AbstractBackgroundLeucine‐rich repeat kinase 2 (LRRK2) common gene variants (tagged by rs76904798) are associated with Parkinson’s disease (PD) risk. In a previous study, we found that rs76904798 was associated with CSF GRN levels, but a comprehensive unbiased analysis of associated proteins remains incomplete due to prior focus on cis‐protein quantitative trait loci (pQTL). Using the largest aptamer‐based CSF proteomics study to date (7,006 aptamers (6,138 unique proteins) in 3,107 individuals), we performed a trans‐pQTL study to identify proteins associated with the LRRK2 variants and used additional mediation and pathway analyses to better understand downstream effects (Figure 1).MethodSNP selection using Conditional and Joint Association Analysis (GTCA‐COJO) and PLINK LD r2 scores identified 11 other independently associated SNPs. Fine mapping was performed between each significant aptamer and PD GWAS via proteome‐wide association studies (PWAS) and Mendelian randomization (MR). These aptamers were further analyzed based on PD risk association, brain cell‐type specificity, and gene pathway annotations.ResultOverall, 26 proteins passed FDR correction and eleven were implicated in PD prior like GRN and GPNMB. PWAS analyses using TWAS/FUSION also indicate 12 proteins were significant and positively associated with PD risk, such as novel proteins C1QTNF1 and SDCBP2, and half were validated by the PPMI data. MR analyses indicate that GRN, GPNMB, HLA‐DQA2, CD68, and LCT are also causal for PD risk (Table 1). Cell‐type enrichment analyses indicate microglia‐specific protein enrichment (Fold change: 7.35, P = 4.91×10−5). Enrichment analyses indicate enrichment for leukocyte activation (GO:0045321, P = 0.002) and microglial cell activation (GO:0001774, P = 0.003) pathways.ConclusionTrans‐pQTL can identify novel protein interactions in an unbiased manner. This study linked LRRK2 variants with both PD implicated (GRN, GPNMB) and novel (ITGB2, C1QTNF1) proteins that have support in our PWAS, MR, and PPMI differential protein level analyses. Microglia and lysosome enrichment support the previous observations regarding the importance of microglia and immune system function in the underlying pathobiology of PD (Figure 2). Our results suggest that the CSF concentrations of these proteins (such as GRN, GPNMB, C1QTNF1, and ITGB2) have potential as biomarkers for target engagement and disease progression modification in clinical trials that target LRRK2.