Monoamine oxidase A
|Monoamine oxidase A|
Ribbon diagram of an MAO-A monomer, with FAD and clorgiline bound, oriented as if attached to the outer membrane of a mitochondrion.
|External IDs||ChEMBL: GeneCards:|
|RNA expression pattern|
Monoamine oxidase A, also known as MAO-A, is an enzyme that in humans is encoded by the MAOA gene. Monoamine oxidase A is an isozyme of monoamine oxidase. It preferentially deaminates norepinephrine (noradrenaline), epinephrine (adrenaline), serotonin, and dopamine (dopamine is equally deaminated by MAO-A and MAO-B).
It is inhibited by clorgyline and befloxatone. Inhibition of both MAO-A and MAO-B using a monoamine oxidase inhibitor (MAO inhibitor) is used in the treatment of clinical depression, erectile disfunction and anxiety.
Monoamine oxidase A is an enzyme that degrades amine neurotransmitters, such as dopamine, norepinephrine, and serotonin. The protein localizes to the outer mitochondrial membrane. Its encoding gene is adjacent to a related gene (MAOB) on the opposite strand of the X chromosome. Mutation in this gene results in monoamine oxidase deficiency, or Brunner syndrome.
Clinical significance 
In humans, there is a 30-base repeat sequence repeated in one of several different numbers of times in the promoter region of the gene coding for MAO-A. There are 2R (two repeats), 3R, 3.5R, 4R, and 5R variants of the repeat sequence, with the 3R and 4R variants most common in Caucasians. The 3.5R and 4R variants have been found to be more highly active than 3R or 5R, in a study which did not examine the 2R variant. An association between the 2R allele of the VNTR region of the gene and an increase in the likelihood of committing serious crime or violence has been found.
MAO-A levels in the brain as measured using positron emission tomography are elevated by an average of 34% in patients with major depressive disorder. Genetic association studies examining the relationship between high-activity MAOA variants and depression have produced mixed results, with some studies linking the high-activity variants to major depression in females, depressed suicide in males, major depression and sleep disturbance in males and major depressive disorder in both males and females.
Other studies failed to find a significant relationship between high-activity variants of the MAOA gene and major depressive disorder. In patients with major depressive disorder, those with MAOA G/T polymorphisms (rs6323) coding for the highest-activity form of the enzyme have a significantly lower magnitude of placebo response than those with other genotypes.
Aggression and the "Warrior gene" 
A version of the monoamine oxidase-A gene has been popularly referred to as the warrior gene. Several different versions of the gene are found in different individuals, although a functional gene is present in most humans (with the exception of a few individuals with Brunner syndrome). In the variant, the allele associated with behavioural traits is shorter (30 bases) and may produce less MAO-A enzyme. This gene variation is in a regulatory promoter region about 1000 bases from the start of the region that encodes the MAO-A enzyme.
The frequency distribution of variants of the MAOA gene differs between ethnic groups. 59% of Black men, 56% of Maori men, 54% of Chinese men, and 34% of Caucasian men carry the 3R allele. 5.5% of Black men, 0.1% of Caucasian men, and 0.00067% of Asian men carry the 2R allele.
A connection between a version of the monoamine oxidase A gene (3R) and several types of antisocial behavior has been found. MAOA had no statistically significant main effect on antisocial behavior. Maltreated children with genes causing high levels of MAO-A were less likely to develop antisocial behavior. Low MAO-A activity in combination with abuse experienced during childhood results in an increased risk of aggressive behaviour as an adult. High testosterone, maternal tobacco smoking during pregnancy, poor material living standards, dropping out of school, and low IQ can also trigger violent behavior in men with the low-activity alleles (which are overwhelmingly the 3R allele).
In individuals with the low activity MAOA gene, when faced with social exclusion or ostracism showed higher levels of aggression than individuals with the high activity MAOA gene. Low activity MAO-A could significantly predict aggressive behaviour in a high provocation situation, but was less associated with aggression in a low provocation situation. Individuals with the low activity variant of the MAOA gene were just as likely as participants with the high activity variant to retaliate when the loss was small. However, they were more likely to retaliate and with greater force when the loss was large.
