Biology: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]

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:

  • 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 patients.[24]
  • FABP7, coding the Fatty acid-binding protein 7 (brain), one SNP of which was associated with schizophrenia in one 2008 study,[25] is also linked to prepulse inhibition in mice.[25] 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.[26]

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-HT1B, known to be relevant in aggressive behaviors.[30]

See also

References

  1. ↑ Preston, Gilbert A.; Weinberger, Daniel R. (June 2005). "Intermediate phenotypes in schizophrenia: a selective review". Dialogues in Clinical Neuroscience 7 (2): 165–179. doi:10.31887/DCNS.2005.7.2/gpreston. ISSN 1294-8322. PMID 16262211. 
  2. ↑ Kendler, K S; Neale, M C (2010-08-15). "Endophenotype: a conceptual analysis" (in en). Molecular Psychiatry 15 (8): 789–797. doi:10.1038/mp.2010.8. ISSN 1359-4184. PMID 20142819. 
  3. ↑ "Chromosome variability and geographic distribution in insects". Science 152 (3723): 711–21. May 1966. doi:10.1126/science.152.3723.711. PMID 17797432. Bibcode: 1966Sci...152..711J. 
  4. ↑ Lenzenweger, Mark F. (2013-03-06). "ENDOPHENOTYPE, INTERMEDIATE PHENOTYPE, BIOMARKER: DEFINITIONS, CONCEPT COMPARISONS, CLARIFICATIONS: The Cutting Edge: Endophenotype, Intermediate Phenotype, and Biomarker" (in en). Depression and Anxiety 30 (3): 185–189. doi:10.1002/da.22042. PMID 23325718. 
  5. ↑ 5.0 5.1 5.2 "The endophenotype concept in psychiatry: etymology and strategic intentions". The American Journal of Psychiatry 160 (4): 636–45. April 2003. doi:10.1176/appi.ajp.160.4.636. PMID 12668349. 
  6. ↑ "Initial heritability analyses of endophenotypic measures for schizophrenia: the consortium on the genetics of schizophrenia". Archives of General Psychiatry 64 (11): 1242–50. November 2007. doi:10.1001/archpsyc.64.11.1242. PMID 17984393. 
  7. ↑ Goos, Lisa M.; Crosbie, Jennifer; Payne, Shalaine; Schachar, Russell (2009-06-01). "Validation and Extension of the Endophenotype Model in ADHD Patterns of Inheritance in a Family Study of Inhibitory Control" (in en). American Journal of Psychiatry 166 (6): 711–717. doi:10.1176/appi.ajp.2009.08040621. ISSN 0002-953X. PMID 19448185. http://psychiatryonline.org/doi/abs/10.1176/appi.ajp.2009.08040621. 
  8. ↑ "Competing core processes in attention-deficit/hyperactivity disorder (ADHD): do working memory deficiencies underlie behavioral inhibition deficits?". Journal of Abnormal Child Psychology 38 (4): 497–507. May 2010. doi:10.1007/s10802-010-9387-0. PMID 20140491. 
  9. ↑ "Abnormal brain structure implicated in stimulant drug addiction". Science 335 (6068): 601–4. February 2012. doi:10.1126/science.1214463. PMID 22301321. Bibcode: 2012Sci...335..601E. 
  10. ↑ "Endophenotypes in normal brain morphology and Alzheimer's disease: a review". Neuroscience 164 (1): 174–90. November 2009. doi:10.1016/j.neuroscience.2009.04.006. PMID 19362127. 
  11. ↑ "The genetic basis of plasma variation in adiponectin, a global endophenotype for obesity and the metabolic syndrome". The Journal of Clinical Endocrinology and Metabolism 86 (9): 4321–5. September 2001. doi:10.1210/jcem.86.9.7878. PMID 11549668. 
  12. ↑ "An association study on contrasting cystic fibrosis endophenotypes recognizes KRT8 but not KRT18 as a modifier of cystic fibrosis disease severity and CFTR mediated residual chloride secretion". BMC Medical Genetics 12: 62. May 2011. doi:10.1186/1471-2350-12-62. PMID 21548936. 
  13. ↑ "Endophenotype, intermediate phenotype, biomarker: definitions, concept comparisons, clarifications". Depression and Anxiety 30 (3): 185–9. March 2013. doi:10.1002/da.22042. PMID 23325718. 
