on behalf GeneStroke Consortium and International Stroke Genetics Consortium.
The genetic architecture of cardioembolic stroke (CES) is still poorly understood. Atrial fibrillation (AF) is the main cause of CES, with which it shares heritability. We aimed to discover novel loci associated with CES by performing a Multitrait Analysis of the GWAS (MTAG) with atrial fibrillation genetic data.
For the MTAG analysis we used the MEGASTROKE cohort, which comprises European patients with CES and controls (n=362,661) and an AF cohort composed of 1,030,836 subjects. Regional genetic pleiotropy of the significant results was explored using an alternative Bayesian approach, GWAS-pairwise method. As replication we performed Genome Wide Association Studies (GWAS) for CES and AF in an independent cohort comprising 9,128 subjects.
MTAG analysis revealed 40 novel and significant loci (p-value<5x10-8) associated with CES, four of which had not previously been associated with AF. Interestingly, 51 AF risk loci were not associated with CES. Gene Ontology (GO) analysis revealed that these exclusive AF genes from the 51 loci participate in processes related mainly to cardiac development, whereas genes associated with AF and CES participate mainly in muscle contraction and the conduction of electrical impulses. A significant replication was assessed for five novel loci showing a p-value<0.05 in the CES vs controls analysis, being one of them a locus not previously described associated to AF.
This study expands the number of loci associated with CES, replicates five of them and provides novel insights into the pathogenesis of CES, highlighting multiple candidate genes for use in future functional experiments.
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