“Monoamine oxidases (MAOs) are enzymes that are involved in the breakdown of neurotransmitters such as serotonin and dopamine and are, therefore, capable of influencing feelings, mood, and behaviour of individuals”. According to this, if there was a mutation to the gene that is involved in the process of promoting or inhibiting MAO enzymes, it could affect a person’s personality or behaviour and could therefore make them more prone to aggression. A deficiency in the MAOA gene has shown higher levels of aggression in males, which could further stimulate more research into this controversial topic. “A deficiency in monoamine oxidase A (MAOA) has been shown to be associated with aggressive behaviour in men of a Dutch family”. These findings suggest that further research is needed in this topic of debate.
Animal studies 
A dysfunctional MAOA gene has been correlated with increased aggression levels in mice, and has been correlated with heightened levels of aggression in humans. In mice, a dysfunctional MAOA gene is created through insertional mutagenesis (called ‘Tg8’).  Tg8 is a transgenic mouse strain that lacks functional MAO-A enzymatic activity. Mice that lacked a functional MAOA gene exhibited increased aggression towards intruder mice.  
Some types of aggression exhibited by these mice were territorial aggression, predatory aggression, and isolation-induced aggression. The MAO-A deficient mice that exhibited increased isolation-induced aggression reveals that an MAO-A deficiency may also contribute to a disruption in social interactions. There is research in both humans and mice to support that a nonsense point mutation in the eighth exon of the MAOA gene is responsible for impulsive aggressiveness due to a complete MAO-A deficiency.
Epigenetics likely plays an important role in the expression of the MAOA gene through methylation in women. Studies have linked methylation of the MAOA gene with nicotine and alcohol dependence in women. A second MAOA VNTR promoter, P2, influences epigenetic methylation in women only and interacts with having experienced child abuse to influence antisocial personality disorder symptoms, also only in women. Epigenetic methylation of MAOA in men is very low and with little variability compared to women. It also has a much higher heritability in men than women.
Legal implications 
In a 2009 criminal trial in the United States, an argument based on a combination of "warrior gene" and history of child abuse was successfully used to avoid a conviction of first-degree murder and the death penalty; however, the convicted murderer was sentenced to 32 years in prison.
Cancer Research 
MAOA produces an amine oxidase, which is a class of enzyme known to affect carcinogenesis. Clorgyline, an MAO-A enzyme inhibitor, prevents apoptosis in melanoma cells, in vitro. Cholangiocarcinoma suppresses MAOA expression, and those patients with higher MAOA expression had less adjacent organ invasion and better prognosis and survival.
Some MAO-A inhibitors 
- Synthetic compounds
- Herbal sources
- PDB 2BXS; De Colibus L, Li M, Binda C, Lustig A, Edmondson DE, Mattevi A (September 2005). "Three-dimensional structure of human monoamine oxidase A (MAO A): relation to the structures of rat MAO A and human MAO B". Proc. Natl. Acad. Sci. U.S.A. 102 (36): 12684–9. doi:10.1073/pnas.0505975102. PMC 1200291. PMID 16129825.
- Hotamisligil GS, Breakefield XO (August 1991). "Human monoamine oxidase A gene determines levels of enzyme activity". Am. J. Hum. Genet. 49 (2): 383–92. PMC 1683299. PMID 1678250.
- Grimsby J, Chen K, Wang LJ, Lan NC, Shih JC (May 1991). "Human monoamine oxidase A and B genes exhibit identical exon-intron organization". Proc. Natl. Acad. Sci. U.S.A. 88 (9): 3637–41. doi:10.1073/pnas.88.9.3637. PMC 51507. PMID 2023912.
- "Entrez Gene: MAOA monoamine oxidase A".
- Guo G, Ou XM, Roettger M, Shih JC (May 2008). "The VNTR 2 repeat in MAOA and delinquent behavior in adolescence and young adulthood: associations and MAOA promoter activity". Eur. J. Hum. Genet. 16 (5): 626–34. doi:10.1038/sj.ejhg.5201999. PMC 2922855. PMID 18212819.
- Guo G, Roettger M, Shih JC (August 2008). "The integration of genetic propensities into social-control models of delinquency and violence among male youths". American Sociological Review 73 (4): 543–568. doi:10.1177/000312240807300402.[dead link]
- Beaver KM, et al. (2012). "Exploring the association between the 2-repeat allele of the MAOA gene promoter polymorphism and psychopathic personality traits, arrests, incarceration, and lifetime antisocial behavior". Personality and Individual Differences. doi:10.1016/j.paid.2012.08.014.
