{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:21:40Z","timestamp":1785410500536,"version":"3.56.0"},"reference-count":83,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["GNT2025837"],"award-info":[{"award-number":["GNT2025837"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"award":["GNT2025837"],"award-info":[{"award-number":["GNT2025837"]}],"id":[{"id":"https:\/\/ror.org\/011kf5r70","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a neurodegenerative disorder, whereas myasthenia gravis (MG) is an autoimmune neuromuscular disease. Despite their distinct clinical manifestations, both disorders involve immune dysregulation and cholinergic dysfunction, and epidemiological evidence for an association remains inconclusive. Here, we investigated the genetic architecture underlying the AD\u2013MG relationship using large-scale European-ancestry genome-wide association study (GWAS) data, including early- and late-onset MG, within a multi-resolution analytical framework. Genome-wide analyses indicated modest polygenic overlap between AD and MG, supported by nominally significant and directionally consistent correlations across datasets, SNPeffect concordance in the primary GWAS, and robust gene-level overlap. Evidence for genome-wide correlation was weaker and non-significant across AD-MG subtypes. Local genetic correlation analyses revealed that shared AD-MG signals were largely locus-specific and heterogeneous, with regions showing both concordant and discordant effects, particularly across MG subtypes. Subtype-specific analyses indicated broader and more heterogeneous overlap for AD\u2013late-onset MG, including both major histocompatibility complex (MHC) and non-MHC loci, whereas AD\u2013early-onset MG showed more restricted patterns largely confined to the MHC. Cross-trait meta-analysis and colocalisation further refined these findings, identifying a limited number of loci with evidence of shared AD-MG association, while most regions were consistent with distinct causal variants. A chromosome 16 locus showed the most consistent shared cross-trait AD-MG signal across multiple analytical frameworks. Mendelian randomisation analyses provided no evidence of a causal effect of AD liability on MG and yielded only suggestive, and inconclusive evidence for the reverse direction. Gene-level and expression-informed analyses prioritised immune-related genes, as well as regulators of transcription, chromatin organisation, and synaptic processes, without implying concordant causal variants across traits. Tissue and pathway analyses suggested shared immune involvement, with differential emphasis on innate immune processes in AD and adaptive immune pathways in MG. Notably, heterogeneity of effects within the MHC and across loci suggests that overlap reflects a complex, context-dependent architecture rather than a uniform immune-driven signal. Overall, our findings indicate that the AD\u2013MG relationship is characterised by modest genome-wide polygenic overlap, substantial locus-specific heterogeneity, and partial convergence on immune-related genetic architecture, rather than a uniformly shared mechanism.<\/jats:p>","DOI":"10.3390\/ijms27114792","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T13:28:21Z","timestamp":1779802101000},"page":"4792","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genome-Wide and Locus-Level Analyses Reveal Modest, Heterogeneous Genetic Sharing Between Alzheimer\u2019s Disease and Myasthenia Gravis"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4533-0340","authenticated-orcid":false,"given":"Emmanuel O.","family":"Adewuyi","sequence":"first","affiliation":[{"name":"Curtin School of Population Health, Faculty of Health Sciences, Curtin University, Perth, WA 6102, Australia"},{"name":"Curtin Medical Research Institute, Faculty of Health Sciences, Curtin University, Perth, WA 6102, Australia"},{"name":"Anchor University Centre for Global Health (AUCGH), Anchor University, Lagos 100278, Nigeria"},{"name":"Dementia Centre of Excellence, Curtin enAble Institute, Faculty of Health, Curtin University, Perth, WA 6102, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asa","family":"Auta","sequence":"additional","affiliation":[{"name":"Faculty of Health, Social Care and Medicine, Edge Hill University, Ormskirk L39 4QP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9749-3256","authenticated-orcid":false,"given":"Chinedu I.","family":"Ossai","sequence":"additional","affiliation":[{"name":"Independent Researcher, Melbourne, VIC 3107, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0618-3173","authenticated-orcid":false,"given":"Chidozie C.","family":"Anyaegbu","sequence":"additional","affiliation":[{"name":"Curtin Medical Research Institute, Faculty of Health Sciences, Curtin University, Perth, WA 6102, Australia"},{"name":"Perron Institute for Neurological and Translational Science, Ralph and Patricia Sarich Neuroscience Research Institute, Nedlands, WA 6009, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9088-3965","authenticated-orcid":false,"given":"Thi Thu Huong","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Curtin School of Population Health, Faculty of Health Sciences, Curtin University, Perth, WA 6102, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8739-8714","authenticated-orcid":false,"given":"Md Rezanur","family":"Rahman","sequence":"additional","affiliation":[{"name":"Brain and Mental Health Program, QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD 4006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1235-360X","authenticated-orcid":false,"given":"Blossom C. M.","family":"Stephan","sequence":"additional","affiliation":[{"name":"Dementia Centre of Excellence, Curtin enAble Institute, Faculty of Health, Curtin University, Perth, WA 6102, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4784-8151","authenticated-orcid":false,"given":"Gizachew A.","family":"Tessema","sequence":"additional","affiliation":[{"name":"Curtin School of Population Health, Faculty of Health Sciences, Curtin University, Perth, WA 6102, Australia"},{"name":"Curtin Medical Research Institute, Faculty of Health Sciences, Curtin University, Perth, WA 6102, Australia"},{"name":"Curtin enAble Institute, Curtin University, Perth, WA 6102, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7159-3040","authenticated-orcid":false,"given":"Dale R.","family":"Nyholt","sequence":"additional","affiliation":[{"name":"Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3740-8117","authenticated-orcid":false,"given":"Gavin","family":"Pereira","sequence":"additional","affiliation":[{"name":"Curtin School of Population Health, Faculty of Health Sciences, Curtin University, Perth, WA 6102, Australia"},{"name":"Curtin enAble Institute, Curtin University, Perth, WA 6102, Australia"},{"name":"Faculty of Medicine, Universitas Negeri Malang, Malang 65145, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"key":"ref_1","first-page":"41","article-title":"Association between myasthenia gravis and Alzheimer\u2019s disease","volume":"78","year":"2024","journal-title":"Rev. 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