Proteome Wide Association Studies of LRRK2 variants identify novel causal and druggable for Parkinson’s disease
Open accessAbstract
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 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.
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Trans-pQTLs are subject to pleiotropy and limited mechanistic understanding.
“Analyses involving trans-pQTLs require careful interpretation because of pleiotropy and limited mechanistic understanding, despite their potential to clarify regulatory pathways beyond cis-pQTLs (69, 70).”
From Low overlap of plasma and CSF protein quantitative trait loci affects protein discovery for neurological disease (2026) · cites this paper as [70]
The Mendelian Randomization and Identifying causal proteins for PD risk sections treat pleiotropy at the LRRK2 locus as a reason for caution and check the results using cis-pQTLs only. The Introduction and Discussion describe how trans-pQTLs can reveal protein interactions and pathways beyond cis-pQTLs. However, the Discussion's statement that mechanisms remain unknown concerns many PD-associated loci, not a general limitation of trans-pQTLs. (LLM, conf=0.84)
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- Authors
- Phillips, B., Western, D., Wang, L., Timsina, J., Sun, Y., Gorijala, P., Yang, C., Do, A., Nykänen, N.-P., Alvarez, I., Aguilar, M., Pastor, P., Morris, J. C., Schindler, S. E., Fagan, A. M., Puerta, R., García-González, P., de Rojas, I., Marquié, M., Boada, M., Ruiz, A., Perlmutter, J. S., Dominantly Inherited Alzheimer Network (DIAN) Consortia, Ibanez, L., Perrin, R. J., Sung, Y. J., & Cruchaga, C.
- Affiliations
- Washington University in St. Louis (US)
- University Hospital Mútua de Terrassa (ES)
- Instituto de Salud Carlos III (ES)
- Corresponding author
- Cruchaga, Carlos
- ORCID
- Phillips, Bridget
- Western, Daniel
- Wang, Lihua
- Timsina, Jigyasha
- Gorijala, Priyanka
- Yang, Chengran
- Do, Anh
- Nykänen, Niko-Petteri
- Alvarez, Ignacio
- Pastor, Pau
- Morris, John C.
- Schindler, Suzanne E.
- Fagan, Anne M.
- Puerta, Raquel
- García-González, Pablo
- de Rojas, Itziar
- Marquié, Marta
- Boada, Mercè
- Ruiz, Agustin
- Perlmutter, Joel S.
- Ibanez, Laura
- Perrin, Richard J.
- Sung, Yun Ju
- Cruchaga, Carlos
- Venue
- npj Parkinson s Disease
- Publisher
- openRxiv
- Published
- 2023-01-07
- Volume
- 9
- Issue
- 1
- Pages
- 107-107
- ISSN
- 2373-8057 (ISSN-L)
- PMC
- PMC10329646
- OpenAlex
- W4383602928
- Cited by
- 20
- References
- 2
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 6 · 2023: 2
- FWCI
- 3.26
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- npj Parkinson s Disease (publishedVersion, cc-by)
- medRxiv (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Defense (U01 AG024904, W81XWH, W81XWH-12-2-, W81XWH1220012, W81XWH2010849, AG024904)
- Foundation for the National Institutes of Health (P01AG026276, W81XWH-12-2-0012, U01AG024904, R01AG044546, Grant U01 AG024904, RF1AG053303, U01AG058922, RF1AG058501, AG024904, P01AG003991)
- Michael J. Fox Foundation for Parkinson's Research
- Alzheimer's Association (ZEN-22-848604, SG-20-690363-DIAN, U01 AG024904, W81XWH-12-2-0012)
- Bristol-Myers Squibb (U01 AG024904, AG024904, W81XWH-12-2-0012)
- Eli Lilly and Company (U01 AG024904, AG024904, W81XWH-12-2-0012)
- Pfizer (AG024904, W81XWH-12-2-0012, U01 AG024904)
- Biogen (W81XWH-12-2-0012, U01 AG024904, AG024904)
- University of Southern California (W81XWH-12-2-0012, U01 AG024904)
- F. Hoffmann-La Roche (W81XWH-12-2-0012, AG024904, U01 AG024904)
- Meso Scale Diagnostics (U01 AG024904, AG024904, W81XWH-12-2-0012)
- Alzheimer's Disease Neuroimaging Initiative (P01AG026276, W81XWH-12-2–0012, U01AG024904, AG024904, W81XWH-12-2-, Department of Defense award number W81XWH-12-2-0012, P01AG03991)
- BioClinica (U01 AG024904, W81XWH-12-2-0012, AG024904)
- Novartis Pharmaceuticals Corporation (W81XWH-12-2-0012, U01 AG024904, AG024904)
- Fondation Brain Canada
- Japan Agency for Medical Research and Development
- Northern California Institute for Research and Education (U01 AG024904, W81XWH-12-2-0012)
- Hope Center for Neurological Disorders
- Korea Health Industry Development Institute
- Eisai (W81XWH-12-2-0012, U01 AG024904, AG024904)
- Deutsches Zentrum für Neurodegenerative Erkrankungen
- Servier (AG024904, W81XWH-12-2-0012, U01 AG024904)
- H. Lundbeck A/S (U01 AG024904, AG024904, W81XWH-12-2-0012)
- IXICO (AG024904, W81XWH-12-2-0012, U01 AG024904)
- Fleni
- National Institutes of Health (3u01ag024904-10s2, W81XWH, W81XWH-12-2-0012, U01-AG024904, Grant U01 AG024904, AG024904, P01AG003991(CC)
- Genentech (W81XWH-12-2-0012, AG024904, U01 AG024904)
- Canadian Institutes of Health Research (U01 AG024904, W81XWH-12-2-0012)
- Instituto de Salud Carlos III
- National Institute on Aging (U01-AG-024904, W81XWH-12-2–0012, AG 024904, RF1AG053303, R01AG044546, P01AG003991, U19AG032438, RF1AG074007, U01AG058922, RF1AG058501, P30AG066444, P01AG026276, U24AG021886)
- National Institute of Biomedical Imaging and Bioengineering (W81XWH-12-2-0012, U01 AG024904, AG024904)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- Parkinson's disease, LRRK2, proteome-wide association study, CSF proteomics, aptamer-based proteomics, genetic correlation, protein abundance, microglia, lysosomal trafficking, pQTL, GPNMB, LCT, CD68, CD18, causal proteins, druggable proteins, Mendelian randomization
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