- Meyer JH, Ginovart N, Boovariwala A, Sagrati S, Hussey D, Garcia A, Young T, Praschak-Rieder N, Wilson AA, Houle S (November 2006). "Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression". Arch. Gen. Psychiatry 63 (11): 1209–16. doi:10.1001/archpsyc.63.11.1209. PMID 17088501.
- Schulze TG, Müller DJ, Krauss H, Scherk H, Ohlraun S, Syagailo YV, Windemuth C, Neidt H, Grässle M, Papassotiropoulos A, Heun R, Nöthen MM, Maier W, Lesch KP, Rietschel M (December 2000). "Association between a functional polymorphism in the monoamine oxidase A gene promoter and major depressive disorder". Am. J. Med. Genet. 96 (6): 801–3. doi:10.1002/1096-8628(20001204)96:6<801::AID-AJMG21>3.0.CO;2-4. PMID 11121185.
- Du L, Faludi G, Palkovits M, Sotonyi P, Bakish D, Hrdina PD (July 2002). "High activity-related allele of MAOA gene associated with depressed suicide in males". NeuroReport 13 (9): 1195–8. doi:10.1097/00001756-200207020-00025. PMID 12151768.
- Du L, Bakish D, Ravindran A, Hrdina PD (September 2004). "MAOA gene polymorphisms are associated with major depression and sleep disturbance in males". NeuroReport 15 (13): 2097–101. doi:10.1097/00001756-200409150-00020. PMID 15486489.
- Yu YW, Tsai SJ, Hong CJ, Chen TJ, Chen MC, Yang CW (September 2005). "Association study of a monoamine oxidase a gene promoter polymorphism with major depressive disorder and antidepressant response". Neuropsychopharmacology 30 (9): 1719–23. doi:10.1038/sj.npp.1300785. PMID 15956990.
- Serretti A, Cristina S, Lilli R, Cusin C, Lattuada E, Lorenzi C, Corradi B, Grieco G, Costa A, Santorelli F, Barale F, Nappi G, Smeraldi E (May 2002). "Family-based association study of 5-HTTLPR, TPH, MAOA, and DRD4 polymorphisms in mood disorders". Am. J. Med. Genet. 114 (4): 361–9. doi:10.1002/ajmg.10356. PMID 11992558.
- Huang SY, Lin MT, Lin WW, Huang CC, Shy MJ, Lu RB (2009). "Association of monoamine oxidase A (MAOA) polymorphisms and clinical subgroups of major depressive disorders in the Han Chinese population". World J. Biol. Psychiatry 10 (4 Pt 2): 544–51. doi:10.1080/15622970701816506. PMID 19224413.
- Leuchter AF, McCracken JT, Hunter AM, Cook IA, Alpert JE (August 2009). "Monoamine oxidase a and catechol-o-methyltransferase functional polymorphisms and the placebo response in major depressive disorder". J Clin Psychopharmacol 29 (4): 372–7. doi:10.1097/JCP.0b013e3181ac4aaf. PMID 19593178.
- Online 'Mendelian Inheritance in Man' (OMIM) MONOAMINE OXIDASE A; MAOA. -309850
- Sabol SZ, Hu S, Hamer D (September 1998). "A functional polymorphism in the monoamine oxidase A gene promoter". Hum. Genet. 103 (3): 273–9. doi:10.1007/s004390050816. PMID 9799080.
- Lea R, Chambers G (2007). "Monoamine oxidase, addiction, and the "warrior" gene hypothesis". N. Z. Med. J. 120 (1250): U2441. PMID 17339897.
- Lu RB, Lin WW, Lee JF, Ko HC, Shih JC (June 2003). "Neither antisocial personality disorder nor antisocial alcoholism is associated with the MAOA gene in Han Chinese males". Alcohol. Clin. Exp. Res. 27 (6): 889–93. doi:10.1097/01.ALC.0000071927.64880.0E. PMID 12824808.
- Zhang M, Chen X, Way N, Yoshikawa H, Deng H, Ke X, Yu W, Chen P, He C, Chi X, Lu Z (September 2011). "The association between infants' self-regulatory behavior and MAOA gene polymorphism". Dev Sci 14 (5): 1059–65. doi:10.1111/j.1467-7687.2011.01047.x. PMID 21884321.
- Zhou Q, Hofer C, Eisenberg N, Reiser M, Spinrad TL, Fabes RA (March 2007). "The developmental trajectories of attention focusing, attentional and behavioral persistence, and externalizing problems during school-age years". Dev Psychol 43 (2): 369–85. doi:10.1037/0012-16220.127.116.119. PMC 1832154. PMID 17352545.
