There are many important caveats, some of which we note here: Some disorders might not be amenable to GWAS, e.g., if all risk alleles have very low GRRs; or if genetic risks are conferred by multiple rare SNPs or by CNVs too small to be detected reliably. Discoveries for these disorders might only be possible with larger-scale resequencing studies.Current diagnostic categories might be inadequate. Endophenotypic variables (neuroimaging, electrophysiological, neuropsychological, biochemical or other markers) might better index the underlying gene effects (73), although none has yet proven more heritable than diagnostic categories. These measures are not usually available in large datasets.Genetic heterogeneity reduces power. Low frequency alleles are examples of heterogeneity (i.e., most cases do not share that risk factor). Power (Figure 1) is best for frequencies above around 20%, and poor at much below 10% unless GRR is high. Heterogeneity might be increased in large multicenter samples; e.g., despite the generally high inter-rater reliability for these disorders, research groups can have diagnostic “biases”, some of which could correlate with specific risk alleles. But power increases with sample size despite some
