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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.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Analyses were conducted in a discovery cohort of 10,857 ischemic stroke cases using a linear regression framework. We meta-analyzed all SNPs with <jats:italic>p</jats:italic>-value &amp;lt;1 x 10<jats:sup>−5</jats:sup> in a sexcombined or sex-stratified analysis using summary data from two additional replication cohorts.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>In the women-only meta-analysis, we detected significant evidence for the association of AAO with rs429358, an exonic variant in apolipoprotein E (<jats:italic>APOE</jats:italic>) that encodes for the APOE-Є4 allele. Each copy of the rs429358:T&amp;gt;C allele was associated with a 1.29-year earlier stroke AAO (meta <jats:italic>p</jats:italic>-value = 2.48 x 10<jats:sup>−11</jats:sup>). 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.</jats:p></jats:sec><jats:sec><jats:title>Discussion</jats:title><jats:p>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.</jats:p></jats:sec>"],"publicationDate":"2023-12-01","publisher":"Frontiers Media SA","embargoEndDate":null,"sources":["Crossref","Front Genet","medRxiv","Frontiers in Genetics, Vol 15 (2024)","Frontiers in Genetics"],"formats":null,"contributors":null,"coverages":null,"bestAccessRight":{"code":"c_abf2","label":"OPEN","scheme":"http://vocabularies.coar-repositories.org/documentation/access_rights/"},"container":{"name":"Frontiers in 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