{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T04:59:26Z","timestamp":1780981166427,"version":"3.54.1"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Parkinson\u2019s disease (PD) lacks reliable peripheral biomarkers and disease-modifying therapies. Although peripheral B-cell alterations have been observed in PD, whether genetically predicted B-cell gene expression contributes to PD risk and can nominate candidate therapeutic targets remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We established a computational framework integrating two-sample Mendelian randomization (MR) based on B-cell subtype-specific sc-eQTLs (OneK1K) and PD GWAS (IPDGC; 33,674 cases\/449,056 controls), Bayesian colocalization with DICE and FinnGen replication, exploratory pseudobulk stage-associated analysis (GSE223138), B-cell subpopulation fine-mapping in 10,466 CD19 + cells (GSE194245), CellChat v2 communication inference, and druggability prioritization with molecular docking-based structural plausibility assessment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Multi-layer computational evidence prioritized eight high-confidence MR causal genes: five risk-increasing genes (CD74, HLA-DRB1, IL2RA, BLK, BANK1) and three protective genes (CR1, PTPN22, FCRL3). Exploratory pseudobulk analysis suggested four tentative stage-associated expression patterns, with early-change genes (CD74, HLA-DRB1, IL2RA) showing expression differences detectable as early as PD-Early in a small exploratory cohort. Subpopulation analysis suggested enrichment in Naive B (BLK, BANK1) and Atypical B cells (CD74, HLA-DRB1, IL2RA, CR1), while acknowledging that these fine-grained assignments are not equivalent to MR exposure categories. CellChat analysis predicted that the MIF signaling pathway showed an inferred communication probability increasing from 0.15 in HC to 0.48 in PD-Late. Five-dimensional evidence convergence nominated CD74, IL2RA, and CR1 as candidate targets, with molecular docking suggesting structural plausibility for selected small-molecule interactions, including Dasatinib-BLK (\u22127.2\u202fkcal\/mol) and ISO-1-CD74 (\u22126.8\u202fkcal\/mol).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These computational findings suggest that genetically influenced B-cell gene expression may contribute to peripheral immune dysregulation in PD and nominate CD74, IL2RA, and CR1 as candidate targets for future validation. The results should be interpreted as hypothesis-generating and require experimental and clinical confirmation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1853077","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T04:28:00Z","timestamp":1780979280000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Peripheral B cell immune dysregulation genetically contributes to stage-dependent neuroinflammation and identifies priority therapeutic targets in Parkinson\u2019s disease: a computational integration of Mendelian randomization and single-cell transcriptomics"],"prefix":"10.3389","volume":"13","author":[{"given":"Lu","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Rehabilitation Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengwei","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Acupuncture, Hubei Provincial Hospital of Traditional Chinese Medicine","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kezhen","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Department of Acupuncture, Geriatric Hospital of Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjun","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,9]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1016\/S1474-4422(19)30287-X","article-title":"The genetic architecture of Parkinson\u2019s disease","volume":"19","author":"Blauwendraat","year":"2020","journal-title":"Lancet Neurol"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1038\/s41577-022-00684-6","article-title":"Inflammation and immune dysfunction in Parkinson disease","volume":"22","author":"Tansey","year":"2022","journal-title":"Nat Rev 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