{"doi":"10.1101/2023.10.16.23297100","title":"Genome-wide association study identifies <i>APOE</i> and <i>ZMIZ1</i> variants as mitophagy modifiers in Lewy body disease","abstract":"Abstract The PINK1-PRKN pathway mediates a critical quality control to maintain mitochondrial health and function. Together the kinase-ligase pair identifies and decorate damaged mitochondria with phosphorylated ubiquitin (p-S65-Ub). This selective label serves as the mitophagy tag and facilitates their degradation via autophagy-lysosome system. While complete loss of PINK1 or PRKN function causes early-onset Parkinson disease, much broader mitophagy impairments are emerging across neurodegenerative disorders. We previously found age- and disease-dependent accumulation of p-S65-Ub signal in the hippocampus of autopsy brains with Lewy body disease (LBD). However, the contribution of genetic variation to mitochondrial damage and p-S65-Ub levels remains unknown in LBD cases. To identify novel regulators of PINK1-PRKN mitophagy in LBD, we performed an unbiased genome-wide association study of hippocampal p-S65-Ub level with 1,012 autopsy confirmed LBD samples. Using an established, mostly automated workflow, hippocampal sections were immunostained for p-S65-Ub, scanned, and quantified with unbiased algorithms. Functional validation of the significant hit was performed in animal model and human induced pluripotent stem cells (hiPSCs). We identified a strong association with p-S65-Ub for APOE4 (rs429358; β : 0.50, 95% CI: 0.41 to 0.69; p =8.67x10 -25 ) and a genome-wide significant association for ZMIZ1 (rs6480922; β : -0.33, 95% CI: -0.45 to -0.22; p =1.42x10 -8 ). The increased p-S65-Ub levels in APOE4 -carrier may be mediated by both co-pathology-dependent and -independent mechanisms, which was confirmed in Apoe-targeted replacement mice and hiPSC-derived astrocytes. Intriguingly, ZMIZ1 rs6480922 also significantly associated with increased brain weight and reduced neuropathological burden indicating a potential role as a resilience factor. Our findings nominate novel mitophagy regulators in LBD brain ( ZMIZ1 locus) and highlight a strong association of APOE4 with mitophagy alteration. With APOE4 being the strongest known risk factor for clinical Alzheimer’s disease and dementia with Lewy bodies, our findings suggest a common mechanistic link underscoring the importance of mitochondrial quality control.","journal":"medRxiv","year":2023,"id":392674,"datarank":0.26876392038420827,"base_score":1.791759469228055,"endowment":1.791759469228055,"self_citation_contribution":0.26876392038420827,"citation_network_contribution":0.0,"self_endowment_contribution":0.26876392038420827,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9523,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":54748,"name":"Michael G. Heckman","orcid":"0000-0003-3770-9331","position":1,"is_corresponding":false},{"id":314473,"name":"Fabienne C. Fiesel","orcid":"0000-0002-1919-9676","position":2,"is_corresponding":false},{"id":238165,"name":"Shunsuke Koga","orcid":"0000-0001-8868-9700","position":3,"is_corresponding":false},{"id":368351,"name":"Alexandra I. Soto‐Beasley","orcid":"0000-0002-0153-1917","position":4,"is_corresponding":false},{"id":314467,"name":"Jens O. Watzlawik","orcid":"0000-0003-0610-0267","position":5,"is_corresponding":false},{"id":230874,"name":"Jing Zhao","orcid":"0000-0002-4520-6307","position":6,"is_corresponding":false},{"id":271282,"name":"Rebecca R. Valentino","orcid":"0000-0001-7253-961X","position":7,"is_corresponding":false},{"id":287564,"name":"Patrick W. Johnson","orcid":"0000-0001-8365-1375","position":8,"is_corresponding":false},{"id":642946,"name":"Launia J. White","orcid":"0000-0003-0251-9431","position":9,"is_corresponding":false},{"id":308845,"name":"Zachary Quicksall","orcid":"0000-0002-8791-0925","position":10,"is_corresponding":false},{"id":308848,"name":"Joseph S. Reddy","orcid":"0000-0002-1783-4453","position":11,"is_corresponding":false},{"id":52693,"name":"José Brás","orcid":"0000-0001-8186-0333","position":12,"is_corresponding":false},{"id":331123,"name":"Rita Guerreiro","orcid":"0000-0001-5879-3486","position":13,"is_corresponding":false},{"id":233772,"name":"Na Zhao","orcid":"0000-0001-8648-9422","position":14,"is_corresponding":false},{"id":230893,"name":"Guojun Bu","orcid":"0000-0003-3491-1016","position":15,"is_corresponding":false},{"id":54753,"name":"Dennis W. Dickson","orcid":"0000-0001-7189-7917","position":16,"is_corresponding":false},{"id":17435,"name":"Owen A. Ross","orcid":"0000-0003-4813-756X","position":17,"is_corresponding":false},{"id":314474,"name":"Wolfdieter Springer","orcid":"0000-0002-1178-3149","position":18,"is_corresponding":false},{"id":314468,"name":"Xu Hou","orcid":"0000-0003-3011-4378","position":0,"is_corresponding":true}],"reference_count":27,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:18:56.730121Z","pmid":"37905059","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}