- Chen Sy, Wang J, Yu Gq, Liu W, Pearce D (May 1997). "Androgen and glucocorticoid receptor heterodimer formation. A possible mechanism for mutual inhibition of transcriptional activity". J. Biol. Chem. 272 (22): 14087–92. doi:10.1074/jbc.272.22.14087. PMID 9162033.
- Ono H, Shirakawa O, Nishiguchi N, Nishimura A, Nushida H, Ueno Y, Maeda K (April 2002). "No evidence of an association between a functional monoamine oxidase a gene polymorphism and completed suicides". Am. J. Med. Genet. 114 (3): 340–2. PMID 11920860. Text "10.1002/ajmg.10237 " ignored (help)
- Wang TJ, Huang SY, Lin WW, Lo HY, Wu PL, Wang YS, Wu YS, Ko HC, Shih JC, Lu RB (January 2007). "Possible interaction between MAOA and DRD2 genes associated with antisocial alcoholism among Han Chinese men in Taiwan". Prog. Neuropsychopharmacol. Biol. Psychiatry 31 (1): 108–14. doi:10.1016/j.pnpbp.2006.08.010. PMID 17007976.
- Lee SY, Hahn CY, Lee JF, Huang SY, Chen SL, Kuo PH, Lee IH, Yeh TL, Yang YK, Chen SH, Ko HC, Lu RB (July 2010). "MAOA interacts with the ALDH2 gene in anxiety-depression alcohol dependence". Alcohol. Clin. Exp. Res. 34 (7): 1212–8. doi:10.1111/j.1530-0277.2010.01198.x. PMID 20477771.
- Caspi A, McClay J, Moffitt TE, Mill J, Martin J, Craig IW, Taylor A, Poulton R (August 2002). "Role of genotype in the cycle of violence in maltreated children". Science 297 (5582): 851–4. doi:10.1126/science.1072290. PMID 12161658. Lay summary – eurekalert.org (2002-08-01).
- Frazzetto G, Di Lorenzo G, Carola V, Proietti L, Sokolowska E, Siracusano A, Gross C, Troisi A (2007). "Early trauma and increased risk for physical aggression during adulthood: the moderating role of MAOA genotype". PLoS ONE 2 (5): e486. doi:10.1371/journal.pone.0000486. PMC 1872046. PMID 17534436.
- Fergusson DM, Boden JM, Horwood LJ, Miller A, Kennedy MA (February 2012). "Moderating role of the MAOA genotype in antisocial behaviour". Br J Psychiatry 200 (2): 116–23. doi:10.1192/bjp.bp.111.093328. PMID 22297589.
- Sjöberg RL, Ducci F, Barr CS, Newman TK, Dell'osso L, Virkkunen M, Goldman D (January 2008). "A non-additive interaction of a functional MAOA VNTR and testosterone predicts antisocial behavior". Neuropsychopharmacology 33 (2): 425–30. doi:10.1038/sj.npp.1301417. PMC 2665792. PMID 17429405.
- Gallardo-Pujol, D.; Andrés-Pueyo, A.; Maydeu-Olivares, A. (1 November 2012). "genotype, social exclusion and aggression: an experimental test of a gene-environment interaction". Genes, Brain and Behavior: n/a–n/a. doi:10.1111/j.1601-183X.2012.00868.x.
- McDermott R, Tingley D, Cowden J, Frazzetto G, Johnson DD (February 2009). "Monoamine oxidase A gene (MAOA) predicts behavioral aggression following provocation". Proc. Natl. Acad. Sci. U.S.A. 106 (7): 2118–23. doi:10.1073/pnas.0808376106. PMC 2650118. PMID 19168625.
- Hook GR (2009). ""Warrior genes" and the disease of being Māori". MAI Review (2): 1–11.
- Cases O, Seif I, Grimsby J, Gaspar P, Chen K, Pournin S, Müller U, Aguet M, Babinet C, Shih JC (June 1995). "Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA". Science 268 (5218): 1763–6. doi:10.1126/science.7792602. PMID 7792602.
- Scott AL, Bortolato M, Chen K, Shih JC (May 2008). "Novel monoamine oxidase A knock out mice with human-like spontaneous mutation". NeuroReport 19 (7): 739–43. doi:10.1097/WNR.0b013e3282fd6e88. PMID 18418249.
