A key unknown was genetic architecture, particularly the sizes of the underlying genetic effects. A decade ago, these were unknown and subject to considerable speculation with hypotheses suggesting that genetic discovery for psychiatric disorders would be anywhere from highly tractable to impossible. If the genetic effects were few, common, and had large genetic effects, relatively modest sample sizes would be sufficient. A few early studies hinted that small samples might suffice (e.g., APOE on Alzheimer’s disease or CFH on age-related macular degeneration) (13, 14), and these may have led to expectations that gene discovery would be straight-forward.
