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We aimed to detect causal associations and shared genetic etiology of neurodegenerative diseases with epigenetic aging and human longevity. We obtained large\u2010scale genome\u2010wide association study summary statistics data for four measures of epigenetic age (GrimAge, PhenoAge, IEAA, and HannumAge) (<jats:italic>N<\/jats:italic>\u2009=\u200934,710), multivariate longevity (healthspan, lifespan, and exceptional longevity) (<jats:italic>N<\/jats:italic>\u2009=\u20091,349,462), and for multiple neurodegenerative diseases (<jats:italic>N<\/jats:italic>\u2009=\u20096618\u2013482,730), including Lewy body dementia, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Main analyses were conducted using multiplicative random effects inverse\u2010variance weighted Mendelian randomization (MR), and conditional\/conjunctional false discovery rate (cond\/conjFDR) approach. Shared genomic loci were functionally characterized to gain biological understanding. Evidence showed that AD patients had 0.309\u2009year less in exceptional longevity (IVW beta\u2009=\u2009\u22120.309, 95% CI: \u22120.38 to \u22120.24, <jats:italic>p<\/jats:italic>\u2009=\u20091.51E\u201019). We also observed suggestively significant causal evidence between AD and GrimAge age acceleration (IVW beta\u2009=\u2009\u22120.10, 95% CI: \u22120.188 to \u22120.013, <jats:italic>p<\/jats:italic>\u2009=\u20090.02). Following the discovery of polygenic overlap, we identified rs78143120 as shared genomic locus between AD and GrimAge age acceleration, and rs12691088 between AD and exceptional longevity. Among these loci, rs78143120 was novel for AD. In conclusion, we observed that only AD had causal effects on epigenetic aging and human longevity, while other neurodegenerative diseases did not. The genetic overlap between them, with mixed effect directions, suggested complex shared genetic etiology and molecular mechanisms.<\/jats:p>","DOI":"10.1111\/acel.14271","type":"journal-article","created":{"date-parts":[[2024,9,20]],"date-time":"2024-09-20T05:14:26Z","timestamp":1726809266000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Causal associations and shared genetic etiology of neurodegenerative diseases with epigenetic aging and human longevity"],"prefix":"10.1111","volume":"23","author":[{"given":"Yu","family":"Guo","sequence":"first","affiliation":[{"name":"School of Computer Science and Technology Harbin Institute of Technology  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guojuan","family":"Ma","sequence":"additional","affiliation":[{"name":"Beidahuang Industry Group General Hospital  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukai","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Computer Science and Technology Harbin Institute of Technology  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingyan","family":"Lin","sequence":"additional","affiliation":[{"name":"School of Computer Science and Technology Harbin Institute of Technology  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4508-5365","authenticated-orcid":false,"given":"Yang","family":"Hu","sequence":"additional","affiliation":[{"name":"School of Computer Science and Technology Harbin Institute of Technology  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyi","family":"Zang","sequence":"additional","affiliation":[{"name":"School of Computer Science and Technology Harbin Institute of Technology  Harbin 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