, ZhiHui Yang, Xiaojing Li, Liansheng Zhao, Wanjun Guo, Wei Deng, Qiang Wang, Xun Hu, Ming Li, Pak Chung Sham, Xiao Xiao, Tao Li
{"title":"揭示NEK4作为精神分裂症和双相情感障碍I期的潜在药物靶点:蛋白质组和基因组方法。","authors":"Chengcheng Zhang, ZhiHui Yang, Xiaojing Li, Liansheng Zhao, Wanjun Guo, Wei Deng, Qiang Wang, Xun Hu, Ming Li, Pak Chung Sham, Xiao Xiao, Tao Li","doi":"10.1093/schbul/sbae094","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and hypothesis: </strong>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.</p><p><strong>Study design: </strong>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.</p><p><strong>Study results: </strong>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.</p><p><strong>Conclusions: </strong>These findings underscore a shared genetic origin for SCZ and BD-I, offering novel insights for potential therapeutic target identification.</p>","PeriodicalId":21530,"journal":{"name":"Schizophrenia Bulletin","volume":null,"pages":null},"PeriodicalIF":5.3000,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11349004/pdf/","citationCount":"0","resultStr":"{\"title\":\"Unraveling NEK4 as a Potential Drug Target in Schizophrenia and Bipolar I Disorder: A Proteomic and Genomic Approach.\",\"authors\":\"Chengcheng Zhang, ZhiHui Yang, Xiaojing Li, Liansheng Zhao, Wanjun Guo, Wei Deng, Qiang Wang, Xun Hu, Ming Li, Pak Chung Sham, Xiao Xiao, Tao Li\",\"doi\":\"10.1093/schbul/sbae094\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and hypothesis: </strong>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.</p><p><strong>Study design: </strong>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.</p><p><strong>Study results: </strong>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.</p><p><strong>Conclusions: </strong>These findings underscore a shared genetic origin for SCZ and BD-I, offering novel insights for potential therapeutic target identification.</p>\",\"PeriodicalId\":21530,\"journal\":{\"name\":\"Schizophrenia Bulletin\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.3000,\"publicationDate\":\"2024-08-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11349004/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Schizophrenia Bulletin\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1093/schbul/sbae094\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PSYCHIATRY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Schizophrenia Bulletin","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/schbul/sbae094","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PSYCHIATRY","Score":null,"Total":0}
引用次数: 0

摘要

背景与假设:调查精神分裂症(SCZ)和双相情感障碍(BD-I)共同的脑蛋白和遗传成分为了解潜在的病理生理过程和确定潜在的药物靶点提供了一个独特的机会:为了确定SCZ和BD-I中重叠的易感性脑蛋白,我们通过整合人类脑蛋白定量性状位点和针对这两种疾病的大规模全基因组关联研究,开展了全蛋白组关联研究(PWAS)和孟德尔随机化研究(MR)。我们利用转录组关联研究(TWAS)来确定这两种疾病的 mRNA 蛋白失调的一致性。我们应用多向性条件假发现率(pleioFDR)分析来确定SCZ和BD-I的共同风险基因位点。此外,我们还在人脑中进行了细胞类型特异性分析,以检测在不同脑细胞类型中明显富集的风险基因。我们还研究了风险基因过表达对神经元树突轴化和轴突长度的影响:研究结果:我们的PWAS发现了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是这两种疾病的共同特征。TWAS和MR分析证实了NEK4是SCZ和BD-I的重要风险基因。PleioFDR分析进一步支持了这两种疾病与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,在培养的初级神经元中,NEK4的过表达可增强树突轴化和轴突长度:这些发现强调了SCZ和BD-I的共同遗传起源,为潜在治疗目标的确定提供了新的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
Unraveling NEK4 as a Potential Drug Target in Schizophrenia and Bipolar I Disorder: A Proteomic and Genomic Approach.

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.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Schizophrenia Bulletin
Schizophrenia Bulletin 医学-精神病学
CiteScore
11.40
自引率
6.10%
发文量
163
审稿时长
4-8 weeks
期刊介绍: Schizophrenia Bulletin seeks to review recent developments and empirically based hypotheses regarding the etiology and treatment of schizophrenia. We view the field as broad and deep, and will publish new knowledge ranging from the molecular basis to social and cultural factors. We will give new emphasis to translational reports which simultaneously highlight basic neurobiological mechanisms and clinical manifestations. Some of the Bulletin content is invited as special features or manuscripts organized as a theme by special guest editors. Most pages of the Bulletin are devoted to unsolicited manuscripts of high quality that report original data or where we can provide a special venue for a major study or workshop report. Supplement issues are sometimes provided for manuscripts reporting from a recent conference.
期刊最新文献
Non-psychotic Outcomes in Young People at Ultra-High Risk of Developing a Psychotic Disorder: A Long-Term Follow-up Study. Network Localization of State and Trait of Auditory Verbal Hallucinations in Schizophrenia. Clarifying Cognitive Control Deficits in Psychosis via Drift Diffusion Modeling and Attractor Dynamics. Understanding the Mechanisms of Cognitive Remediation on Recovery in People With Early Psychosis: A Mediation and Moderation Analysis. The Role of Religion and Ethnic Factors in My Recovery From 10 Years of Schizophrenia and Severe Depression.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1