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

• Published in: Science translational medicine 2022-07, Vol.14 (655), p.eabp8869-eabp8869
• Main Authors: Langston, Rebekah G, Beilina, Alexandra, Reed, Xylena, Kaganovich, Alice, Singleton, Andrew B, Blauwendraat, Cornelis, Gibbs, J Raphael, Cookson, Mark R
• Format: Article
• Language: English
• Subjects: Chromatin; Cortex (frontal); CRISPR; Genetic diversity; Genome-wide association studies; Genome-Wide Association Study; Genomes; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - genetics; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - metabolism; LRRK2 protein; Microglia; Microglia - metabolism; Movement disorders; Neurodegenerative diseases; Non-coding RNA; Parkinson Disease - metabolism; Parkinson's disease; Pathogenicity; Pluripotency; Risk assessment; Stem cells; Substantia nigra; Substantia Nigra - pathology
• ISSN: 1946-6234; 1946-6242; 1946-6242; 1946-3242
• DOI: 10.1126/scitranslmed.abp8869

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 ( ) gene and to a common noncoding variation in the 5' region of the 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 expression is specifically propagated through microglia and not by other cell types that express in the human brain. We find microglia-specific regulatory chromatin regions that modulate the 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 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.