{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T12:00:48Z","timestamp":1764331248144,"version":"3.46.0"},"reference-count":65,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T00:00:00Z","timestamp":1755561600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFC2703101"],"award-info":[{"award-number":["2022YFC2703101"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["movementdisorders.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Movement Disorders"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>This study investigated the interplay between environmental, genetic, and epigenetic factors in Parkinson's disease (PD) etiology, aiming to identify key factors and their impact on disease progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Leveraging genome\u2010wide association study data of PD and environmental\u2010related factors, in conjunction with blood expression quantitative trait loci (QTLs) and methylation QTLs data, we used two\u2010sample Mendelian randomization (MR), summary data\u2013based MR (SMR), and colocalization analysis to explore the association between environmental, epigenetic, and genetic factors and PD risk. We also conducted transcriptomic analysis of the targeted gene and investigated its functional mechanism in PD with mouse datasets. A meta\u2010analysis of relevant prospective cohort studies was also conducted to validate the links between the identified environmental factor and PD risk.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Five modifiable factors were identified as associated with PD, including educational attainment. SMR and colocalization analysis demonstrated 14 methylation sites linked to the expression of eight genes and PD risk. Among them, six methylation sites might affect the expression of SET Domain Containing 1A (\n                      <jats:italic>SETD1A<\/jats:italic>\n                      ). Furthermore, prolonged educational attainment was found to be causally associated with hypermethylation of cg09162137, which downregulated\n                      <jats:italic>SETD1A<\/jats:italic>\n                      and impacted PD risk. Transcriptomic analysis indicated lower expression of\n                      <jats:italic>SETD1A<\/jats:italic>\n                      in PD cases. Pathway enrichment and protein\u2013protein interaction analysis suggested that SETD1A might influence mitochondrial function and \u03b1\u2010synuclein pathogenesis. Finally, a meta\u2010analysis indicated that higher education levels increased PD risk (hazard ratio\u2009=\u20091.15) but did not affect other PD progression phenotypes except cognition.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      We identified five modifiable factors associated with PD. Higher education attainment might increase PD risk by affecting the expression of\n                      <jats:italic>SETD1A<\/jats:italic>\n                      . \u00a9 2025 International Parkinson and Movement Disorder Society.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mds.70010","type":"journal-article","created":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T09:49:56Z","timestamp":1755596996000},"page":"2431-2444","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Epigenetic Mediating Mechanisms in Parkinson's Disease: The Impact of Educational Attainment on\n                    <scp>SETD1A<\/scp>\n                    Expression"],"prefix":"10.1002","volume":"40","author":[{"given":"Kang\u2010Fu","family":"Yin","sequence":"first","affiliation":[{"name":"Department of Neurology West China Hospital, Sichuan University  Chengdu Sichuan China"},{"name":"Department of 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