LAUSR

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. Description Noncoding variation near the LRRK2 gene is linked to Parkinson’s disease through microglia-specific regulatory mechanisms. Microglia modulates PD risk Previous studies have identified variants in the LRRK2 gene that are associated with an increased risk of developing Parkinson’s disease (PD). Here, Langston and colleagues studied the mechanisms of LRRK2 variants to PD and showed that the disease risk is determined by microglial cells. Studying PD-associated LRRK2 variants in patient-derived tissue and iPSC-derived microglia, the authors identified a quantitative trait in microglia, suggesting that, although this cell type expresses LRRK2 in lower amounts compared to other cell types, it might be critical for determining the PD risk. The cell type–specific baseline expression and effect on disease pathophysiology might not be predictive of the mechanisms mediating this and other disease-associated variants in noncoding gene regions.