Endophenotype is a genetic epidemiology term which is used to separate behavioral symptoms into more stable phenotypes with a clear genetic connection. 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".
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. It is therefore more applicable to more heritable disorders, such as bipolar disorder and schizophrenia. Since then, the concept has expanded to many other fields, such as the study of ADHD, addiction, Alzheimer's disease, obesity and cystic fibrosis. 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". The strength of an endophenotype is its ability to differentiate between potential diagnoses that present with similar symptoms.
- An endophenotype must segregate with illness in the population.
- An endophenotype must be heritable.
- An endophenotype must not be state-dependent (i.e., manifests whether illness is active or in remission).
- An endophenotype must co-segregate with illness within families.
- An endophenotype must be present at a higher rate within affected families than in the population.
- An endophenotype must be amenable to reliable measurement, and be specific to the illness of interest.
In the case of schizophrenia, the overt symptom could be a psychosis, but the underlying phenotypes are, for example, a lack of sensory gating and a decline in working memory. Both of these traits have a clear genetic component and can thus be called endophenotypes. A strong candidate for schizophrenia endophenotype is prepulse inhibition, the ability to inhibit the reaction to startling stimuli.
Endophenotypes are quantitative, trait-like deficits that are typically assessed by laboratory-based methods rather than by clinical observation.
The four primary criteria for an endophenotype are that it is present in probands with the disorder, that it is not state-related (that is, it does not occur only during clinical episodes) but instead is present early in the disease course and during periods of remission, that it is observed in unaffected family members at a higher rate than in the general population, and that it is heritable.
Some distinct genes that could underlie certain endophenotypic traits in schizophrenia include:
- RELN – coding the reelin protein downregulated in patients' brains. In one 2008 study its variants were associated with performance in verbal and visual working memory tests in the nuclear families of the sufferers.
- FABP7, coding the Fatty acid-binding protein 7 (brain), one SNP of which was associated with schizophrenia in one 2008 study, is also linked to prepulse inhibition in mice. It is still uncertain though whether the finding will be replicated for human patients.
- CHRNA7, coding the neuronal nicotinic acetylcholine receptor alpha7 subunit. alpha7-containing receptors are known to improve prepulse inhibition, pre-attentive and attentive states.
For bipolar disorder
In bipolar disorder, one commonly identified endophenotype is a deficit in face emotion labeling, which is found in both individuals with bipolar disorder and in individuals who are "at risk" (i.e., have a first degree relative with bipolar disorder). Using fMRI, this endophenotype has been linked to dysfunction in the dorsolateral and ventrolateral prefrontal cortex, anterior cingulate cortex, striatum, and amygdala. A polymorphism in the CACNA1C gene coding for the voltage-dependent calcium channel Cav1.2 has been found to be associated with deficits in facial emotion recognition.
The endophenotype concept has also been used in suicide studies. Personality characteristics can be viewed as endophenotypes that may exert a diathesis effect on an individual's susceptibility to suicidal behavior. Although the exact identification of these endophenotypes is controversial, certain traits such as impulsivity and aggression are commonly cited risk factors. One such genetic basis for one of these at-risk endophenotypes has been suggested in 2007 to be the gene coding for the serotonin receptor 5-HT1B, known to be relevant in aggressive behaviors.
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