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Association of a common genetic variant with Parkinson’s disease is mediated by microglia
Open accessPublished version of a preprint
Abstract
Studies of multiple neurodegenerative disorders have identified many genetic variants that are associated with risk of disease throughout a lifetime. For example, Parkinson’s disease (PD) risk is attributed in part to both coding mutations in the leucine-rich repeat kinase 2 ( LRRK2 ) gene and to a common noncoding variation in the 5′ region of the LRRK2 locus, as identified by genome-wide association studies (GWAS). However, the mechanisms linking GWAS variants to pathogenicity are largely unknown. Here, we found that the influence of PD-associated noncoding variation on LRRK2 expression is specifically propagated through microglia and not by other cell types that express LRRK2 in the human brain. We find microglia-specific regulatory chromatin regions that modulate the LRRK2 expression in human frontal cortex and substantia nigra and confirm these results in a human-induced pluripotent stem cell–derived microglia model. We showed, using a large-scale clustered regularly interspaced short palindromic repeats interference (CRISPRi) screen, that a regulatory DNA element containing the single-nucleotide variant rs6581593 influences the LRRK2 expression in microglia. Our study demonstrates that cell type should be considered when evaluating the role of noncoding variation in disease pathogenesis and sheds light on the mechanism underlying the association of the 5′ region of LRRK2 with PD risk.
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“Importantly, studies have identified a significant association between PD risk variants and microglia.86,87”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [87]
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“The researchers identified microglia-specific chromatin regions that regulated LRRK2 expression and showed that a specific regulatory DNA element containing the PD-associated genetic variant rs6581593 modulates LRRK2 expression in microglia.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [261]
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Dehestani, M., Kozareva, V., Blauwendraat, C., Fraenkel, E., Gasser, T., & Bansal, V. (2024) · Figshare · doi:10.6084/m9.figshare.26759756
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Self-citationKaganovich, A., Horan-Portelance, L., Landeck, N., Acri, D. J., Ding, J., Langston, R. G., & Cookson, M. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.18.695199
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Metadata
- Authors
- Langston, R. G., Beilina, A., Reed, X., Kaganovich, A., Singleton, A. B., Blauwendraat, C., Gibbs, J. R., & Cookson, M. R.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Cookson, Mark R.
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2022-07-27
- Volume
- 14
- Issue
- 655
- Pages
- eabp8869-eabp8869
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC9809150
- OpenAlex
- W4288052118
- Cited by
- 93
- References
- 77
- Citations by year
- 2026: 15 · 2025: 19 · 2024: 24 · 2023: 24 · 2022: 7
- FWCI
- 11.55
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- public-domain
- Locations
- Science Translational Medicine (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, public-domain)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Michael J. Fox Foundation for Parkinson's Research
- Gladstone Institutes
- National Institutes of Health (1z01es101986-03, Z99 AG999999, Z01-ES101986)
- National Institute on Aging (K01AG000947, Z01AG000949, ZIAAG000947, P30AG072946)
- National Heart, Lung, and Blood Institute
- National Cancer Institute
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of Neurological Disorders and Stroke (ZIANS003154)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Parkinson's disease, LRRK2, microglia, 5' regulatory region, cell type specificity, induced pluripotent stem cell-derived microglia, CRISPRi screen, substantia nigra, frontal cortex, neurodegeneration risk
- MeSH terms
- Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Humans, Parkinson Disease, Substantia Nigra, Microglia, Genome-Wide Association Study
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