eprintid: 10120714 rev_number: 35 eprint_status: archive userid: 608 dir: disk0/10/12/07/14 datestamp: 2021-02-08 16:52:04 lastmod: 2021-12-02 00:27:04 status_changed: 2021-05-18 14:48:31 type: article metadata_visibility: show creators_name: Andersen, MS creators_name: Bandres-Ciga, S creators_name: Reynolds, RH creators_name: Hardy, J creators_name: Ryten, M creators_name: Krohn, L creators_name: Gan-Or, Z creators_name: Holtman, IR creators_name: International Parkinson's Disease Genomics Consortium, , creators_name: Pihlstrøm, L title: Heritability enrichment implicates microglia in Parkinson's disease pathogenesis ispublished: pub divisions: UCL divisions: B02 divisions: C07 divisions: D07 divisions: F86 divisions: D13 divisions: G23 note: © 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. abstract: 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. date: 2021-05-01 date_type: published official_url: https://doi.org/10.1002/ana.26032 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1844594 doi: 10.1002/ana.26032 lyricists_name: Hardy, John lyricists_name: Reynolds, Regina lyricists_name: Ryten, Mina lyricists_name: Smalley, June lyricists_id: JHARD28 lyricists_id: RHREY66 lyricists_id: MBARI42 lyricists_id: JASMA87 actors_name: Flynn, Bernadette actors_id: BFFLY94 actors_role: owner full_text_status: public publication: Annals of Neurology volume: 89 number: 5 pagerange: 942-951 event_location: United States citation: Andersen, MS; Bandres-Ciga, S; Reynolds, RH; Hardy, J; Ryten, M; Krohn, L; Gan-Or, Z; ... Pihlstrøm, L; + view all <#> Andersen, MS; Bandres-Ciga, S; Reynolds, RH; Hardy, J; Ryten, M; Krohn, L; Gan-Or, Z; Holtman, IR; International Parkinson's Disease Genomics Consortium, ,; Pihlstrøm, L; - view fewer <#> (2021) Heritability enrichment implicates microglia in Parkinson's disease pathogenesis. Annals of Neurology , 89 (5) pp. 942-951. 10.1002/ana.26032 <https://doi.org/10.1002/ana.26032>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10120714/7/Hardy_ana.26032.pdf