Of the 19 loci identified in our discovery GWAS, only 11 were genome-wide significant in meta-analysis of our GWAS and follow-up samples. These results are not unexpected given small effect sizes, the winner’s curse 28,57 (Supplementary Note and Supplementary Figure 4); SNPs can teeter-totter around the genome-wide significance threshold even as sample sizes increase. Genetic heterogeneity observed among BD GWAS cohorts8 could also contribute to inconsistent replication results; we observed variable polygenic effects between BD subtypes (Figure 2, Supplementary Table 13) as well as between cohorts in our study (Supplementary Figure 2, Supplementary Table 4) which used a diversity of criteria to define cases (Supplementary Note). Remarkably, the strongest association signal from the discovery GWAS, at the TRANK1 locus (rs9834970; pcombined = 5.7E-12, OR = 0.93), exhibited significant heterogeneity among discovery GWAS cohorts (Cochran’s Q p = 1.9×10−4), and did not replicate in the follow-up sample (1-tailed pfollowup = 0.3) (Supplementary Data 2 & 3). This locus has been significant in recent 11,12,17,18 but not earlier BD GWAS 9,13,20. Thus, complex genetic architecture as well as phenotypic heterogeneity may contribute
