Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/34692
Title: Evidence of survival bias in the association between APOE-ϵ4 and age of ischemic stroke onset.
Austin Authors: 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
Affiliation: Center for Molecular Medicine, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.;Oncode Institute, Utrecht, The Netherlands.
Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
Institute for Molecular Medicine Finland FIMM, HiLIFE, University of Helsinki, Helsinki, Finland.
Center for Molecular Medicine, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.;Oncode Institute, Utrecht, The Netherlands.;Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.;Geriatric Research and Education Clinical Center, VA Maryland Health Care System, Baltimore, MD, USA.;Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.;Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.;Institute for Molecular Medicine Finland FIMM, HiLIFE, University of Helsinki, Helsinki, Finland.;Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatle, WA, USA.;University Hospitals Leuven, Department of Neurology, Leuven, Belgium.;KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology, Leuven, Belgium.;Department of Medicine and Surgery, University of Parma, Parma, Italy.;Stroke Care Program, Department of Emergency, Parma University Hospital, Parma, Italy.;Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.;Stroke Theme, The Florey, Heidelberg, Victoria, Australia.;Department of Medicine, University of Melbourne, Victoria, Australia.;Department of Neurology, Austin Health, Heidelberg, Victoria, Australia.;Center of Population Health and Genomics, University of Virginia, Charlottesville, VA, USA.
Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatle, WA, USA.
University Hospitals Leuven, Department of Neurology, Leuven, Belgium.;KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology, Leuven, Belgium.
Department of Medicine and Surgery, University of Parma, Parma, Italy.;Stroke Care Program, Department of Emergency, Parma University Hospital, Parma, Italy.;Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
Neurology
Center for Molecular Medicine, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Geriatric Research and Education Clinical Center, VA Maryland Health Care System, Baltimore, MD, USA.;Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.
Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.;Geriatric Research and Education Clinical Center, VA Maryland Health Care System, Baltimore, MD, USA.
Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.;Center of Population Health and Genomics, University of Virginia, Charlottesville, VA, USA.
The Florey Institute of Neuroscience and Mental Health
Issue Date: 1-Dec-2023
Date: 2023
Publication information: MedRxiv : the Preprint Server for Health Sciences 2023-12-01
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.
URI: https://ahro.austin.org.au/austinjspui/handle/1/34692
DOI: 10.1101/2023.12.01.23294385
ORCID: 0000-0001-7067-1406
0000-0001-6649-0717
0000-0002-7986-8560
0000-0002-4948-5956
0000-0001-8629-3315
0000-0002-6614-8417
0000-0002-2502-3669
0000-0003-4920-4744
0000-0002-0828-3477
Journal: MedRxiv : the Preprint Server for Health Sciences
PubMed URL: 38076909
Type: Journal Article
Appears in Collections:Journal articles

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