Selection of control groups is critical, beyond the problem of ancestral matching. It is ideal to recruit cases and controls systematically from the same population. This is not always feasible for very large samples of a clinically severe disorder, but controls must be sufficiently comparable to cases to avoid systematic biases. Depending on the phenotype, it might be important to match for such variables as age (e.g., for an Alzheimer’s study) or sex. Information about known gene-environment interactions should be considered, e.g., in studies of substance dependence, controls are usually selected who have used the substance but did not become dependent. When the phenotype is relatively uncommon (e.g., 5% prevalence), little power is lost by studying controls without clinical screening, but for more common disorders, power is increased if ill individuals are excluded from the control group. (40) It is reassuring that in the UK Wellcome Trust Case Control Consortium (WTCCC) GWAS of seven common diseases, robust results were obtained when association was tested using control groups recruited from blood donors or from a population-based birth cohort.
