Our inability to replicate any of the novel associations we identified in the discovery phase could be explained by various factors. All non-imputed SNPs in all cohorts were checked for Hardy-Weinberg equilibrium and standard quality control measures were done, including checking for sex mismatch on the basis of three genotypic markers, but we cannot rule out confounding by other means. For example, many of the 12 replication cohorts only directly genotyped the 12 replication SNPs. First, this type of analysis provides no means of adjustment for ancestry-informative principal components, which could lead to results being adversely affected by population structure. Second, our strategy of attempting replication with one SNP from each region might not have been optimum. In regions such as the 12q24 locus, where the linkage disequilibrium patterns are complex, attempting replication in multiple SNPs might have proved more 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
