Proteome Wide Association Studies of LRRK2 variants identify novel causal and druggable for Parkinsons disease

Common and rare variants in the LRRK2 locus are associated with Parkinsons disease (PD) risk, but the downstream effects of these variants on protein levels remains unknown. We performed comprehensive proteogenomic analyses using the largest aptamer-based CSF proteomics study to date (7,006 aptamers (6,138 unique proteins) in 3,107 individuals). We identified eleven independent SNPs in the LRRK2 locus associated with the levels of 26 proteins as well as PD risk. Of these, only eleven proteins have been previously associated with PD risk (e.g., GRN or GPNMB). Proteome-wide association study (PWAS) analyses suggested that the levels of ten of those proteins were genetically correlated with PD risk and seven were validated in the PPMI cohort. Mendelian randomization analyses identified five proteins (GPNMB, GRN, HLA-DQA2, LCT, and CD68) causal for PD and nominate one more (ITGB2). These 26 proteins were enriched for microglia-specific proteins and trafficking pathways (both lysosome and intracellular). This study not only demonstrates that protein phenome-wide association studies (PheWAS) and trans-protein quantitative trail loci (pQTL) analyses are powerful for identifying novel protein interactions in an unbiased manner, but also that LRRK2 is linked with the regulation of PD-associated proteins that are enriched in microglial cells and specific lysosomal pathways.