  14. ↑ "Thinking clearly about the endophenotype-intermediate phenotype-biomarker distinctions in developmental psychopathology research". Development and Psychopathology 25 (4 Pt 2): 1347–57. November 2013. doi:10.1017/S0954579413000655. PMID 24342844. 
  15. ↑ 15.0 15.1 "Facial emotion labeling deficits in children and adolescents at risk for bipolar disorder". The American Journal of Psychiatry 165 (3): 385–9. March 2008. doi:10.1176/appi.ajp.2007.06122050. PMID 18245180. https://zenodo.org/record/1236196. 
  16. ↑ "Clinical methods in psychiatric genetics. I. Robustness of genetic marker investigative strategies". Acta Psychiatrica Scandinavica 74 (2): 113–8. August 1986. doi:10.1111/j.1600-0447.1986.tb10594.x. PMID 3465198. https://zenodo.org/record/1230700. 
  17. ↑ "The Role of Biomarkers and Endophenotypes in Prevention and Treatment of Psychopathological Disorders". Biomarkers in Medicine 3 (1): 1–3. February 2009. doi:10.2217/17520363.3.1.1. PMID 19727417. 
  18. ↑ "Modulation of the startle response and startle laterality in relatives of schizophrenic patients and in subjects with schizotypal personality disorder: evidence of inhibitory deficits". The American Journal of Psychiatry 157 (10): 1660–8. October 2000. doi:10.1176/appi.ajp.157.10.1660. PMID 11007721. 
  19. ↑ "Neurophysiological endophenotypes of schizophrenia: the viability of selected candidate measures". Schizophrenia Bulletin 33 (1): 69–94. January 2007. doi:10.1093/schbul/sbl060. PMID 17135482. 
  20. ↑ "Evidence-based medicine and electrophysiology in schizophrenia". Clinical EEG and Neuroscience 40 (2): 62–77. April 2009. doi:10.1177/155005940904000206. PMID 19534300. 
  21. ↑ "EEG microstates are a candidate endophenotype for schizophrenia". Nature Communications 11 (1): 3089. June 2020. doi:10.1038/s41467-020-16914-1. PMID 32555168. 
  22. ↑ "Social cognition in schizophrenia". Nature Reviews. Neuroscience 16 (10): 620–31. October 2015. doi:10.1038/nrn4005. PMID 26373471. 
  23. ↑ Messamore, Erik (2018-06-30). "The niacin response biomarker as a schizophrenia endophenotype: A status update" (in en). Prostaglandins, Leukotrienes and Essential Fatty Acids 136: 95–97. doi:10.1016/j.plefa.2017.06.014. PMID 28688777. https://linkinghub.elsevier.com/retrieve/pii/S0952327816302496. 
  24. ↑ "Replication of linkage on chromosome 7q22 and association of the regional Reelin gene with working memory in schizophrenia families". Molecular Psychiatry 13 (7): 673–84. July 2008. doi:10.1038/sj.mp.4002047. PMID 17684500. 
  25. ↑ 25.0 25.1 "Fabp7 maps to a quantitative trait locus for a schizophrenia endophenotype". PLOS Biology 5 (11): e297. November 2007. doi:10.1371/journal.pbio.0050297. PMID 18001149. 
  26. ↑ "A cog in cognition: how the alpha 7 nicotinic acetylcholine receptor is geared towards improving cognitive deficits". Pharmacology & Therapeutics 122 (3): 302–11. June 2009. doi:10.1016/j.pharmthera.2009.03.009. PMID 19351547. 
  27. ↑ "Neurocognitive correlates of emotional stimulus processing in pediatric bipolar disorder: a review". Postgraduate Medicine 122 (4): 94–104. July 2010. doi:10.3810/pgm.2010.07.2177. PMID 20675973. 
  28. ↑ "The impact of the CACNA1C risk allele on limbic structures and facial emotions recognition in bipolar disorder subjects and healthy controls". Journal of Affective Disorders 141 (1): 94–101. December 2012. doi:10.1016/j.jad.2012.03.014. PMID 22464935. 
  29. ↑ "Stress–Diathesis Model of Suicidal Behavior". The Neurobiological Basis of Suicide. Frontiers in Neuroscience. Boca Raton: CRC Press. 2012. ISBN 9781439838815. https://www.ncbi.nlm.nih.gov/books/NBK107203/. 
  30. ↑ "The effect of genetic variation of the serotonin 1B receptor gene on impulsive aggressive behavior and suicide". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 144B (8): 996–1002. December 2007. doi:10.1002/ajmg.b.30521. PMID 17510950. 



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