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Abstract
Objective: To investigate the influence of common and low-frequency genetic variants on the risk of ischemic stroke (all IS) and etiologic stroke subtypes.
Methods: We meta-analyzed 12 individual genome-wide association studies comprising 10,307 cases and 19,326 controls imputed to the 1000 Genomes (1 KG) phase I reference panel. We selected variants showing the highest degree of association (p < 1E-5) in the discovery phase for replication in Caucasian (13,435 cases and 29,269 controls) and South Asian (2,385 cases and 5,193 controls) samples followed by a transethnic meta-analysis. We further investigated the p value distribution for different bins of allele frequencies for all IS and stroke subtypes.
Results: We showed genome-wide significance for 4 loci: ABO for all IS, HDAC9 for large vessel disease (LVD), and both PITX2 and ZFHX3 for cardioembolic stroke (CE). We further refined the association peaks for ABO and PITX2. Analyzing different allele frequency bins, we showed significant enrichment in low-frequency variants (allele frequency <5%) for both LVD and small vessel disease, and an enrichment of higher frequency variants (allele frequency 10% and 30%) for CE (all p < 1E-5).
Conclusions: Our findings suggest that the missing heritability in IS subtypes can in part be attributed to low-frequency and rare variants. Larger sample sizes are needed to identify the variants associated with all IS and stroke subtypes.
GLOSSARY
- AF=
- atrial fibrillation;
- CADISP=
- Cervical Artery Dissection and Ischemic Stroke Patients;
- CE=
- cardioembolic stroke;
- FDR=
- false discovery rate;
- GWAS=
- genome-wide association studies;
- IS=
- ischemic stroke;
- LD=
- linkage disequilibrium;
- LVD=
- large vessel disease;
- MAF=
- minor allele frequency;
- MAGENTA=
- Meta-Analysis Gene-set Enrichment of Variant Associations;
- NINDS-SiGN=
- National Institute of Neurological Disorders and Stroke–Stroke Genetics Network;
- NK=
- natural killer;
- NO=
- nitric oxide;
- RACE=
- Risk Assessment of Cardiovascular Events;
- SNP=
- single nucleotide polymorphism;
- SVD=
- small vessel disease;
- TOAST=
- Trial of Org 10172 in Acute Stroke Treatment
Footnotes
↵* These authors contributed equally to this work.
Authors' affiliations are listed at the end of the article.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Supplemental data at Neurology.org
- Received July 28, 2015.
- Accepted in final form December 14, 2015.
- © 2016 American Academy of Neurology
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