Endophenotype

In genetic epidemiology, endophenotype (or intermediate phenotype^[1]) is a term used to separate behavioral symptoms into more stable phenotypes with a clear genetic connection. By seeing the EP notion as a special case of a larger collection of multivariate genetic models, which may be fitted using currently accessible methodology, it is possible to maximize its valuable potential lessons for etiological study in psychiatric disorders.^[2] The concept was coined by Bernard John and Kenneth R. Lewis in a 1966 paper attempting to explain the geographic distribution of grasshoppers. They claimed that the particular geographic distribution could not be explained by the obvious and external "exophenotype" of the grasshoppers, but instead must be explained by their microscopic and internal "endophenotype".^[3] The endophenotype idea represents the influence of two important conceptual currents in biology and psychology research. An adequate technology would be required to perceive the endophenotype, which represents an unobservable latent entity that cannot be directly observed with the unaided naked eye. In the investigation of anxiety and affective disorders, the endophenotype idea has gained popularity.^[4]

The next major use of the term was in psychiatric genetics, to bridge the gap between high-level symptom presentation and low-level genetic variability, such as single nucleotide polymorphisms.^[5] It is therefore more applicable to more heritable disorders, such as bipolar disorder and schizophrenia.^[6] Through their impact on the growth and operation of the vital components of the nervous system, such as neurons, transmitter systems, and neural networks, genes have an impact on complex behavior. Therefore, heritable differences in mental abilities may be caused by changes in the code describing the shape and operation of the underlying neural network. One significant expression of this idea is believed to be the many cognitive deficiencies seen in ADHD, making them ideal candidates for an endophenotype approach.^[7] Since then, the concept has expanded to many other fields, such as the study of ADHD,^[8] addiction,^[9] Alzheimer's disease,^[10] obesity^[11] and cystic fibrosis.^[12] Some other terms which have a similar meaning but do not stress the genetic connection as highly are "intermediate phenotype", "biological marker", "subclinical trait", "vulnerability marker", and "cognitive marker".^[13][14] The strength of an endophenotype is its ability to differentiate between potential diagnoses that present with similar symptoms.^[15]