Cited by 107Parkinson's Disease Mechanisms and TreatmentsNuclear Receptors and SignalingNeuroinflammation and Neurodegeneration Mechanisms

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Association of a common genetic variant with Parkinson’s disease is mediated by microglia

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Langston, Rebekah G., Beilina, Alexandra, Reed, Xylena, Kaganovich, Alice, Singleton, Andrew B., Blauwendraat, Cornelis, Gibbs, J. Raphael, Cookson, Mark R.·2022·Science Translational Medicine

DOI 10.1126/scitranslmed.abp8869PMC PMC9809150

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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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Additional file 10 of Transcriptomic changes in oligodendrocytes and precursor cells associate with clinical outcomes of Parkinson’s disease
Dehestani, M., Kozareva, V., Blauwendraat, C., Fraenkel, E., Gasser, T., & Bansal, V. (2024) · Figshare · doi:10.6084/m9.figshare.26759750
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Additional file 6 of Transcriptomic changes in oligodendrocytes and precursor cells associate with clinical outcomes of Parkinson’s disease
Dehestani, M., Kozareva, V., Blauwendraat, C., Fraenkel, E., Gasser, T., & Bansal, V. (2024) · Figshare · doi:10.6084/m9.figshare.26759738
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Additional file 4 of Transcriptomic changes in oligodendrocytes and precursor cells associate with clinical outcomes of Parkinson’s disease
Dehestani, M., Kozareva, V., Blauwendraat, C., Fraenkel, E., Gasser, T., & Bansal, V. (2024) · Figshare · doi:10.6084/m9.figshare.26759732
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Additional file 1 of Single molecule array measures of LRRK2 kinase activity in serum link Parkinson’s disease severity to peripheral inflammation
Yuan, Y., Li, H., Sreeram, K., Malankhanova, T. B., Boddu, R., Strader, S., Chang, A., Bryant, N., Yacoubian, T. A., Standaert, D. G., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26019592
Additional file 3 of Single molecule array measures of LRRK2 kinase activity in serum link Parkinson’s disease severity to peripheral inflammation
Yuan, Y., Li, H., Sreeram, K., Malankhanova, T. B., Boddu, R., Strader, S., Chang, A., Bryant, N., Yacoubian, T. A., Standaert, D. G., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26732620
Additional file 8 of Transcriptomic changes in oligodendrocytes and precursor cells associate with clinical outcomes of Parkinson’s disease
Dehestani, M., Kozareva, V., Blauwendraat, C., Fraenkel, E., Gasser, T., & Bansal, V. (2024) · Figshare · doi:10.6084/m9.figshare.26759744
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Additional file 9 of Transcriptomic changes in oligodendrocytes and precursor cells associate with clinical outcomes of Parkinson’s disease
Dehestani, M., Kozareva, V., Blauwendraat, C., Fraenkel, E., Gasser, T., & Bansal, V. (2024) · Figshare · doi:10.6084/m9.figshare.26759747
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Additional file 11 of Transcriptomic changes in oligodendrocytes and precursor cells associate with clinical outcomes of Parkinson’s disease
Dehestani, M., Kozareva, V., Blauwendraat, C., Fraenkel, E., Gasser, T., & Bansal, V. (2024) · Figshare · doi:10.6084/m9.figshare.26759753
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Additional file 7 of Transcriptomic changes in oligodendrocytes and precursor cells associate with clinical outcomes of Parkinson’s disease
Dehestani, M., Kozareva, V., Blauwendraat, C., Fraenkel, E., Gasser, T., & Bansal, V. (2024) · Figshare · doi:10.6084/m9.figshare.26759741
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Additional file 2 of Single molecule array measures of LRRK2 kinase activity in serum link Parkinson’s disease severity to peripheral inflammation
Yuan, Y., Li, H., Sreeram, K., Malankhanova, T. B., Boddu, R., Strader, S., Chang, A., Bryant, N., Yacoubian, T. A., Standaert, D. G., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26019737
Additional file 1 of Transcriptomic changes in oligodendrocytes and precursor cells associate with clinical outcomes of Parkinson’s disease
Dehestani, M., Kozareva, V., Blauwendraat, C., Fraenkel, E., Gasser, T., & Bansal, V. (2024) · Figshare · doi:10.6084/m9.figshare.26759723
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Additional file 3 of Transcriptomic changes in oligodendrocytes and precursor cells associate with clinical outcomes of Parkinson’s disease
Dehestani, M., Kozareva, V., Blauwendraat, C., Fraenkel, E., Gasser, T., & Bansal, V. (2024) · Figshare · doi:10.6084/m9.figshare.26759729
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Additional file 5 of Transcriptomic changes in oligodendrocytes and precursor cells associate with clinical outcomes of Parkinson’s disease
Dehestani, M., Kozareva, V., Blauwendraat, C., Fraenkel, E., Gasser, T., & Bansal, V. (2024) · Figshare · doi:10.6084/m9.figshare.26759735
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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: Langston, Rebekah G.
Beilina, Alexandra
Reed, Xylena
Kaganovich, Alice
Singleton, Andrew B.
Blauwendraat, Cornelis
Gibbs, J. Raphael
Cookson, Mark R.
Venue: Science Translational Medicine
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2022-07-27
Volume: 14
Issue: 655
Pages: eabp8869-eabp8869
ISSN: 1946-6234 (ISSN-L)
1946-6242
DOI: 10.1126/scitranslmed.abp8869
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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Association of a common genetic variant with Parkinson’s disease is mediated by microglia

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