The most crucial issue in a case-control study is how to define cases and controls, and this is particularly so in psychiatric genetics. This is more difficult to define and measure than for most non-psychiatric disorders. Further, we have less knowledge of the causes and mechanisms of pathogenesis. Our current official classification systems, DSM and ICD, are descriptive systems that were developed to have clinical utility, acceptable reliability, but with no expectation that the categories represented valid entities with respect to etiology. Although these phenotype definitions are moderately to highly heritable and hence sensible starting points for genetic research, it is generally agreed that the most useful biological categories and/or dimensional definitions and measures are still unknown. The strikingly high level of co-occurrence of different diagnoses within the same individual (“co-morbidity”) almost certainly reflects a substantial overlap in the underlying biology of currently defined syndromes. This is further evidenced by family studies demonstrating shared familial liability across diagnostic boundaries (e.g., schizophrenia and bipolar disorder) (Lichtenstein et al., 2009). It is interesting to note that some of the strongest association signals to emerge from GWAS of schizophrenia and bipolar disorder show an overlap across traditional disorder categories (International Schizophrenia Consortium, 2009).
