Abstract
Objective To determine whether the polygenic risk score (PRS) derived from MEGASTROKE is associated with ischemic stroke (IS) and its subtypes in an independent tertiary health care system and to identify the PRS derived from gene sets of known biological pathways associated with IS.
Methods Controls (n = 19,806/7,484, age ≥69/79 years) and cases (n = 1,184/951 for discovery/replication) of acute IS with European ancestry and clinical risk factors were identified by leveraging the Geisinger Electronic Health Record and chart review confirmation. All Geisinger MyCode patients with age ≥69/79 years and without any stroke-related diagnostic codes were included as low risk control. Genetic heritability and genetic correlation between Geisinger and MEGASTROKE (EUR) were calculated using the summary statistics of the genome-wide association study by linkage disequilibrium score regression. All PRS for any stroke (AS), any ischemic stroke (AIS), large artery stroke (LAS), cardioembolic stroke (CES), and small vessel stroke (SVS) were constructed by PRSice-2.
Results A moderate heritability (10%–20%) for Geisinger sample as well as the genetic correlation between MEGASTROKE and the Geisinger cohort was identified. Variation of all 5 PRS significantly explained some of the phenotypic variations of Geisinger IS, and the R2 increased by raising the cutoff for the age of controls. PRSLAS, PRSCES, and PRSSVS derived from low-frequency common variants provided the best fit for modeling (R2 = 0.015 for PRSLAS). Gene sets analyses highlighted the association of PRS with Gene Ontology terms (vascular endothelial growth factor, amyloid precursor protein, and atherosclerosis). The PRSLAS, PRSCES, and PRSSVS explained the most variance of the corresponding subtypes of Geisinger IS suggesting shared etiologies and corroborated Geisinger TOAST subtyping.
Conclusions We provide the first evidence that PRSs derived from MEGASTROKE have value in identifying shared etiologies and determining stroke subtypes.
Glossary
- AFib=
- atrial fibrillation;
- APP=
- amyloid precursor protein;
- ASL=
- a synthesized TOAST subtype that represents a combination of Acute SVS (n = 79) and LAS (n = 124);
- AUC-ROC=
- area under the curve for receiver operating characteristics;
- BMI=
- body mass index;
- CAD=
- coronary artery disease;
- CES=
- cardioembolic stroke;
- CI=
- confidence interval;
- DETERMINED=
- strokes of other determined etiology;
- EHR=
- electronic health record;
- EUR=
- European ancestry;
- GO=
- Gene Ontology;
- GWAS=
- genome-wide association study;
- HWE=
- Hardy-Weinberg equilibrium;
- ICD=
- International Classification of Diseases;
- IS=
- ischemic stroke;
- LAS=
- large artery stroke;
- LDSC=
- linkage disequilibrium score regression;
- MAF=
- minor allele frequency;
- ML=
- machine learning;
- OR=
- odds ratio;
- PCA=
- principal component analysis;
- PRS=
- polygenic risk score;
- SNP=
- single nucleotide polymorphism;
- SVS=
- small vessel stroke;
- T2D=
- type 2 diabetes;
- TOAST=
- trial of ORG 10172 in acute stroke treatment;
- UNDETERMINED=
- strokes of undetermined etiology
Footnotes
Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article.
The Article Processing Charge was funded by the authors.
Regeneron Genetics Center coinvestigators are listed in appendix 2 at the end of the article.
- Received October 7, 2020.
- Accepted in final form December 2, 2020.
- Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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