TY - JOUR IS - 5 AV - public N2 - OBJECTIVE: Understanding how different parts of the immune system contribute to pathogenesis in Parkinson's disease is a burning challenge with important therapeutic implications. We studied enrichment of common variant heritability for Parkinson's disease stratified by immune and brain cell types. METHODS: We used summary statistics from the most recent meta-analysis of genome-wide association studies in Parkinson's disease and partitioned heritability using linkage disequilibrium score regression, stratified for specific cell types as defined by open chromatin regions. We also validated enrichment results using a polygenic risk score approach and intersected disease-associated variants with epigenetic data and expression quantitative loci to nominate and explore a putative microglial locus. RESULTS: We found significant enrichment of Parkinson's disease risk heritability in open chromatin regions of microglia and monocytes. Genomic annotations overlapped substantially between these two cell types, and only the enrichment signal for microglia remained significant in a joint model. We present evidence suggesting P2RY12, a key microglial gene and target for the anti-thrombotic agent clopidogrel, as the likely driver of a significant Parkinson's disease association signal on chromosome 3. INTERPRETATION: Our results provide further support for the importance of immune mechanisms in PD pathogenesis, highlight microglial dysregulation as a contributing etiological factor and nominate a targetable microglial gene candidate as a pathogenic player. Immune processes can be modulated by therapy, with potentially important clinical implications for future treatment in Parkinson's disease. A1 - Andersen, MS A1 - Bandres-Ciga, S A1 - Reynolds, RH A1 - Hardy, J A1 - Ryten, M A1 - Krohn, L A1 - Gan-Or, Z A1 - Holtman, IR A1 - International Parkinson's Disease Genomics Consortium, , A1 - Pihlstrøm, L EP - 951 SP - 942 VL - 89 JF - Annals of Neurology UR - https://doi.org/10.1002/ana.26032 Y1 - 2021/05/01/ ID - discovery10120714 N1 - © 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution?NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. TI - Heritability enrichment implicates microglia in Parkinson's disease pathogenesis ER -