Investigation of the sources of heterogeneity in the replication samples indicated that controls were genetically similar to the original sample in the PCLO region but that cases were dissimilar. We observed, a posteriori, that both principal components derived from PCLO region genotypes in QIMR cases and effect size estimates in the QIMR replication sample tended to be similar to the original sample. This is notable because, of all the replication samples, ascertainment of QIMR subjects was most similar to the primary NESDA/NTR sample in that cases were identified from population-based sources (100% for QIMR and 60% for NESDA) rather than tertiary sources as for the other replication samples. MDD cases from clinical samples may differ from population-based cases due to selection bias (93), Berkson's bias (94, 95), differing referral filters (96), or even a different genetic basis (97) with respect to genetic variation in the PCLO region.
