Phenotype in Psychiatric Genetic Research

Mental illnesses differ from medical conditions in their lack of objectively assessable biological markers for the establishment of a diagnosis. In the absence of clear external validators such as laboratory tests or radiological examinations, accurate assessment of the clinical picture and phenomenology becomes crucial. Common diseases with successful genetic mapping studies are generally characterized by diagnostic assessments that are objective, have a clear biological basis, and measure phenotypic features shared relatively uniformly among affected individuals. For example, type 2 diabetes is diagnosed based on elevation in blood glucose above a generally accepted threshold, as assessed by a simple assay. This phenotypic feature is at the core of the diagnosis, even though other disease components may vary between affected individuals. For mental illness, however, no biological assays are currently available for diagnostic purposes; the phenotypic features are generally assessed by subjective ratings, and individuals are assigned a diagnosis based on report of symptoms, no one of which is present in all individuals assigned that diagnosis. There is now considerable interest in identifying quantitative assessments, which may provide a more objective means of rating psychopathology. Many researchers on psychiatric genetics have given attention to populations that are more genetically homogeneous due to historical reasons. These isolated populations have been useful for the identification of genes for disorders in other medical fields. In addition to the genetic homogeneity, these unique groups may also help in the definition of the phenotype. Particularly, psychiatric disorders with psychosis such as schizophrenia (SZ), schizoaffective disorder (SCA) and bipolar disorder type I with psychosis (BPI) are major public health burdens and their biology is still largely unknown. It is unlikely that these disorders represent a single illness, however they overlap on many dimensions, including symptoms, neurocognition, and treatment. Families of individuals with SZ very often have other members with BPI and SCA (Kendler et al., 2010). Many authors argue that modifying genes may determine why one person develops SZ and another develops BPI or SCA (Van Erp et al., 2002). Nevertheless, the question whether or not phenotype uncertainty is responsible of the presumed genetic overlap remains unanswered. The use of multiple sources of information in the diagnostic process is essential in genetic studies of mental illness. A best-estimation diagnostic approach ensures diagnostic precision and reduces misclassifications getting better phenotype characterization of the study subjects. Along with the clinical complexity and the assumed genetic heterogeneity, environmental factors play an important role in the final outcome of most psychiatric disorders. In this instance, stressful environmental factors have been clearly associated with