Endophenotypes, Dimensions, Risks: Is Psychosis Analogous to Common Inherited Medical Illnesses?

Psychiatric illnesses are perceived as fundamentally different from common medical disorders, a view arising from the mind-body problem and difficulties relating the brain's emergent properties to its physiological substrates. However, schizophrenia and many common medical illnesses are heritable and result from the influence of both genetic and environmental sources. Unlike illnesses such as Huntington's disease, which are caused by a fully penetrant dominant mutation, no single “schizophrenia gene” has been identified. Instead, schizophrenia is likely caused by common variants of many genes, each contributing a subtle effect. Schizophrenia genetically resembles common medical illnesses such as type 2 diabetes, ischemic heart disease, and familial hypercholesterolemia, that have an associated genetic variant, but that are also influenced by other factors such as diet, culture and habits. Just as these illnesses operate through complex gene/environment interaction, schizophrenia is likely caused by several gene variants, neurodevelopmental processes, and learned behavioral response biases. These clinical diseases, however, represent severe forms of the phenotype for both psychiatric and medical illnesses. From a dimensional perspective, individuals possessing the same genotype could express milder forms of the clinical disorder along a spectrum of related traits. We discuss this perspective in the context of an endophenotypic and biological marker approach to understanding schizophrenia and present a research strategy to compare schizophrenia endophenotypes to risk for common medical illnesses.