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Proteome\u2010wide association studies (PWAS) were conducted using the OTTERS framework for plasma proteins and the FUSION tool for brain proteins, examining associations with PD onset and three progression phenotypes: composite, motor, and cognitive. Significant protein associations (FDR\u2010corrected\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) from PWAS were further validated using summary\u2010based Mendelian randomization (SMR), colocalization analyses, and reverse Mendelian randomization (MR) to establish causality. Phenome\u2010wide Mendelian randomization (PheW\u2010MR) was performed to assess potential side effects across 679 disease traits when targeting these proteins to reduce PD\u2010related phenotype risk by 20%. Additionally, we conducted cellular distribution\u2010based clustering using gene expression data from the Allen Brain Atlas (ABA) to explore the distribution of key proteins across brain regions, constructed protein\u2013protein interaction (PPI) networks via the STRING database to explore interactions among proteins, and evaluated the druggability of identified targets using the DrugBank database to identify opportunities for drug repurposing.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Result<\/jats:title>\n                    <jats:p>Our analyses identified 25 candidate proteins associated with PD phenotypes, including 16 plasma proteins linked to PD progression (10 cognitive, 4 motor, and 3 composite) and 9 plasma proteins associated with PD onset. Notably, GPNMB was implicated in both plasma and brain tissues for PD onset. PheW\u2010MR revealed predominantly beneficial side effects for the identified targets, with 83.7% of associations indicating positive outcomes and 16.3% indicating adverse effects. Cellular clustering categorized candidate targets into three distinct expression profiles across brain cell types using ABA. PPI network analysis highlighted one key interaction cluster among the proteins for PD cognitive progression and PD onset. Druggability assessment revealed 15 out of 25 proteins had repurposing opportunities for PD treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>We have identified 25 causal protein targets associated with the onset and progression of PD, providing new insights into the research and development of treatment strategies for PD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/cns.70294","type":"journal-article","created":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T06:47:40Z","timestamp":1740984460000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Proteome\u2010Wide Association Study for Finding Druggable Targets in Progression and Onset of Parkinson's Disease"],"prefix":"10.1111","volume":"31","author":[{"given":"Chenhao","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Neurology, Henan Provincial People's Hospital Zhengzhou University People's Hospital  Zhengzhou Henan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haobin","family":"Zhou","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8594-5988","authenticated-orcid":false,"given":"Weixuan","family":"Liang","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuofeng","family":"Wen","sequence":"additional","affiliation":[{"name":"The Sixth School of Clinical Medicine Guangzhou Medical University  Guangzhou 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