Like most investigators in human complex disease genomics, we had limited data to allow us to narrow bounds on the search space. We quickly learned that optimistic assumptions of large genetic effect sizes for these disorders were incorrect. The initial GWAS for psychiatric disorders had sample sizes ~1,000 cases enabling excellent power to detect GRR ≥2.5. However, these effects were not found for schizophrenia (15), bipolar disorder (16), MDD (17), or attention-deficit hyperactivity disorder (ADHD) (18). Figure 1a also shows the 90% power curve for the most successful GWAS of any psychiatric disorder (37,000 schizophrenia cases) (19), and only two of 128 independent loci had GRR ≥1.2. Compellingly, we can now demonstrate that common genetic variants with GRR above ~1.24 for schizophrenia can be excluded with ~100% power.
