However, we observed, a posteriori, that there was potentially important heterogeneity in the replication samples for eight SNPs that were strongly associated in the original sample (I2≥0.4, ninth column in Table 4a). In investigating this further (Supplemental Methods), we determined that there was little evidence for genetic heterogeneity in the genotyped region for controls but, unexpectedly, there was significant heterogeneity in the cases. Principal components analysis and inspection of Table 4a and the forest plots in Figure 3 indicated that the outlier was the Australian QIMR sample. Notably, the original and QIMR samples were particularly similar in that both studies included population-based cases and controls were selected to be at low liability for MDD based on longitudinal assessments. Of the nine SNPs with p<0.05 in the QIMR sample, eight had both low p-values and Z-scores with the same sign as in the NESDA/NTR sample. As an exploratory analysis, we analyzed the original and QIMR samples jointly, and the minimum p-value was 6.4×10−8 at the non-synonymous SNP rs2522833 that gives rise to a serine to alanine substitution near the C2A calcium-binding-domain of the PCLO protein.
