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We studied enrichment of common variant heritability for Parkinson's disease stratified by immune and brain cell types.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We used summary statistics from the most recent meta\u2010analysis of genomewide 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\u2010associated variants with epigenetic data and expression quantitative loci to nominate and explore a putative microglial locus.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We found significant enrichment of Parkinson's disease risk heritability in open chromatin regions of microglia and monocytes. Genomic annotations overlapped substantially between these 2 cell types, and only the enrichment signal for microglia remained significant in a joint model. We present evidence suggesting\n                      <jats:italic>P2RY12<\/jats:italic>\n                      , a key microglial gene and target for the antithrombotic agent clopidogrel, as the likely driver of a significant Parkinson's disease association signal on chromosome 3.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>Our results provide further support for the importance of immune mechanisms in Parkinson's disease 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. ANN NEUROL 2021;89:942\u2013951<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.26032","type":"journal-article","created":{"date-parts":[[2021,1,27]],"date-time":"2021-01-27T08:06:23Z","timestamp":1611734783000},"page":"942-951","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":65,"title":["Heritability Enrichment Implicates Microglia in Parkinson's Disease Pathogenesis"],"prefix":"10.1002","volume":"89","author":[{"given":"Maren Stolp","family":"Andersen","sequence":"first","affiliation":[{"name":"Department of Neurology Oslo University Hospital  Oslo Norway"},{"name":"Institute of Clinical Medicine University of Oslo  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Bandres\u2010Ciga","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics, National Institute on Aging National Institutes of Health  Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regina H.","family":"Reynolds","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, Queen Square Institute of Neurology University College London  London UK"},{"name":"NIHR Great Ormond Street Hospital Biomedical Research Centre University College London  London UK"},{"name":"Great Ormond Street Institute of Child Health, Genetics and Genomic Medicine University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Hardy","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, Queen Square Institute of Neurology University College London  London UK"},{"name":"UK Dementia Research Institute at UCL and Department of Neurodegenerative Disease, UCL Institute of Neurology University College London  London UK"},{"name":"Reta Lila Weston Institute, UCL Queen Square Institute of Neurology  London UK"},{"name":"UCL Movement Disorders Centre University College London  London UK"},{"name":"Institute for Advanced Study The Hong Kong University of Science and Technology  Hong Kong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mina","family":"Ryten","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, Queen Square Institute of Neurology University College London  London UK"},{"name":"NIHR Great Ormond Street Hospital Biomedical Research Centre University College London  London UK"},{"name":"Great Ormond Street Institute of Child Health, Genetics and Genomic Medicine University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6554-1666","authenticated-orcid":false,"given":"Lynne","family":"Krohn","sequence":"additional","affiliation":[{"name":"Montreal Neurological Institute McGill University  Montreal Qu\u00e9bec Canada"},{"name":"Department of Human Genetics McGill University  Montreal Qu\u00e9bec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0332-234X","authenticated-orcid":false,"given":"Ziv","family":"Gan\u2010Or","sequence":"additional","affiliation":[{"name":"Montreal Neurological Institute McGill University  Montreal Qu\u00e9bec Canada"},{"name":"Department of Human Genetics McGill University  Montreal Qu\u00e9bec Canada"},{"name":"Department of Neurology and Neurosurgery McGill University  Montreal Qu\u00e9bec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inge R.","family":"Holtman","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences of Cells &amp; Systems, Section Molecular Neurobiology, University of Groningen University Medical Center Groningen  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7635-8645","authenticated-orcid":false,"given":"Lasse","family":"Pihlstr\u00f8m","sequence":"additional","affiliation":[{"name":"Department of Neurology Oslo University Hospital  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the International Parkinson's Disease Genomics Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,3,4]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aag2590"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-020-0344-4"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.369"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep30509"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1249547"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(17)30276-4"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4475"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.642"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(19)30320-5"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awz295"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006933"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-018-0523-8"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-08912-9"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-020-02181-3"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3955"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2653"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0081-4"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aay0793"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3646"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2008-9-9-r137"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1081"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12859-017-1708-7"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3404"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/gigascience\/giz082"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004722"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2017.08.040"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aal3222"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4632"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-04558-1"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3801"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4156"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41531-019-0076-6"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-020-00721-x"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0148-2"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.28197"},{"key":"e_1_2_9_37_1","doi-asserted-by":"crossref","unstructured":"V\u00f5saU ClaringbouldA WestraHJ et al. 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