Endophenotypes in Studies of the Genetics of Schizophrenia

The power and appeal of the molecular biology mantra, ‘‘DNA to RNA to protein,’’ to explicate cell biology comes from its universal appearance and application in all species, from microorganisms to human beings. Based on this mantra, the genomes of viruses, bacteria, fruit flies, and now humans are being mapped and sequenced, so that all the genes and, ultimately, their corresponding biological activity can be identified. As these genes are identified, it is reasonable to ask how this information can be related to the inheritance of risk for psychiatric illness. For a bacterial enzyme, genetic coding of the amino acid sequence of proteins can be closely associated with a functional change in enzymatic activity. For a complex psychiatric illness, as defined by DSM-IV criteria, the relationship is obviously not as straightforward. Psychiatric illnesses such as schizophrenia are generally conceptualized as multifactorial and most likely reflect the combined influence and interactions of both genetic and nongenetic factors. Furthermore, there is no reason to presuppose that only one gene is responsible for a complex psychiatric disorder such as schizophrenia, as there is in some simple mendelian illnesses. Persons who are ill may differ in more than one gene from the rest of the population, and different sets of genes may be associated with illness in different populations. Thus, how best to use the power of molecular genetics to understand the inheritance and pathophysiology of complex genetic psychiatric illnesses remains an enigma that is only now beginning to be solved. In the simplest and most commonly used strategy of molecular genetics that is applied to complex psychiatric disorders, it is assumed that the distribution of illness in a family represents the effect of a single gene, and techniques of genetic analysis are used to identify that gene. This approach does not necessarily overlook the complexity of psy-