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. 2024 Sep 2:15:1392061.
doi: 10.3389/fgene.2024.1392061. eCollection 2024.

Evidence of survival bias in the association between APOE-Є4 and age at ischemic stroke onset

Joanna von Berg  1   2 , Patrick F McArdle  3 , Paavo Häppölä  4 , Jeffrey Haessler  1   2   3   4   5   6   7   8   9   10   11   12   13   14   15   16 , Charles Kooperberg  5 , Robin Lemmens  6   7 , Alessandro Pezzini  8   9 , Vincent Thijs  10   11   12 , Sara L Pulit  1 , Steven J Kittner  13   14 , Braxton D Mitchell  3   13 , Jeroen de Ridder  1   2 , Sander W van der Laan  15   16
Affiliations

Evidence of survival bias in the association between APOE-Є4 and age at ischemic stroke onset

Joanna von Berg et al. Front Genet. .

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.

Keywords: APOE; age at onset; atherosclerosis; genome-wide association study; stroke.

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Conflict of interest statement

SWvdL received funding from Roche Diagnostics International Ltd for unrelated work. JdR is co-founder and director of Cyclomics, a genomics company. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision

Figures

FIGURE 1
FIGURE 1
Association of APOE rs429358 with the age at stroke onset in women (red), men (blue), and sex-combined meta-analyses. Point estimate represents the effect of each copy of the minor (C) allele on the AAO (in years); 95% confidence intervals are indicated by error bars.
FIGURE 2
FIGURE 2
Data generating model for the simulation study. Five variables were generated at birth (DOB, GENO, and SEX), and the subsequent risks of stroke and death were estimated annually. The date of death and date of stroke (if applicable) are outputted from the model. The genotypic effect varied from 1.0 (null) to 2.0 by increments of 0.1. The probability draw parameters for the Markov chain Monte Carlo simulations are given with B(p|c) notation, indicating a draw from the binomial distribution (B) with a probability (p) of stroke, given the conditions (C), i.e., sex, age, and geno(types).
FIGURE 3
FIGURE 3
Estimated power to detect an association between the genotype and stroke according to the effect size for variants associated with age at death (green), additive effect on stroke susceptibility (red), and multiplicative effect on stroke susceptibility (blue) for (left) case–control analysis and (right) age-at-onset analysis. The x-axis shows the effect size in the relative risk for a given genetic variant. The y-axis shows the power, given a genetic effect size.
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