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Endophenotype

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Endophenotype is a psychiatric concept and a special kind of biomarker. The purpose of the concept is to divide behavioral symptoms into more stable phenotypes with a clear genetic connection. The concept was originally borrowed by Gottesman & Shields from insect biology.

Other terms with similar meaning but not stressing the genetic connection are "intermediate phenotype", "biological marker", "subclinical trait", "vulnerability marker", and "cognitive marker".

Definition

The accepted criteria that a biomarker must fulfill to be called an endophenotype include: [1] [2]

  1. The endophenotype is associated with illness in the population.
  2. The endophenotype is heritable.
  3. The endophenotype is primarily state-independent (manifests in an individual whether or not illness is active).
  4. Within families, endophenotype and illness co-segregate.

Subsequently, an additional criterion that may be useful for identifying endophenotypes of diseases that display complex inheritance patterns was suggested:

  • The endophenotype found in affected family members is found in nonaffected family members at a higher rate than in the general population. [3]

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.[2] A strong candidate for schizophrenia endophenotype is prepulse inhibition, the ability to inhibit the reaction to startling stimuli.

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

  • RELN – coding the reelin protein downregulated in patients' brains. In one study its variants were associated with performance in verbal and visual working memory tests in the nuclear families of the sufferers.[4]
  • FABP7, coding the Fatty acid-binding protein 7 (brain), one SNP of which was associated with schizophrenia in one study,[5] is also linked to prepulse inhibition in mice.[5] 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.[6]

For suicide

The endophenotype concept has also been used in suicide studies. A tentative endophenotype between the phenotype of completed suicide and the genetic basis is impulsive-aggressive behaviors (IABs). The genetic basis of the trait has been suggested to be the gene coding for the serotonin receptor 5-HT1B, known to be relevant in aggressive behaviors.[7]

See also

References

  1. ^ Gershon ES, Goldin LR (1986) Clinical methods in psychiatric genetics, I: robustness of genetic marker investigative strategies. Acta Psychiatr Scand. 74:113–118.
  2. ^ a b Gottesman II, Gould TD (2003). "The endophenotype concept in psychiatry: etymology and strategic intentions". Am J Psychiatry. 160 (4): 636–45. doi:10.1176/appi.ajp.160.4.636. PMID 12668349. {{cite journal}}: Unknown parameter |month= ignored (help)
  3. ^ Leboyer M, Bellivier F, Nosten-Bertrand M, Jouvent R, Pauls D, Mallet J (1998) Psychiatric genetics: search for phenotypes. Trends Neurosci. 21:102–105.
  4. ^ Wedenoja J, Loukola A, Tuulio-Henriksson A, Paunio T, Ekelund J, Silander K, Varilo T, Heikkilä K, Suvisaari J, Partonen T, Lönnqvist J, Peltonen L (2008). "Replication of linkage on chromosome 7q22 and association of the regional Reelin gene with working memory in schizophrenia families". Mol. Psychiatry. 13 (7): 673–84. doi:10.1038/sj.mp.4002047. PMID 17684500. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ a b Watanabe A, Toyota T, Owada Y; et al. (2007). "Fabp7 maps to a quantitative trait locus for a schizophrenia endophenotype". PLoS Biol. 5 (11): e297. doi:10.1371/journal.pbio.0050297. PMC 2071943. PMID 18001149. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  6. ^ Leiser SC, Bowlby MR, Comery TA, Dunlop J (2009). "A cog in cognition: How the alpha7 nicotinic acetylcholine receptor is geared towards inproving cognitive deficits". Pharmacology and Therapeutics. 122 (3): 302–11. doi:10.1016/j.pharmthera.2009.03.009. PMID 19351547.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ Zouk H, McGirr A, Lebel V, Benkelfat C, Rouleau G, Turecki G (2007). "The effect of genetic variation of the serotonin 1B receptor gene on impulsive aggressive behavior and suicide". Am. J. Med. Genet. B Neuropsychiatr. Genet. 144B (8): 996–1002. doi:10.1002/ajmg.b.30521. PMID 17510950. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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