Contribution of Common Genetic Variants to Risk of Early-Onset Ischemic Stroke

Abstract

Background and Objectives:Current genome-wide association studies of ischemic stroke have focused primarily on late onset disease. As a complement to these studies, we sought to identifythe contribution of common genetic variants to risk of early onset ischemic stroke.Methods:We performed a meta-analysis of genome-wide association studies of early onset stroke (EOS), ages 18-59, using individual level data or summary statistics in 16,730 cases and 599,237 non-stroke controls obtained across 48 different studies. We further compared effect sizes at associated loci between EOS and late onset stroke (LOS) and compared polygenic risk scores for venous thromboembolism between EOS and LOS.Results:We observed genome-wide significant associations of EOS with two variants in ABO, a known stroke locus. These variants tag blood subgroups O1 and A1, and the effect sizes of both variants were significantly larger in EOS compared to LOS. The odds ratio (OR) for rs529565, tagging O1, 0.88 (95% CI: 0.85-0.91) in EOS vs 0.96 (95% CI: 0.92-1.00) in LOS, and the OR for rs635634, tagging A1, was 1.16 (1.11-1.21) for EOS vs 1.05 (0.99-1.11) in LOS; p-values for interaction = 0.001 and 0.005, respectively. Using polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with EOS compared to LOS (p=0.008).Discussion:The ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with EOS than with LOS, supporting a stronger role of prothrombotic factors in EOS.

Genomic Risk Scores and Oral Contraceptive-Associated Ischemic Stroke Risk

“…We have previously shown that polygenic risk for deep venous thrombosis is associated with early-onset ischemic stroke at more significant level compared to later onset ischemic stroke, emphasizing that thromboembolic mechanisms likely play a more central role in early-onset ischemic stroke compared to later onset ischemic stroke. 6 Considering OC's impact on both venous and arterial thrombosis, adding a venous thrombosis polygenic risk into the model may further improve risk . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.…”

“…Study subjects were genotyped with the Illumina 1M array and imputed using the TOPMed reference panel on the University of Michigan Imputation Server, as previously described. 6…”

“…Study subjects were genotyped with the Illumina 1M array and imputed using the TOPMed reference panel on the University of Michigan Imputation Server, as previously described. 6 We used a previously validated genomic risk score (metaGRS) for ischemic stroke that is based on 19 polygenic risk scores for vascular events and cardiovascular risk factors and validated in nearly 400,000 subjects from the UK BioBank. 7 We first stratified our sample of GEOS women into tertiles of genomic risk based on their metaGRS scores and evaluated the association between OC use and ischemic stroke within each tertile.…”

Differential enzymatic deglycosylation reveals attachment of red cell B antigen onto the carbohydrate moiety of glycophorin A and glycophorin B

“…Besides supporting the anion transport function of band 3, GPA is decorated with sialic acids on its carbohydrate moiety, which are the main contributors of red cell negative charges (glycocalyx) that prevent agglutination during blood circulation. Although the red cell ABO antigen is functionally unclear, numerous reports continue to show its effects on individual health [3] (e.g., the risk associated with the early onset of ischaemic stroke [33]). The finding of ABO expression on glycophorin glycocalyx may open the door to potential roles of ABO antigen in red cell circulation.…”

Common Genetic Variants and Early Onset Stroke

“…In this issue of Neurology ® , Jaworek et al report a transethnic meta-analysis of 48 genome-wide association studies (GWASs) of ischemic stroke (IS). 3 The consortium analyzed approximately 17,000 IS cases, split between EOS (age 18-59 years) and late-onset stroke (LOS: age older than 60 years) and 25,000 nonstroke controls. The analyses uncovered novel and previously known associations between common genetic variants and EOS, including a strong association between EOS and serologically defined ABO blood groups (A, B, AB, and O).…”