{"title":"帕金森病和路易体痴呆症之间共同脑蛋白和基因位点的鉴定","authors":"Tingting Jia, Fuhua Yang, Fengqin Qin, Yongji He, Feng Han, Chengcheng Zhang","doi":"10.1111/cns.70370","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>Parkinson's disease (PD) and Lewy body dementia (LBD) have many common features, including clinical manifestations, neurochemistry, and pathology, but little is known about their shared brain proteins and genetic factors.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>To identify susceptibility-related brain proteins that are shared between PD and LBD patients, proteome-wide association studies (PWASs) were conducted by integrating human brain protein quantitative trait loci (pQTLs) with large-scale genome-wide association studies (GWASs) of both diseases. Subsequently, pleiotropy-informed conditional false discovery rate (pleioFDR) analysis was performed to identify common risk genetic loci between PD and LBD. Finally, the downregulation of these risk genes in different disease states was validated by differential gene expression analysis.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>PWASs identified 12 PD risk proteins and nine LBD risk proteins, among which <i>TMEM175</i> (<i>z</i><sub>PD</sub> = −7.25, <i>P</i><sub>PD</sub> = 4.12E-13; <i>z</i><sub>LBD</sub> = −6.02, <i>P</i><sub>LBD</sub> = 1.75E-09) and <i>DOC2A</i> (<i>z</i><sub>PD</sub> = −4.13, <i>P</i><sub>PD</sub> = 3.71E-05; <i>z</i><sub>LBD</sub> = −3.91, <i>P</i><sub>LBD</sub> = 9.08E-05) were shared. PleioFDR analysis revealed that five genetic risk loci mapped to eight genes associated with PD and LBD, including the proteome-wide significant risk gene <i>TMEM175</i> (ConjFDR = 5.74E-03). Differential expression analysis verified that <i>TMEM175</i> was significantly downregulated in the midbrains of PD patients (<i>p</i> = 1.19E-02), and further exploration revealed that <i>TMEM175</i> was also dramatically downregulated in the substantia nigra of PD patients (<i>p</i> = 1.16E-02) and incidental Lewy body disease patients (<i>p</i> = 7.52E-03). Moreover, <i>TMEM175</i> was significantly downregulated in induced pluripotent stem cell-derived dopaminergic neurons from PD patients (<i>p</i> = 4.60E-02).</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>Dysregulation of <i>TMEM175</i> may confer PD and LBD risk and may be partly responsible for their comorbidity. Our results revealed the common genetic risk factors between PD and LBD, which elucidated the shared genetic basis of these diseases.</p>\n </section>\n </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 4","pages":""},"PeriodicalIF":4.8000,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70370","citationCount":"0","resultStr":"{\"title\":\"Identification of Common Brain Protein and Genetic Loci Between Parkinson's Disease and Lewy Body Dementia\",\"authors\":\"Tingting Jia, Fuhua Yang, Fengqin Qin, Yongji He, Feng Han, Chengcheng Zhang\",\"doi\":\"10.1111/cns.70370\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background</h3>\\n \\n <p>Parkinson's disease (PD) and Lewy body dementia (LBD) have many common features, including clinical manifestations, neurochemistry, and pathology, but little is known about their shared brain proteins and genetic factors.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>To identify susceptibility-related brain proteins that are shared between PD and LBD patients, proteome-wide association studies (PWASs) were conducted by integrating human brain protein quantitative trait loci (pQTLs) with large-scale genome-wide association studies (GWASs) of both diseases. Subsequently, pleiotropy-informed conditional false discovery rate (pleioFDR) analysis was performed to identify common risk genetic loci between PD and LBD. Finally, the downregulation of these risk genes in different disease states was validated by differential gene expression analysis.