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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. 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".[2]

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.[3] It is therefore more applicable to more heritable disorders, such as bipolar disorder and schizophrenia.[4] Since then, the concept has expanded to many other fields, such as the study of ADHD,[5] addiction,[6] Alzheimer's disease,[7] obesity[8] and cystic fibrosis.[9] 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".[10][11] The strength of an endophenotype is its ability to differentiate between potential diagnoses that present with similar symptoms.[12]


In psychiatry research, the accepted criteria which a biomarker must fulfill to be called an endophenotype include:[3][13][14]

  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). [This is a debatable criterion. Why we cannot use state-dependent endophenotype? It does not make sense.]
  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[edit]

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.[3] A strong candidate for schizophrenia endophenotype is prepulse inhibition, the ability to inhibit the reaction to startling stimuli.[15] However, several other task-related candidate endophenotypes have been proposed for schizophrenia,[16] and even resting measures extracted from EEG, such as, power of frequency bands[17] and EEG microstates.[18]

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.[19]

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.[20]
  • FABP7, coding the Fatty acid-binding protein 7 (brain), one SNP of which was associated with schizophrenia in one 2008 study,[21] is also linked to prepulse inhibition in mice.[21] 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.[22]

For bipolar disorder[edit]

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).[12] Using fMRI, this endophenotype has been linked to dysfunction in the dorsolateral and ventrolateral prefrontal cortex, anterior cingulate cortex, striatum, and amygdala.[23] 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.[24]

For suicide[edit]

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.[25] 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.[26]

See also[edit]


