Endophenotype is a genetic epidemiology term which is used to parse behavioral symptoms into more stable phenotypes with a clear genetic connection. The concept was first coined by Bernard John and Kenneth R. Lewis in a 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.
- The endophenotype is associated with illness in the population.
- The endophenotype is heritable.
- The endophenotype is primarily state-independent (manifests in an individual whether or not illness is active).
- 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.
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.
Some 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.
- FABP7, coding the Fatty acid-binding protein 7 (brain), one SNP of which was associated with schizophrenia in one 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 to be the gene coding for the serotonin receptor 5-HT1B, known to be relevant in aggressive behaviors.
- John, Bernard; Kenneth R. Lewis (1966). "Chromosome Variability and Geographic Distribution in Insects". Science. doi:10.1126/science.152.3723.711. Retrieved 22 April 2012.
- Gottesman, Irving; Todd Gould (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.
- Greenwood, Tiffany (2007). "Initial Heritability Analyses of Endophenotypic Measures for Schizophrenia". Arch Gen Psychiatry 64 (11): 1242–50. doi:10.1001/archpsyc.64.11.1242. PMID 17984393. Retrieved 22 April 2012.
- <Alderson, R.M., Rapport, M.D., Hudec, K.L., Sarver, D.E., & Kofler, M.J. (2010). Competing core processes in attention-deficit/hyperactivity disorder (ADHD): Do working memory deficiencies underlie behavioral inhibition deficits? Journal of Abnormal Child Psychology, 38, 497-507>
- Karen D. Ersche, P. Simon Jones, Guy B. Williams, Abigail J Turton, Trevor W. Robbins, and Edward T. Bullmore (Feb 3, 2012). "Abnormal Brain Structure Implicated in Stimulant Drug Addiction". Science 335 (6068): 601–4. doi:10.1126/science.1214463. PMID 22301321.
- ,Reitz, C (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. Retrieved 22 April 2012.
- ,Comuzzie, Anthony (2001). "The Genetic Basis of Plasma Variation in Adiponectin, a Global Endophenotype for Obesity and the Metabolic Syndrome". The Journal of Clinical Endocrinology & Metabolism. doi:10.1210/jc.86.9.4321.
- Frauke, Stanke (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. doi:10.1186/1471-2350-12-62.
- Lenzenweger MF (2013). "Endophenotype, intermediate phenotype, biomarker: Definitions, concept comparisons, clarifications". Depression and Anxiety 30: 185–189. doi:10.1002/da.22042. PMID 23325718.
- Lenzenweger MF (2013). "Thinking clearly about the endophenotype-intermediate phenotype-biomarker distinctions in developmental psychopathology research". Development and Psychopathology 25: 1347–1357. doi:10.1017/S0954579413000655. PMID 24342844.
- Brotman, Melissa (2008). "Facial Emotion Labeling Deficits in Children and Adolescents at Risk for Bipolar Disorder". Am J Psychiatry. doi:10.1176/appi.ajp.2007.06122050.
- Gershon ES, Goldin LR (1986). "Clinical methods in psychiatric genetics, I: robustness of genetic marker investigative strategies". Acta Psychiatr Scand 74 (2): 113–118. doi:10.1111/j.1600-0447.1986.tb10594.x. PMID 3465198.
- Gottesman II, Gould TD (April 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.
- Leboyer M, Bellivier F, Nosten-Bertrand M, Jouvent R, Pauls D, Mallet J (1998). "Psychiatric genetics: search for phenotypes". Trends Neurosci 21: 102–105. doi:10.1016/s0166-2236(97)01187-9.
- 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 (July 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.
- Watanabe A, Toyota T, Owada Y, et al. (November 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.
- Leiser SC, Bowlby MR, Comery TA, Dunlop J (2009). "A cog in cognition: How the alpha7 nicotinic acetylcholine receptor is geared towards improving cognitive deficits". Pharmacology and Therapeutics 122 (3): 302–11. doi:10.1016/j.pharmthera.2009.03.009. PMID 19351547.
- Rosen, H (2010). "Neurocognitive correlates of emotional stimulus processing in pediatric bipolar disorder: a review.". Postgrad Med 122 (4): 94–104. doi:10.3810/pgm.2010.07.2177. PMID 20675973.
- Soeiro-de-Souza, Marcio (2012). "The impact of the CACNA1C risk allele on limbic structures and facial emotions recognition in bipolardisorder subjects and healthy controls". Journal of Affective Disorders. doi:10.1016/j.jad.2012.03.014.
- Dwivedi, Y (2012). The Neurobiological Basis of Suicide. Boca Raton: CRC Press.
- 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". Am. J. Med. Genet. B Neuropsychiatr. Genet. 144B (8): 996–1002. doi:10.1002/ajmg.b.30521. PMID 17510950.