Abstract
Introduction:
Genetic studies of early-onset disease have been an effective strategy to identify novel pathways and drug targets relevant to later-onset disease. Few studies have investigated the role of common genetic variation in the etiology of early-onset ischemic stroke (IS).
Methods:
We performed a GWAS meta-analysis of 38 studies from 10 countries, comprised of 5,847 IS cases of European ancestry under age 60 and 32,533 controls.
Results:
We identified two genome-wide significant (p< 5 x 10
-8
) loci (see Figure). The
ABO
locus has previously been associated with venous thrombosis and ischemic stroke in predominantly older adults, but the effect size of our top SNP (OR 1.18; p = 9.1 x 10
-12
) is larger than the effect size for this same SNP in MEGASTROKE (OR: 1.05; p = 6.5 x 10
-5
). The lead SNP at the
BCL7A/MLXIP
locus is a novel GWAS finding for stroke (OR 1.14, 95% CI 1.08-1.19; p = 1.7 x 10
-8
) and is noteworthy because of prior reports linking SNPs in these genes to BMI and blood pressure.
Conclusions:
We identified a novel locus that is near variants associated with BMI and blood pressure. Further studies are needed to confirm this locus, examine subtype specificity, and determine its function. The larger effect size observed at the ABO in this early-onset IS sample compared to older-onset IS samples is consistent with a larger role for prothrombotic mechanisms in early-onset IS.