- Vishnivetskaya GB, Skrinskaya JA, Seif I, Popova NK (2007). "Effect of MAOA deficiency on different kinds of aggression and social investigation in mice". Aggress Behav 33 (1): 1–6. doi:10.1002/ab.20161. PMID 17441000.
- Brunner HG, Nelen M, Breakefield XO, Ropers HH, van Oost BA (October 1993). "Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A". Science 262 (5133): 578–80. doi:10.1126/science.8211186. PMID 8211186.
- Vishnivetskaya, Galina B.; Skrinskaya, Julia A., Seif, Isabelle, Popova, Nina K. (1 January 2007). "Effect of MAOA deficiency on different kinds of aggression and social investigation in mice". Aggressive Behavior 33 (1): 1–6. doi:10.1002/ab.20161. PMID 17441000.
- Hebebrand J, Klug B (September 1995). "Specification of the phenotype required for men with monoamine oxidase type A deficiency". Hum. Genet. 96 (3): 372–6. doi:10.1007/BF00210430. PMID 7649563.
- Jiang Y, Langley B, Lubin FD, Renthal W, Wood MA, Yasui DH, Kumar A, Nestler EJ, Akbarian S, Beckel-Mitchener AC (November 2008). "Epigenetics in the nervous system". J. Neurosci. 28 (46): 11753–9. doi:10.1523/JNEUROSCI.3797-08.2008. PMID 19005036.
- Philibert RA, Gunter TD, Beach SR, Brody GH, Madan A (July 2008). "MAOA methylation is associated with nicotine and alcohol dependence in women". Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B (5): 565–70. doi:10.1002/ajmg.b.30778. PMID 18454435.
- Philibert RA, Wernett P, Plume J, Packer H, Brody GH, Beach SRH (July 2011). "Gene environment interactions with a novel variable Monoamine oxidase A transcriptional enhancer are associated with antisocial personality disorder". Biol. Psychol. 87 (3): 366–71. doi:10.1016/j.biopsycho.2011.04.007. PMC 3134149. PMID 21554924.
- Wong CCY, Caspi A, Williams B, Craig IW, Houts R, Ambler A, Moffitt TE, Mill J (August 2010). "A longitudinal study of epigenetic variation in twins". Epigenetics 5 (6): 516–26. doi:10.4161/epi.5.6.12226. PMC 3322496. PMID 20505345.
- Barber N (2010-07-13). "Pity the poor murderer, his genes made him do it". The Human Beast: Why we do what we do. Psychology Today. Retrieved 2010-10-17.
- Hagerty BB (2010-07-01). "Can Your Genes Make You Murder?". News > Science > Inside The Criminal Brain. National Public Radio. Retrieved 2010-10-17.
- Pietrangeli P, Mondovi B (January 2004). "Amine oxidases and tumors". Neurotoxicology 25 (1-2): 317–24. doi:10.1016/S0161-813X(03)00109-8. PMID 14697906.
- Huang L, Frampton G, Rao A, Zhang KS, Chen W, Lai JM, Yin XY, Walker K, Culbreath B, Leyva-Illades D, Quinn M, McMillin M, Bradley M, Liang LJ, DeMorrow S (October 2012). "Monoamine oxidase A expression is suppressed in human cholangiocarcinoma via coordinated epigenetic and IL-6-driven events". Lab Invest. 92 (10): 1451–60. doi:10.1038/labinvest.2012.110. PMID 22906985.
Further reading 
- "'Warrior Gene' Predicts Aggressive Behavior After Provocation". Science News. Science Daily. 2009-01-23.
- McDermott R, Tingley D, Cowden J, Frazzetto G, Johnson DD (January 2009). "Monoamine oxidase A gene (MAOA) predicts behavioral aggression following provocation". Proc. Natl. Acad. Sci. U.S.A. 106 (7): 2118–23. doi:10.1073/pnas.0808376106. PMC 2650118. PMID 19168625.
- Edmondson DE, Binda C, Mattevi A (2004). "The FAD binding sites of human monoamine oxidases A and B". Neurotoxicology 25 (1–2): 63–72. doi:10.1016/S0161-813X(03)00114-1. PMID 14697881.
- Craig IW (2007). "The importance of stress and genetic variation in human aggression". BioEssays 29 (3): 227–36. doi:10.1002/bies.20538. PMID 17295220.