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