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

doi:10.1101/2023.12.01.23294385

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[Preprint]. 2023 Dec 1:2023.12.01.23294385.

doi: 10.1101/2023.12.01.23294385.

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

Joanna von Berg^{1

2}, Patrick F McArdle³, Paavo Häppölä⁴, Jeffrey Haessler^{1

2

3

5

6

7

4

8

9

10

11

12

13

14

15

16

17}, Charles Kooperberg⁸, Robin Lemmens^{9

10}, Alessandro Pezzini^{11

12

13}, Vincent Thijs^{14

15

16}; SiGN, FinnGen, Women’s Health Initiative; Sara L Pulit¹, Steven J Kittner^{5

6}, Braxton D Mitchell^{3

5}, Jeroen de Ridder^{1

2}, Sander W van der Laan^{7

17}

Affiliations

¹ Center for Molecular Medicine, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
² Oncode Institute, Utrecht, The Netherlands.
³ Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
⁴ Institute for Molecular Medicine Finland FIMM, HiLIFE, University of Helsinki, Helsinki, Finland.
⁵ Geriatric Research and Education Clinical Center, VA Maryland Health Care System, Baltimore, MD, USA.
⁶ Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.
⁷ Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
⁸ Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatle, WA, USA.
⁹ University Hospitals Leuven, Department of Neurology, Leuven, Belgium.
¹⁰ KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology, Leuven, Belgium.
¹¹ Department of Medicine and Surgery, University of Parma, Parma, Italy.
¹² Stroke Care Program, Department of Emergency, Parma University Hospital, Parma, Italy.
¹³ Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
¹⁴ Stroke Theme, The Florey, Heidelberg, Victoria, Australia.
¹⁵ Department of Medicine, University of Melbourne, Victoria, Australia.
¹⁶ Department of Neurology, Austin Health, Heidelberg, Victoria, Australia.
¹⁷ Center of Population Health and Genomics, University of Virginia, Charlottesville, VA, USA.

PMID: 38076909
PMCID: PMC10705635
DOI: 10.1101/2023.12.01.23294385

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

Joanna von Berg et al. medRxiv. 2023.

[Preprint]. 2023 Dec 1:2023.12.01.23294385.

doi: 10.1101/2023.12.01.23294385.

Authors

Affiliations

¹ Center for Molecular Medicine, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
² Oncode Institute, Utrecht, The Netherlands.
³ Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
⁴ Institute for Molecular Medicine Finland FIMM, HiLIFE, University of Helsinki, Helsinki, Finland.
⁵ Geriatric Research and Education Clinical Center, VA Maryland Health Care System, Baltimore, MD, USA.
⁶ Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.
⁷ Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
⁸ Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatle, WA, USA.
⁹ University Hospitals Leuven, Department of Neurology, Leuven, Belgium.
¹⁰ KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology, Leuven, Belgium.
¹¹ Department of Medicine and Surgery, University of Parma, Parma, Italy.
¹² Stroke Care Program, Department of Emergency, Parma University Hospital, Parma, Italy.
¹³ Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
¹⁴ Stroke Theme, The Florey, Heidelberg, Victoria, Australia.
¹⁵ Department of Medicine, University of Melbourne, Victoria, Australia.
¹⁶ Department of Neurology, Austin Health, Heidelberg, Victoria, Australia.
¹⁷ Center of Population Health and Genomics, University of Virginia, Charlottesville, VA, USA.

PMID: 38076909
PMCID: PMC10705635
DOI: 10.1101/2023.12.01.23294385

Update in

Evidence of survival bias in the association between APOE-Є4 and age at ischemic stroke onset.
von Berg J, McArdle PF, Häppölä P, Haessler J, Kooperberg C, Lemmens R, Pezzini A, Thijs V, Pulit SL, Kittner SJ, Mitchell BD, de Ridder J, van der Laan SW. von Berg J, et al. Front Genet. 2024 Sep 2;15:1392061. doi: 10.3389/fgene.2024.1392061. eCollection 2024. Front Genet. 2024. PMID: 39286457 Free PMC article.

Abstract

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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Figures

**Figure 1:. Association of APOE rs429358 with age of stroke onset in women (red), men (blue), and sex-combined meta-analysis.**
Point estimate represents effect of each copy of the minor (C) allele on AOO (in years); 95 % confidence intervals are indicated by error bars.

**Figure 2:. Data generating model for simulation study.**
Five variables were generated at birth (DOB, GENO and SEX) and subsequent risk of stroke and death were estimated annually. Date of death and date of stroke (if applicable) are outputted from the model.

Figure 3:. Estimated power to detect an association between genotype and stroke according to 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 relative risk for a given genetic variant. The y-axis shows the power given a genetic effect size.

See this image and copyright information in PMC

References

1. Naj A. C. et al. Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study. JAMA Neurol. 71, 1394–1404 (2014). - PMC - PubMed
1. Blauwendraat C. et al. Parkinson’s disease age at onset genome-wide association study: Defining heritability, genetic loci, and α-synuclein mechanisms. Mov. Disord. 34, 866–875 (2019). - PMC - PubMed
1. Lagging C. et al. APOE ε4 is associated with younger age at ischemic stroke onset but not with stroke outcome. Neurology 93, 849–853 (2019). - PMC - PubMed
1. Zaitlen N. et al. Informed conditioning on clinical covariates increases power in case-control association studies. PLoS Genet. 8, e1003032 (2012). - PMC - PubMed
1. Traylor M. et al. A novel MMP12 locus is associated with large artery atherosclerotic stroke using a genome-wide age-at-onset informed approach. PLoS Genet. 10, e1004469 (2014). - PMC - PubMed

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[1] Naj A. C. et al. Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study. JAMA Neurol. 71, 1394–1404 (2014). - PMC - PubMed

[2] Naj A. C. et al. Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study. JAMA Neurol. 71, 1394–1404 (2014). - PMC - PubMed

[3] Blauwendraat C. et al. Parkinson’s disease age at onset genome-wide association study: Defining heritability, genetic loci, and α-synuclein mechanisms. Mov. Disord. 34, 866–875 (2019). - PMC - PubMed

[4] Blauwendraat C. et al. Parkinson’s disease age at onset genome-wide association study: Defining heritability, genetic loci, and α-synuclein mechanisms. Mov. Disord. 34, 866–875 (2019). - PMC - PubMed

[5] Lagging C. et al. APOE ε4 is associated with younger age at ischemic stroke onset but not with stroke outcome. Neurology 93, 849–853 (2019). - PMC - PubMed

[6] Lagging C. et al. APOE ε4 is associated with younger age at ischemic stroke onset but not with stroke outcome. Neurology 93, 849–853 (2019). - PMC - PubMed

[7] Zaitlen N. et al. Informed conditioning on clinical covariates increases power in case-control association studies. PLoS Genet. 8, e1003032 (2012). - PMC - PubMed

[8] Zaitlen N. et al. Informed conditioning on clinical covariates increases power in case-control association studies. PLoS Genet. 8, e1003032 (2012). - PMC - PubMed

[9] Traylor M. et al. A novel MMP12 locus is associated with large artery atherosclerotic stroke using a genome-wide age-at-onset informed approach. PLoS Genet. 10, e1004469 (2014). - PMC - PubMed

[10] Traylor M. et al. A novel MMP12 locus is associated with large artery atherosclerotic stroke using a genome-wide age-at-onset informed approach. PLoS Genet. 10, e1004469 (2014). - PMC - PubMed

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This is a preprint.

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

Affiliations

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

Authors

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Update in

Abstract

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This is a preprint.

Update in

Abstract

Figures

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References

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Research Materials

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