Evidence of survival bias in the association between APOE-Є4 and age at ischemic stroke onset
Loading...
Citations
Scopus:
Altmetric:
Altmetric::
Download
Associated Records
Authors
File Licence
Editors
Date
2024
Source Title
Frontiers in Genetics
Journal Title
Journal ISSN
Volume Title
Publisher
Frontiers Media S.A.
Melbourne Authors
Affiliation
Melbourne Medical School
Document Type
Journal Article
Subject Code
Citation
von Berg, J., McArdle, P. F., Häppölä, P., Haessler, J., Kooperberg, C., Lemmens, R., Pezzini, A., Thijs, V., Pulit, S. L., Kittner, S. J., Mitchell, B. D., de Ridder, J. & van der Laan, S. W. (2024). Evidence of survival bias in the association between APOE-Є4 and age at ischemic stroke onset. Frontiers in Genetics, 15, https://doi.org/10.3389/fgene.2024.1392061.
Access Status
Open Access
Access URL
Open Access URL
Open Access at PMC
Linked Resource URL
NHMRC Grant Code
ARC Grant Code
Description
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.