the discovery sample, which is likely an overestimation.28 The definition of infarcts may also have differed across discovery and replication cohorts, especially concerning the discrimination of infarcts from enlarged perivascular spaces. Furthermore, identified SNPs may not be the causal variants but merely markers in linkage disequilibrium with causal variants. Substantial differences in linkage patterns between whites and African-Americans could result in different markers being in linkage disequilibrium with the causal variant in the 2 populations. Interestingly, 4 SNPs located in the same locus as rs2208454 were associated with MRI-infarcts in the African-American sample. Although these exploratory results do not provide direct replication, as these SNPs were in weak LD with rs2208454, they suggest that the locus may be worthy of further exploration. If replication can be obtained in the future, including in African Americans samples, the latter could perhaps help refine the signal and prove useful for the identification of a causal variant. Finally, even though the studies included in the meta-analysis are population-based, the samples are not perfectly representative of the total cohort, as they include subsets of individuals who were able to undergo brain MRI and agreed to do so.