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>PWASs identified 12 PD risk proteins and nine LBD risk proteins, among which <i>TMEM175</i> (<i>z</i><sub>PD</sub> = −7.25, <i>P</i><sub>PD</sub> = 4.12E-13; <i>z</i><sub>LBD</sub> = −6.02, <i>P</i><sub>LBD</sub> = 1.75E-09) and <i>DOC2A</i> (<i>z</i><sub>PD</sub> = −4.13, <i>P</i><sub>PD</sub> = 3.71E-05; <i>z</i><sub>LBD</sub> = −3.91, <i>P</i><sub>LBD</sub> = 9.08E-05) were shared. PleioFDR analysis revealed that five genetic risk loci mapped to eight genes associated with PD and LBD, including the proteome-wide significant risk gene <i>TMEM175</i> (ConjFDR = 5.74E-03). Differential expression analysis verified that <i>TMEM175</i> was significantly downregulated in the midbrains of PD patients (<i>p</i> = 1.19E-02), and further exploration revealed that <i>TMEM175</i> was also dramatically downregulated in the substantia nigra of PD patients (<i>p</i> = 1.16E-02) and incidental Lewy body disease patients (<i>p</i> = 7.52E-03). Moreover, <i>TMEM175</i> was significantly downregulated in induced pluripotent stem cell-derived dopaminergic neurons from PD patients (<i>p</i> = 4.60E-02).</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusion</h3>\\n \\n <p>Dysregulation of <i>TMEM175</i> may confer PD and LBD risk and may be partly responsible for their comorbidity. Our results revealed the common genetic risk factors between PD and LBD, which elucidated the shared genetic basis of these diseases.</p>\\n </section>\\n </div>\",\"PeriodicalId\":154,\"journal\":{\"name\":\"CNS Neuroscience & Therapeutics\",\"volume\":\"31 4\",\"pages\":\"\"},\"PeriodicalIF\":4.8000,\"publicationDate\":\"2025-04-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70370\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"CNS Neuroscience & Therapeutics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/cns.70370\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"CNS Neuroscience & Therapeutics","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/cns.70370","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
Identification of Common Brain Protein and Genetic Loci Between Parkinson's Disease and Lewy Body Dementia
Background
Parkinson's disease (PD) and Lewy body dementia (LBD) have many common features, including clinical manifestations, neurochemistry, and pathology, but little is known about their shared brain proteins and genetic factors.
Methods
To identify susceptibility-related brain proteins that are shared between PD and LBD patients, proteome-wide association studies (PWASs) were conducted by integrating human brain protein quantitative trait loci (pQTLs) with large-scale genome-wide association studies (GWASs) of both diseases. Subsequently, pleiotropy-informed conditional false discovery rate (pleioFDR) analysis was performed to identify common risk genetic loci between PD and LBD. Finally, the downregulation of these risk genes in different disease states was validated by differential gene expression analysis.
Results
PWASs identified 12 PD risk proteins and nine LBD risk proteins, among which TMEM175 (zPD = −7.25, PPD = 4.12E-13; zLBD = −6.02, PLBD = 1.75E-09) and DOC2A (zPD = −4.13, PPD = 3.71E-05; zLBD = −3.91, PLBD = 9.08E-05) were shared. PleioFDR analysis revealed that five genetic risk loci mapped to eight genes associated with PD and LBD, including the proteome-wide significant risk gene TMEM175 (ConjFDR = 5.74E-03). Differential expression analysis verified that TMEM175 was significantly downregulated in the midbrains of PD patients (p = 1.19E-02), and further exploration revealed that TMEM175 was also dramatically downregulated in the substantia nigra of PD patients (p = 1.16E-02) and incidental Lewy body disease patients (p = 7.52E-03). Moreover, TMEM175 was significantly downregulated in induced pluripotent stem cell-derived dopaminergic neurons from PD patients (p = 4.60E-02).
Conclusion
Dysregulation of TMEM175 may confer PD and LBD risk and may be partly responsible for their comorbidity. Our results revealed the common genetic risk factors between PD and LBD, which elucidated the shared genetic basis of these diseases.
期刊介绍：
CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.
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