Interpretation of the PCLO replication efforts is consistent with two broad possibilities. The first possibility is that genetic variation in PCLO is truly not associated with MDD. This interpretation is supported by the replication analyses (specified a priori) in which no SNP was significantly associated after correction for multiple comparisons and SNP dependence due to LD. This strict interpretation is generally viewed as “best practice” in human genetics (21) but implicitly assumes etiological homogeneity for MDD in the PCLO region. The second possibility invokes a less parsimonious model involving heterogeneity, that genetic variation in PCLO is etiologically causal to some subtypes of MDD. This interpretation is an a posteriori hypothesis consistent with the empirical results particularly in the notable differences in associations between samples, case ascertainment strategies, and indications from principal components analysis that NESDA and QIMR cases are more similar than the clinically ascertained subjects. It is notable that the control samples from each site were considerably more similar than cases from the same sites.