  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. PMC 3181731. PMID 16262211.
  2. ^ John B, Lewis KR (May 1966). "Chromosome variability and geographic distribution in insects". Science. 152 (3723): 711–21. Bibcode:1966Sci...152..711J. doi:10.1126/science.152.3723.711. PMID 17797432.
  3. ^ a b c Gottesman II, Gould TD (April 2003). "The endophenotype concept in psychiatry: etymology and strategic intentions". The American Journal of Psychiatry. 160 (4): 636–45. doi:10.1176/appi.ajp.160.4.636. PMID 12668349.
  4. ^ Greenwood TA, Braff DL, Light GA, Cadenhead KS, Calkins ME, Dobie DJ, et al. (November 2007). "Initial heritability analyses of endophenotypic measures for schizophrenia: the consortium on the genetics of schizophrenia". Archives of General Psychiatry. 64 (11): 1242–50. doi:10.1001/archpsyc.64.11.1242. PMID 17984393.
  5. ^ Alderson RM, Rapport MD, Hudec KL, Sarver DE, Kofler MJ (May 2010). "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. doi:10.1007/s10802-010-9387-0. PMID 20140491. S2CID 1641972.
  6. ^ Ersche KD, Jones PS, Williams GB, Turton AJ, Robbins TW, Bullmore ET (February 2012). "Abnormal brain structure implicated in stimulant drug addiction". Science. 335 (6068): 601–4. Bibcode:2012Sci...335..601E. doi:10.1126/science.1214463. PMID 22301321. S2CID 13958119.
  7. ^ Reitz C, Mayeux R (November 2009). "Endophenotypes in normal brain morphology and Alzheimer's disease: a review". Neuroscience. 164 (1): 174–90. doi:10.1016/j.neuroscience.2009.04.006. PMC 2812814. PMID 19362127.
  8. ^ Comuzzie AG, Funahashi T, Sonnenberg G, Martin LJ, Jacob HJ, Black AE, et al. (September 2001). "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. doi:10.1210/jc.86.9.4321. PMID 11549668.
  9. ^ Stanke F, Hedtfeld S, Becker T, Tümmler B (May 2011). "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. doi:10.1186/1471-2350-12-62. PMC 3107781. PMID 21548936.
  10. ^ Lenzenweger MF (March 2013). "Endophenotype, intermediate phenotype, biomarker: definitions, concept comparisons, clarifications". Depression and Anxiety. 30 (3): 185–9. doi:10.1002/da.22042. PMID 23325718. S2CID 6848146.
  11. ^ Lenzenweger MF (November 2013). "Thinking clearly about the endophenotype-intermediate phenotype-biomarker distinctions in developmental psychopathology research". Development and Psychopathology. 25 (4 Pt 2): 1347–57. doi:10.1017/S0954579413000655. PMID 24342844. S2CID 13629102.
  12. ^ a b Brotman MA, Guyer AE, Lawson ES, Horsey SE, Rich BA, Dickstein DP, et al. (March 2008). "Facial emotion labeling deficits in children and adolescents at risk for bipolar disorder". The American Journal of Psychiatry. 165 (3): 385–9. doi:10.1176/appi.ajp.2007.06122050. PMID 18245180.
  13. ^ Gershon ES, Goldin LR (August 1986). "Clinical methods in psychiatric genetics. I. Robustness of genetic marker investigative strategies". Acta Psychiatrica Scandinavica. 74 (2): 113–8. doi:10.1111/j.1600-0447.1986.tb10594.x. PMID 3465198. S2CID 6158883.
  14. ^ Beauchaine TP (February 2009). "The Role of Biomarkers and Endophenotypes in Prevention and Treatment of Psychopathological Disorders". Biomarkers in Medicine. 3 (1): 1–3. doi:10.2217/17520363.3.1.1. PMC 2735891. PMID 19727417.
  15. ^ Cadenhead KS, Swerdlow NR, Shafer KM, Diaz M, Braff DL (October 2000). "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. doi:10.1176/appi.ajp.157.10.1660. PMID 11007721.
  16. ^ Turetsky BI, Calkins ME, Light GA, Olincy A, Radant AD, Swerdlow NR (January 2007). "Neurophysiological endophenotypes of schizophrenia: the viability of selected candidate measures". Schizophrenia Bulletin. 33 (1): 69–94. doi:10.1093/schbul/sbl060. PMC 2632291. PMID 17135482.
  17. ^ Galderisi S, Mucci A, Volpe U, Boutros N (April 2009). "Evidence-based medicine and electrophysiology in schizophrenia". Clinical EEG and Neuroscience. 40 (2): 62–77. doi:10.1177/155005940904000206. PMID 19534300. S2CID 36463105.
  18. ^ da Cruz JR, Favrod O, Roinishvili M, Chkonia E, Brand A, Mohr C, et al. (June 2020). "EEG microstates are a candidate endophenotype for schizophrenia". Nature Communications. 11 (1): 3089. doi:10.1038/s41467-020-16914-1. PMC 7303216. PMID 32555168. S2CID 219730748.
  19. ^ Green MF, Horan WP, Lee J (October 2015). "Social cognition in schizophrenia". Nature Reviews. Neuroscience. 16 (10): 620–31. doi:10.1038/nrn4005. PMID 26373471. S2CID 3328671.
  20. ^ Wedenoja J, Loukola A, Tuulio-Henriksson A, Paunio T, Ekelund J, Silander K, et al. (July 2008). "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. doi:10.1038/sj.mp.4002047. PMID 17684500.
  21. ^ a b Watanabe A, Toyota T, Owada Y, Hayashi T, Iwayama Y, Matsumata M, et al. (November 2007). "Fabp7 maps to a quantitative trait locus for a schizophrenia endophenotype". PLOS Biology. 5 (11): e297. doi:10.1371/journal.pbio.0050297. PMC 2071943. PMID 18001149.
  22. ^ Leiser SC, Bowlby MR, Comery TA, Dunlop J (June 2009). "A cog in cognition: how the alpha 7 nicotinic acetylcholine receptor is geared towards improving cognitive deficits". Pharmacology & Therapeutics. 122 (3): 302–11. doi:10.1016/j.pharmthera.2009.03.009. PMID 19351547.
  23. ^ Rosen HR, Rich BA (July 2010). "Neurocognitive correlates of emotional stimulus processing in pediatric bipolar disorder: a review". Postgraduate Medicine. 122 (4): 94–104. doi:10.3810/pgm.2010.07.2177. PMID 20675973. S2CID 26175461.
  24. ^ Soeiro-de-Souza MG, Otaduy MC, Dias CZ, Bio DS, Machado-Vieira R, Moreno RA (December 2012). "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. doi:10.1016/j.jad.2012.03.014. PMID 22464935.
  25. ^ Dwivedi Y (2012). "Stress–Diathesis Model of Suicidal Behavior". The Neurobiological Basis of Suicide. Frontiers in Neuroscience. Boca Raton: CRC Press. ISBN 9781439838815.
  26. ^ Zouk H, McGirr A, Lebel V, Benkelfat C, Rouleau G, Turecki G (December 2007). "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. doi:10.1002/ajmg.b.30521. PMID 17510950. S2CID 42101776.