ABSTRACTObjectiveTo identify and validate causal protein targets that may serve as potential therapeutic interventions for both the onset and progression of Parkinson's disease (PD) through integrative proteomic and genetic analyses.MethodWe utilized large‐scale plasma and brain protein quantitative trait loci (pQTL) datasets from the deCODE Health study and the Religious Orders Study/Rush Memory and Aging Project (ROS/MAP), respectively. Proteome‐wide 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‐corrected p < 0.05) from PWAS were further validated using summary‐based Mendelian randomization (SMR), colocalization analyses, and reverse Mendelian randomization (MR) to establish causality. Phenome‐wide Mendelian randomization (PheW‐MR) was performed to assess potential side effects across 679 disease traits when targeting these proteins to reduce PD‐related phenotype risk by 20%. Additionally, we conducted cellular distribution‐based clustering using gene expression data from the Allen Brain Atlas (ABA) to explore the distribution of key proteins across brain regions, constructed protein–protein 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.ResultOur 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‐MR 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.ConclusionWe 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.