The search for intermediate phenotypes is best conducted in specific populations that carry risk genes for the disorder without confounding factors related to the state of the disease (e.g. treatment, smoking, etc). Unaffected relatives of patients with psychiatric disorders, ideally healthy cotwins or siblings, fulfill both criteria: they are enriched in risk genes and are healthy. Many aspects of human brain function, behavior and physiology have been studied in such populations with evidence that a variety of such measures are heritable and enriched in relatives [13]. Phenotype studies of relatives of patients with schizophrenia, however, have potentially serious methodological problems which should be appreciated. Relatives may share environmental or behavioral characteristics (e.g. drug or tobacco use, temperament) that can impact on measures of brain function. Moreover, comparisons of relatives across generations are especially problematic because they involve age and life experience factors that are difficult to control.
