While intermediate phenotypes have many advantages, a major limitation is that replication samples are seldom available. We were unable to identify any suitable replication dataset for the association between the SNP (rs3784943) in CDH13 and positive subjective response. Replication of this result was challenging because a suitable study would have included administration of a stimulant drug, under similar conditions and corresponding dosage, and would have had to collect the same or related measurements of subjective response. In addition, the associated SNP had a fairly low minor allele frequency and only a moderate effect on the phenotype, so a relatively large dataset would be needed to have sufficient power for replication. Alternatively, our results can be viewed as replicating prior associations with CDH13, however the lack of convergence on a single SNP or haplotype across studies is a cause for concern. Because of these limitations, the results from Cdh13 knockout mice and other biologically based studies of CDH13 function may be the best route for further investigation and replication of our results.
