In view of these observations, it can be expected that a range of approaches to the clinical phenotype may be required in order to maximize the potential from molecular genetic studies. This includes analyses across the traditional illness categories (“lumping”) and analyses of clinically-meaningful subsets within a category or set of categories (“splitting”). It is also possible to use approaches that are not based on any specific prior model of the clinical phenotype and to seek clinical entities (whether they are categories or dimensions) that would “make more sense” from a genetic perspective. For example, for a highly significant and consistently replicated genetic association, cases with and without the genetic variant can be investigated to attempt to identify the phenotypic consequences of the variant – do cases with the variant have earlier onset, more severe symptoms, worse response to treatment, or alter brain structure or function? This is also know as “reverse phenotyping” or “phenotype refinement”. Another analytic possibility, which will be particularly valuable if there is a high degree of polygenicity (i.e., hundreds or thousands of susceptibility alleles of
