The Strategy and Utility of the Endophenotype Approach to Neurobehavioral Function

Abstract

The current lack of understanding as to the root causes of psychiatric illnesses hinders improvements in prevention, diagnosis, and treatment. While certainly influenced by environmental factors, there is ample evidence for a genetic component to a wide variety of mental disorders, as well as normal cognitive traits. Heritability estimates, a measure of the proportion of variation in a trait attributable to genetic variation, display a broad range for many disorders depending on the methodology and population used for calculation but may be as high as 90% for autism-spectrum disorders. For more than twenty years, increased genetic liability (i.e., cumulative risk factors) in combination with environmental triggers has been recognized as the best-fitting model for most psychiatric disorders. From a diagnostic perspective, clinicians are interested predominantly in the end product of disease genetic and environmental interactions and whether the manifestation is significant enough to require treatment. In contrast, the geneticist is focused on understanding only what factors increase the genetic liability, regardless of the distal disease phenotype, because the alleles influencing genetic liability, not the environmental triggers, are heritable. In practice, however, symptoms are frequently the only recorded manifestation of liability. This illustrates why a dichotomous (i.e., affected/unaffected) diagnostic approach may be appropriate for determining the need for treatment, but insufficient for describing disease liability in genetic research. The endophenotype approach provides a means for identifying traits that are correlated with disease liability such that they can be used to improve understanding of the biological, pathological, and etiological underpinnings of disease. In addition to operationalizing studies based on a liability-threshold model of disease, the use of endophenotypes, particularly in genetic research, increases power to identify causative factors. The following discussion of the shortcomings of existing research methods and the advantages of an endophenotype approach will illustrate the utility of the latter for parsing genetic liability for neurobehavioral traits. (PsycINFO Database Record (c) 2019 APA, all rights reserved)