Proteome Wide Association Studies of LRRK2 variants identify novel causal and druggable for Parkinson’s disease

Abstract

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.

Large-scale network analysis of the cerebrospinal fluid proteome identifies molecular signatures of frontotemporal lobar degeneration

“…As expected, CSF progranulin protein (unassigned to a module) exhibited the largest decreased abundance in both pre-and symptomatic GRN carriers vs. controls. C1QTNF1 (unassigned to a module), another lysosomal protein with CSF levels shown to be strongly colinear with GRN levels 25 , exhibited a similar pattern of decreased abundance in GRN carriers.…”

“…SomaScan has been applied in other neurodegenerative diseases 21,25,56,57 and has high coverage for FTLD-relevant markers such as RNA splicing proteins 21 , however platforms such as Olink and TMT-MS may exhibit greater coverage for other molecular pathways (e.g., immune). Importantly, our crosscohort/cross-platform analyses recapitulated SomaScan FTLD signatures with Olink data and demonstrated module overlap between our SomaScan only network and prior networks that included Olink and TMT-MS.…”

A 3’UTR Insertion Is a Candidate Causal Variant at theTMEM106BLocus Associated with Increased Risk for FTLD-TDP

“…To expand beyond these eQTL and pQTL results from publicly available databases, we tested the association between rs1990622 and TMEM106B expression, TMEM106B protein levels, and GRN protein levels in the WUSTL Neurogenomics dataset 36,37,38 . First, we examined GRN and TMEM106B protein levels in a group of 11 carriers of FTLD-TDP-causing progranulin ( PGRN ) mutations.…”

Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and informs causal proteins for Alzheimer’s disease

“…While we have successfully identi ed novel candidate proteins in AD, we foresee this dataset being a useful resource for the investigation of all neurological traits. Previous evidence suggests that numerous candidate proteins can be identi ed for many neurological traits, even with smaller sample sizes 13,16 , and this dataset has already been applied to identify associations between proteins regulated by the LRRK2 genetic locus and Parkinson's disease 130 . We intend these results to add to the growing knowledge of genetic regulation of protein levels, and as such, we have made all summary statistics publicly available for use at https://www.niagads.org/knight-adrc-collection.…”