Evidence of survival bias in the association between APOE-ϵ4 and age of ischemic stroke onset.

2023-12-01

von Berg, Joanna

McArdle, Patrick F

Häppölä, Paavo

Haessler, Jeffrey

Kooperberg, Charles

Lemmens, Robin

Pezzini, Alessandro

Thijs, Vincent N

Pulit, Sara L

Kittner, Steven J

Mitchell, Braxton D

de Ridder, Jeroen

van der Laan, Sander W

Journal Article

0000-0001-7067-1406

0000-0001-6649-0717

#PLACEHOLDER_PARENT_METADATA_VALUE#

#PLACEHOLDER_PARENT_METADATA_VALUE#

0000-0002-7986-8560

0000-0002-4948-5956

0000-0001-8629-3315

0000-0002-6614-8417

#PLACEHOLDER_PARENT_METADATA_VALUE#

0000-0002-2502-3669

#PLACEHOLDER_PARENT_METADATA_VALUE#

0000-0003-4920-4744

0000-0002-0828-3477

10.1101/2023.12.01.23294385

Large genome-wide association studies (GWAS) employing 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 age at onset (AAO) of ischemic stroke. 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 < 1×10-5 in a sex-combined or sex-stratified analysis using summary data from two additional replication cohorts. In the women-only meta-analysis, we detected significant evidence for association of AAO with rs429358, an exonic variant in APOE that encodes for the APOE-ϵ4 allele. Each copy of the rs429358:T>C allele was associated with a 1.29 years earlier stroke AOO (meta p-value = 2.48×10-11). 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 decline in mortality among APOE-ϵ4 carriers and have no association to stroke AAO per se. Using a simulation study, we found that a variant associated with overall mortality might indeed be detected with an AAO analysis. A variant with a two-fold increase on mortality risk would lead to an observed effect of AAO that is comparable to what we found. 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.

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MedRxiv : the Preprint Server for Health Sciences 2023-12-01

MedRxiv : the Preprint Server for Health Sciences