Endophenotypes in Psychopathology Research: Where Do We Stand?

Abstract

Endophenotypes for psychopathology have been conceived as latent, unobserved, but measureable manifestations of phenomena that causally connect genetic liability to clinical disorder. Several decades of research have led to refinement of the construct and identification of some candidate endophenotypes, but rather limited progress on finding the genes involved or the mechanisms by which endophenotypes are driven by genetic and environmental factors and in turn drive psychopathology. Currently promising avenues for research involve development of transdiagnostic concepts not limited to traditional diagnostic categories, measures of endophenotypic and manifest psychopathology that have higher validity than those categories, and methods for modeling complex relationships among diverse contributors to etiology. With more grounding in animal neuroscience and other aspects of basic biological and psychological science, exemplified in the Research Domain Criteria initiative, there is every reason to anticipate that the endophenotype concept will grow more central in the psychopathology literature.

Overactive Performance Monitoring as an Endophenotype for Obsessive-Compulsive Disorder: Evidence From a Treatment Study

“…In general, evidence identifying specific genes or mechanisms by which endophenotypes drive psychopathology has been limited (46). However, one major gain from endophenotype research may be the development of transdiagnostic concepts that are not limited to categorical diagnoses (46) as proposed in the Research Domain Criteria (38). Furthermore, the identification of endophenotypes enhances our understanding of the complex psychiatric disorders and can enable the early detection of individuals at Am J Psychiatry 172:7, July 2015 ajp.psychiatryonline.org 671 risk and inspire research on new treatment strategies and targets.…”

The Research Domain Criteria (RDoC): An analysis of methodological and conceptual challenges

“…Moreover, because many endophenotypes cut across traditional disorder categories, these phenotypes accord well with RDoC's transdiagnostic approach and emphasis on identifying etiological processes that underlie multiple DSM conditions (Miller & Rockstroh, 2013).…”

“…The hope is that compared with exophenotypes, endophenotypes are closer to the gene end of the lengthy and circuitous gene-behavior pathway, and should therefore yield more fruitful clues regarding the correlates and causes of psychopathology (Kendler & Neale, 2010;Miller & Rockstroh, 2013). In the words of Gottesman and Gould (2003), endophenotypes hold out the promise of "simpler clues to genetic underpinnings than the disease itself" (p. 636).…”

“…Despite high initial expectations and provisional successes for certain conditions, such as schizophrenia (see Cannon & Keller, 2006;Miller & Rockstroh, 2013, for reviews), the promise offered by endophenotypes has often proven difficult to realize. In particular, it is not evident that the endophenotypes identified to date are necessarily more genetically informative than are traditional exophenotypes.…”

A review of selected candidate endophenotypes for depression

“…In light of the complicated genetics underlying psychological disorders, endophenotypes, constructs that dot the pathway between genes and clinical phenotypes, have been proposed as a strategy to study pathology and discover susceptibility genes (Cannon & Keller, 2006; Gottesman & Gould, 2003; Miller & Rockstroh, 2013). Gottesman and Gould (2003) hypothesized that endophenotypes can be used to parse the genetics of a given disorder into smaller, more tractable, components.…”