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Despite the widespread deposition of p\u2010S65\u2010Ub in aged and diseased human brain, the genetic contribution to its accumulation remains unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>To identify novel mitophagy regulators, we performed a genome\u2010wide association study using p\u2010S65\u2010Ub level as a quantitative trait in 1012 autopsy\u2010confirmed Lewy body disease (LBD) samples.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>We identified a significant genome\u2010wide association with p\u2010S65\u2010Ub for rs429358 (<jats:italic>apolipoprotein E \u03b54<\/jats:italic> [<jats:italic>APOE<\/jats:italic>4])\u00a0and a suggestive association for rs6480922 (<jats:italic>ZMIZ1<\/jats:italic>). <jats:italic>APOE<\/jats:italic>4 was associated with higher p\u2010S65\u2010Ub levels and greater neuropathological burden. Functional validation in mouse and human induced pluripotent stem cell (iPSC) models confirmed <jats:italic>APOE<\/jats:italic>4\u2010mediated mitophagy alterations. Intriguingly, <jats:italic>ZMIZ1<\/jats:italic> rs6480922 was associated with lower p\u2010S65\u2010Ub levels, reduced neuropathological load, and increased brain weight, indicating a potential protective role.<\/jats:p><\/jats:sec><jats:sec><jats:title>DISCUSSION<\/jats:title><jats:p>Our findings underscore the importance of mitochondrial quality control in LBD pathogenesis and nominate regulators that may contribute to disease risk or resilience.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>p\u2010S65\u2010Ub levels were used as a quantitative marker of mitochondrial damage.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>A GWAS identified two genetic variants that modify mitophagy in LBD autopsy brain.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p><jats:italic>APOE<\/jats:italic>4 was associated with increased p\u2010S65\u2010Ub accumulation and neuropathology.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p><jats:italic>APOE<\/jats:italic>4 altered mitophagy via pathology\u2010dependent and pathology\u2010independent mechanisms.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p><jats:italic>ZMIZ1<\/jats:italic> was linked to reduced p\u2010S65\u2010Ub and neuropathology indicative of protection.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.70198","type":"journal-article","created":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T07:11:18Z","timestamp":1746083478000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Genome\u2010wide association analysis identifies <i>APOE<\/i> as a mitophagy modifier in Lewy body disease"],"prefix":"10.1002","volume":"21","author":[{"given":"Xu","family":"Hou","sequence":"first","affiliation":[{"name":"Department of Neuroscience Mayo Clinic  Jacksonville Florida 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