Joanna von Berg, Patrick F. McArdle, Paavo Häppölä, Charles Kooperberg, SiGN consortium, FinnGen, Women’s Health Initiative, Steven J. Kittner, Braxton D. Mitchell, Jeroen de Ridder, Sander W. van der Laan.
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 under a linear regression framework. We meta-analyzed all SNPs with p-value < 1x10-5 in a sex-combined or sex-stratified analysis using summary data from two additional Replication cohorts (11,539)). 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-Є4 allele. Each copy of the rs429358:T>C allele was associated with a 1.63 years earlier stroke AOO (meta p-value = 2.4x10-8).
This APOE variant has previously been associated with increased mortality, but not with ischemic stroke AAO. We therefore hypothesized that the association with AAO may reflect a survival bias attributable to an age-related decline in mortality among APOE-Є4 carriers and having 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 twofold increase on mortality risk would lead to an observed effect of AAO that is comparable to what we found. We conclude that the APOE-age of stroke onset association may reflect a general association of APOE with mortality, especially pronounced in women, or alternatively, may reflect a female-specific effect on ischemic stroke AAO.
You can load this project in RStudio by opening the file called 'AAO_IschemicStroke.git.Rproj'.
| File | Description | Usage |
|---|---|---|
| README.md | Description of project | Human editable |
| AAO_IschemicStroke.git.Rproj | Project file | Loads project |
| LICENSE | User permissions | Read only |
| .worcs | WORCS metadata YAML | Read only |
| prepare_data.R | Script to process raw data | Human editable |
| renv.lock | Reproducible R environment | Read only |
This project uses the Workflow for Open Reproducible Code in Science (WORCS) to ensure transparency and reproducibility. The workflow is designed to meet the principles of Open Science throughout a research project.
To learn how WORCS helps researchers meet the TOP-guidelines and FAIR principles, read the preprint at https://osf.io/zcvbs/
- To get started with
worcs, see the setup vignette - For detailed information about the steps of the WORCS workflow, see the workflow vignette
Please refer to the vignette on reproducing a WORCS project for step by step advice.
This work was supported by NIH grants R01 NS100178 and R01 NS105150 from the U.S. National Institutes of Health. JdR is supported by a Vidi Fellowship (639.072.715) from the Dutch Organization for Scientific Research (Nederlandse Organisatie voor Wetenschappelijk Onderzoek, NWO). SJK is additionally supported by the Department of Veterans Affairs RR&D N1699-R and BX004672-01A1. SWvdL is funded through EU H2020 TO_AITION (grant number: 848146).
We are thankful for the support of the Netherlands CardioVascular Research Initiative of the Netherlands Heart Foundation (CVON 2011/B019 and CVON 2017-20: Generating the best evidence-based pharmaceutical targets for atherosclerosis [GENIUS I&II]), the ERA-CVD program ‘druggable-MI-targets’ (grant number: 01KL1802), and the Leducq Fondation ‘PlaqOmics’.
The Women’s Health Initiatives (WHI) program was funded by the National Heart, Lung, and Blood Institute, NIH, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118 to 32119, 32122, 42107-26, 42129-32, and 44221.
The framework was based on the WORCS package.
Version: v1.0.0
Last update: 2022-04-12
Written by: Sander W. van der Laan (s.w.vanderlaan-2[at]umcutrecht.nl).
Description: Script to get some figures for AAO.
Minimum requirements: R version 3.4.3 (2017-06-30) -- 'Single Candle', Mac OS X El Capitan
Changes log
* v1.0.0 Initial version.
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