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Background: Ischemic stroke is a heterogeneous trait and its genetic architecture is poorly understood. The genetic contribution may be stronger for stroke occurring at younger (vs. older) ages. To identify additional stroke susceptibility variants, we genotyped participants in the Genetics of Early Onset Stroke (GEOS) with the exome array and conducted association analyses with the goal of identifying functional risk variants by interrogating the protein-coding portion of genes.Methods: The GEOS Study was initiated as a biracial population-based study of cases with first-ever ischemic stroke 15 to 49 years of age (n=828) and matched controls (n=850). All participants underwent exome-chip genotyping. Logistic regression was used to calculate associations in European-Caucasians (EUR) and African-Americans (AA), and summary results were combined by meta-analysis.Results: Our analyses revealed four highly associated variants for all-stroke and several others that were stroke subtype specific. Among these for all-stroke, we identified a missense variant in VWDE (rs6460939 (K (AAG) --> N (AAC)), which encodes the Von Willebrand Factor D and EGF domain-containing protein. This protein plays a role in intracellular calcium ion binding within a variety of cell-types. The association was present in both European-Caucasians (OR = 1.34, p = 0.002) and African-Americans (OR = 1.32, p = 0.01), and was strengthened in a meta-analysis of both ethnic groups (OR = 1.41, p = 8.95 х 10-6). The frequency of the effect C allele was 0.46 in EUR and 0.55 in AA. Efforts in additional data sets to further replicate this association, and the others identified, are ongoing.Conclusion: Exome-based analyses in the setting of young-onset stroke is a productive methodology to identify genetic risk variants.