ArticleNPJ Parkinson's disease2023
Proteome wide association studies of LRRK2 variants identify novel causal and druggable proteins for Parkinson's disease.
Article in NPJ Parkinson's disease, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 21 citations in OpenAlex.
- Leucine-rich repeat kinase 2 (LRRK2): balancing cellular homeostasis and Parkinson's disease (PD) pathogenesis.Annals of medicine · 2026Review
- Chemical Genetic Targeting of the LRRK2 GTPase Domain.bioRxiv : the preprint server for biology · 2026Article
- Understanding Neurodegenerative Diseases From the -Omics Perspective: Lessons Learnt.Annals of neurology · 2026Review
- Human CSF proteogenomics links genetic variation to neurodegenerative disease proteins.medRxiv : the preprint server for health sciences · 2026Article
- GPNMB is a biomarker for lysosomal dysfunction and is secreted via LRRK2-modulated lysosomal exocytosis.Science advances · 2025Article
- Blood plasma proteome-wide association study implicates novel proteins in the pathogenesis of multiple cardiovascular diseases.Cardiovascular diabetology · 2025Article
- Large-scale network analysis of the cerebrospinal fluid proteome identifies molecular signatures of frontotemporal lobar degeneration.Nature aging · 2025Article
- Biomarker identification for Alzheimer's disease through integration of comprehensive Mendelian randomization and proteomics data.Journal of translational medicine · 2025Article
- A network-based systems genetics framework identifies pathobiology and drug repurposing in Parkinson's disease.NPJ Parkinson's disease · 2025Article
- Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer's disease.Nature genetics · 2024Article
- Genetic and multi-omic resources for Alzheimer disease and related dementia from the Knight Alzheimer Disease Research Center.Scientific data · 2024Article
- Article
- Alzheimer's polygenic risk scores are associated with cognitive phenotypes in Down syndrome.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Article
- A 3'UTR Insertion Is a Candidate Causal Variant at theNeurology. Genetics · 2024Article
- Proteo-genomics of soluble TREM2 in cerebrospinal fluid provides novel insights and identifies novel modulators for Alzheimer's disease.Molecular neurodegeneration · 2024Article
- Micro-and mesoscale aspects of neurodegeneration in engineered human neural networks carrying the LRRK2 G2019S mutation.Frontiers in cellular neuroscience · 2024Article
- A 3'UTR Insertion Is a Candidate Causal Variant at themedRxiv : the preprint server for health sciences · 2023Article
- Connectome-based modelling of neurodegenerative diseases: towards precision medicine and mechanistic insight.Nature reviews. Neuroscience · 2023Review
- Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and informs causal proteins for Alzheimer's disease.Research square · 2023Article
Corrections and comments
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Authors and funding
27 authors at 4 institutions in 2 countries.
Funding
Abstract
Common and rare variants in the LRRK2 locus are associated with Parkinson's disease (PD) risk, but the downstream effects of these variants on protein levels remain unknown. We performed comprehensive proteogenomic analyses using the largest aptamer-based CSF proteomics study to date (7006 aptamers (6138 unique proteins) in 3107 individuals). The dataset comprised six different and independent cohorts (five using the SomaScan7K (ADNI, DIAN, MAP, Barcelona-1 (Pau), and Fundació ACE (Ruiz)) and the PPMI cohort using the SomaScan5K panel). We identified eleven independent SNPs in the LRRK2 locus associated with the levels of 25 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 GPNMB, LCT, and CD68 causal for PD and nominate one more (ITGB2). These 25 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.