{"doi":"10.3389/fgene.2024.1392061","title":"Evidence of survival bias in the association between APOE-Є4 and age at ischemic stroke onset","abstract":"Introduction Large genome-wide association studies (GWASs) using case–control study designs have now identified tens of loci associated with ischemic stroke (IS). As a complement to these studies, we performed GWAS in a case-only design to identify loci influencing the age at onset (AAO) of ischemic stroke. Methods Analyses were conducted in a discovery cohort of 10,857 ischemic stroke cases using a linear regression framework. We meta-analyzed all SNPs with p -value <1 x 10 −5 in a sexcombined or sex-stratified analysis using summary data from two additional replication cohorts. Results In the women-only meta-analysis, we detected significant evidence for the association of AAO with rs429358, an exonic variant in apolipoprotein E ( APOE ) that encodes for the APOE-Є4 allele. Each copy of the rs429358:T>C allele was associated with a 1.29-year earlier stroke AAO (meta p -value = 2.48 x 10 −11 ). This APOE variant has previously been associated with increased mortality and ischemic stroke AAO. We hypothesized that the association with AAO may reflect a survival bias attributable to an age-related decrease in mortality among APOE-Є4 carriers and have no association to stroke AAO per se. A simulation study showed that a variant associated with overall mortality might indeed be detected with an AAO analysis. A variant with a 2-fold increase in mortality risk would lead to an observed effect of AAO that is comparable to what we found. Discussion In conclusion, we detected a robust association of the APOE locus with stroke AAO and provided simulations to suggest that this association may be unrelated to ischemic stroke per se but related to a general survival bias.","journal":"Frontiers in Genetics","year":2024,"id":462233,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":2,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9591,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":24992,"name":"Patrick F. McArdle","orcid":"0000-0001-6649-0717","position":1,"is_corresponding":false},{"id":565858,"name":"Paavo Häppölä","orcid":"0000-0002-8502-0582","position":2,"is_corresponding":false},{"id":11227,"name":"Jeffrey Haessler","orcid":null,"position":3,"is_corresponding":false},{"id":11363,"name":"Charles Kooperberg","orcid":"0000-0002-7986-8560","position":4,"is_corresponding":false},{"id":249926,"name":"Robin Lemmens","orcid":"0000-0002-4948-5956","position":5,"is_corresponding":false},{"id":241691,"name":"Alessandro Pezzini","orcid":"0000-0001-8629-3315","position":6,"is_corresponding":false},{"id":249938,"name":"Vincent Thijs","orcid":"0000-0002-6614-8417","position":7,"is_corresponding":false},{"id":272377,"name":"Sara L. Pulit","orcid":"0000-0002-2502-3669","position":8,"is_corresponding":false},{"id":310711,"name":"Steven J. Kittner","orcid":"0000-0002-8457-8744","position":9,"is_corresponding":false},{"id":24663,"name":"Braxton D. Mitchell","orcid":"0000-0003-4920-4744","position":10,"is_corresponding":false},{"id":37195,"name":"Jeroen de Ridder","orcid":"0000-0002-0828-3477","position":11,"is_corresponding":false},{"id":21722,"name":"Sander W. van der Laan","orcid":"0000-0001-6888-1404","position":12,"is_corresponding":false},{"id":411738,"name":"Joanna von Berg","orcid":"0000-0001-7067-1406","position":0,"is_corresponding":true}],"reference_count":39,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:04:20.631898Z","pmid":"39286457","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":[]}