fruitful. Furthermore, one SNP (rs13407662) associated with small-vessel disease in the discovery phase failed genotyping in more than half of the replication cohorts. Genotyping multiple SNPs at this locus might have avoided this issue. We also cannot rule out confounding because of other environmental factors or phenotypic heterogeneity. Although phenotyping was done using the TOAST classification system, interpretation of exact classification criteria and definitions can differ across countries and studies, which becomes more of an issue when there are many smaller cohorts, such as in the replication phase of this study. Varying cohort study designs might also increase heterogeneity in large-scale meta-analyses.
