Endophenotype

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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]

Contents

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]

Definition

In psychiatry research, the accepted criteria which a biomarker must fulfill to be called an endophenotype include: [5] [16] [17]

  1. An endophenotype must segregate with illness in the population.
  2. An endophenotype must be heritable.
  3. An endophenotype must not be state-dependent (i.e., manifests whether illness is active or in remission).
  4. An endophenotype must co-segregate with illness within families.
  5. An endophenotype must be present at a higher rate within affected families than in the population.
  6. An endophenotype must be amenable to reliable measurement, and be specific to the illness of interest.

For schizophrenia

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. [5] A strong candidate for schizophrenia endophenotype is prepulse inhibition, the ability to inhibit the reaction to startling stimuli. [18] However, several other task-related candidate endophenotypes have been proposed for schizophrenia, [19] and even resting measures extracted from EEG, such as, power of frequency bands [20] and EEG microstates. [21]

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. [22] The behavioral syndrome of schizophrenia is no longer thought to be a singular disease with a single underlying cause, as is once again becoming clear. Instead, it could have a number of different etiologies, and the symptoms could have many different origins. Such heterogeneity may explain some of the challenges in determining the genetics of schizophrenia and may also account for the clinical observations of schizophrenia treatment response variability. [23]

Some distinct genes that could underlie certain endophenotypic traits in schizophrenia include:

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). [15] Using fMRI, this endophenotype has been linked to dysfunction in the dorsolateral and ventrolateral prefrontal cortex, anterior cingulate cortex, striatum, and amygdala. [27] 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. [28]

For suicide

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. [29] 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-HT 1B, known to be relevant in aggressive behaviors. [30]

See also

Related Research Articles

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Schizophrenia is a mental disorder characterized by reoccurring episodes of psychosis that are correlated with a general misperception of reality. Other common signs include hallucinations, delusions, disorganized thinking, social withdrawal, and flat affect. Symptoms develop gradually and typically begin during young adulthood and are never resolved. There is no objective diagnostic test; diagnosis is based on observed behavior, a psychiatric history that includes the person's reported experiences, and reports of others familiar with the person. For a diagnosis of schizophrenia, the described symptoms need to have been present for at least six months or one month. Many people with schizophrenia have other mental disorders, especially substance use disorders, depressive disorders, anxiety disorders, and obsessive–compulsive disorder.

<span class="mw-page-title-main">Causes of mental disorders</span> Etiology of psychopathology

A mental disorder is an impairment of the mind disrupting normal thinking, feeling, mood, behavior, or social interactions, and accompanied by significant distress or dysfunction. The causes of mental disorders are very complex and vary depending on the particular disorder and the individual. Although the causes of most mental disorders are not fully understood, researchers have identified a variety of biological, psychological, and environmental factors that can contribute to the development or progression of mental disorders. Most mental disorders result in a combination of several different factors rather than just a single factor.

<span class="mw-page-title-main">Anhedonia</span> Inability to feel pleasure

Anhedonia is a diverse array of deficits in hedonic function, including reduced motivation or ability to experience pleasure. While earlier definitions emphasized the inability to experience pleasure, anhedonia is currently used by researchers to refer to reduced motivation, reduced anticipatory pleasure (wanting), reduced consummatory pleasure (liking), and deficits in reinforcement learning. In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), anhedonia is a component of depressive disorders, substance-related disorders, psychotic disorders, and personality disorders, where it is defined by either a reduced ability to experience pleasure, or a diminished interest in engaging in previously pleasurable activities. While the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) does not explicitly mention anhedonia, the depressive symptom analogous to anhedonia as described in the DSM-5 is a loss of interest or pleasure.

<span class="mw-page-title-main">Mood swing</span> Extreme or rapid change in mood

A mood swing is an extreme or sudden change of mood. Such changes can play a positive part in promoting problem solving and in producing flexible forward planning, or be disruptive. When mood swings are severe, they may be categorized as part of a mental illness, such as bipolar disorder, where erratic and disruptive mood swings are a defining feature.

Schizotypal personality disorder, also known as schizotypal disorder, is a cluster A personality disorder. The Diagnostic and Statistical Manual of Mental Disorders (DSM) classification describes the disorder specifically as a personality disorder characterized by thought disorder, paranoia, a characteristic form of social anxiety, derealization, transient psychosis, and unconventional beliefs. People with this disorder feel pronounced discomfort in forming and maintaining social connections with other people, primarily due to the belief that other people harbor negative thoughts and views about them. Peculiar speech mannerisms and socially unexpected modes of dress are also characteristic. Schizotypal people may react oddly in conversations, not respond, or talk to themselves. They frequently interpret situations as being strange or having unusual meanings for them; paranormal and superstitious beliefs are common. Schizotypal people usually disagree with the suggestion that their thoughts and behaviors are a 'disorder' and seek medical attention for depression or anxiety instead. Schizotypal personality disorder occurs in approximately 3% of the general population and is more commonly diagnosed in males.

<span class="mw-page-title-main">Heritability of autism</span>

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Peter McGuffin was a Northern Irish psychiatrist and geneticist from Belfast.

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Behavioural genetics, also referred to as behaviour genetics, is a field of scientific research that uses genetic methods to investigate the nature and origins of individual differences in behaviour. While the name "behavioural genetics" connotes a focus on genetic influences, the field broadly investigates the extent to which genetic and environmental factors influence individual differences, and the development of research designs that can remove the confounding of genes and environment. Behavioural genetics was founded as a scientific discipline by Francis Galton in the late 19th century, only to be discredited through association with eugenics movements before and during World War II. In the latter half of the 20th century, the field saw renewed prominence with research on inheritance of behaviour and mental illness in humans, as well as research on genetically informative model organisms through selective breeding and crosses. In the late 20th and early 21st centuries, technological advances in molecular genetics made it possible to measure and modify the genome directly. This led to major advances in model organism research and in human studies, leading to new scientific discoveries.

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References

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