View source for Monoamine oxidase A

{{Infobox_gene}}
[[File:MAOA location.png|thumb|MAOA gene is located on the short (p) arm of the black [[X chromosome]] at position 11.3.]]
'''Monoamine oxidase A''', also known as '''MAO-A''', is an [[enzyme]] that in [[human]]s is encoded by the ''MAOA'' [[gene]].<ref name="pmid1678250">{{vcite2 journal | vauthors = Hotamisligil GS, Breakefield XO | title = Human monoamine oxidase A gene determines levels of enzyme activity | journal = American Journal of Human Genetics | volume = 49 | issue = 2 | pages = 383–92 | date = Aug 1991 | pmid = 1678250 | pmc = 1683299 | doi =  }}</ref><ref name="pmid2023912">{{vcite2 journal | vauthors = Grimsby J, Chen K, Wang LJ, Lan NC, Shih JC | title = Human monoamine oxidase A and B genes exhibit identical exon-intron organization | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 88 | issue = 9 | pages = 3637–41 | date = May 1991 | pmid = 2023912 | pmc = 51507 | doi = 10.1073/pnas.88.9.3637 }}</ref> This gene is one of two neighboring gene family members that encode [[mitochondria]]l enzymes which [[catalyze]] the [[oxidative]] [[deamination]] of [[amine]]s, such as [[dopamine]], [[norepinephrine]], and [[serotonin]]. A mutation of this gene results in [[Brunner syndrome]]. This gene has also been associated with a variety of other psychiatric disorders, including [[Anti-social behavior|antisocial]] behavior. [[Alternatively spliced]] transcript variants encoding multiple isoforms have been observed.<ref name=entrez>{{cite web | title = Entrez Gene: MAOA monoamine oxidase A | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4128}}</ref>

== Structure ==

=== Gene ===
[[Monoamine oxidase]] A, also known as MAO-A, is an [[enzyme]] that in [[human]]s is encoded by the ''MAOA'' [[gene]].<ref name="pmid1678250">{{vcite2 journal | vauthors = Hotamisligil GS, Breakefield XO | title = Human monoamine oxidase A gene determines levels of enzyme activity | journal = American Journal of Human Genetics | volume = 49 | issue = 2 | pages = 383–92 | date = Aug 1991 | pmid = 1678250 | pmc = 1683299 | doi =  }}</ref><ref name="pmid2023912">{{vcite2 journal | vauthors = Grimsby J, Chen K, Wang LJ, Lan NC, Shih JC | title = Human monoamine oxidase A and B genes exhibit identical exon-intron organization | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 88 | issue = 9 | pages = 3637–41 | date = May 1991 | pmid = 2023912 | pmc = 51507 | doi = 10.1073/pnas.88.9.3637 }}</ref> 
The promoter of ''MAOA'' contains conserved binding sites for [[Sp1 transcription factor|Sp1]], [[GATA2]], and [[TATA Binding Protein|TBP]].<ref name=pmid25810277>{{cite journal | vauthors = Gupta V, Khan AA, Sasi BK, Mahapatra NR | title = Molecular mechanism of monoamine oxidase A gene regulation under inflammation and ischemia-like conditions: key roles of the transcription factors GATA2, Sp1 and TBP | journal = Journal of Neurochemistry | volume = 134 | issue = 1 | pages = 21–38 | date = Jul 2015 | pmid = 25810277 | doi = 10.1111/jnc.13099 }}</ref> This gene is adjacent to a related gene (''[[MAOB]]'') on the opposite strand of the [[X chromosome]].{{cn|date=May 2017}}

In humans, there is a 30-base [[Variable number tandem repeat|repeat sequence]] repeated several different numbers of times in the [[Promoter (biology)|promoter region]] of 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.<ref name="pmid18212819">{{vcite2 journal |vauthors=Guo G, Ou XM, Roettger M, Shih JC |title=The VNTR 2 repeat in MAOA and delinquent behavior in adolescence and young adulthood: associations and MAOA promoter activity |journal=European Journal of Human Genetics |volume=16 |issue=5 |pages=626–34 |date=May 2008 |pmid=18212819 |pmc=2922855 |doi=10.1038/sj.ejhg.5201999}}</ref>

Studies have found differences in the frequency distribution of variants of the ''MAOA'' gene between ethnic groups:<ref name="pmid9799080" /><ref name="pmid17339897">{{vcite2 journal |vauthors=Lea R, Chambers G |title=Monoamine oxidase, addiction, and the "warrior" gene hypothesis |journal=The New Zealand Medical Journal |volume=120 |issue=1250 |pages=U2441 |year=2007 |pmid=17339897 |url=http://journal.nzma.org.nz/journal/120-1250/2441/}}</ref> of the participants, 59% of Black men, 54% <!--The 77% of Asian  men is a copy edit, see talk-->of Chinese men, 56% of Maori men, and 34% of Caucasian men carried the 3R allele, while 5.5% of Black men, 0.1% of Caucasian men, and 0.00067% of Asian men carried the 2R allele.<ref name="beaver2012" /><ref name="pmid9799080" /><ref name="pmid17339897" /><ref name="pmid12824808">{{vcite2 journal |vauthors=Lu RB, Lin WW, Lee JF, Ko HC, Shih JC |title=Neither antisocial personality disorder nor antisocial alcoholism is associated with the MAO-A gene in Han Chinese males |journal=Alcoholism: Clinical and Experimental Research |volume=27 |issue=6 |pages=889–93 |date=Jun 2003 |pmid=12824808 |doi=10.1097/01.ALC.0000071927.64880.0E}}</ref><ref name="pmid21884321">{{vcite2 journal |vauthors=Zhang M, Chen X, Way N, Yoshikawa H, Deng H, Ke X, Yu W, Chen P, He C, Chi X, Lu Z |title=The association between infants' self-regulatory behavior and MAOA gene polymorphism |journal=Developmental Science |volume=14 |issue=5 |pages=1059–65 |date=Sep 2011 |pmid=21884321 |doi=10.1111/j.1467-7687.2011.01047.x}}</ref><ref name="pmid17352545">{{vcite2 journal |vauthors=Zhou Q, Hofer C, Eisenberg N, Reiser M, Spinrad TL, Fabes RA |title=The developmental trajectories of attention focusing, attentional and behavioral persistence, and externalizing problems during school-age years |journal=Developmental Psychology |volume=43 |issue=2 |pages=369–385 |date=Mar 2007 |pmid=17352545 |pmc=1832154 |doi=10.1037/0012-1649.43.2.369}}</ref><ref name="pmid9162033">{{vcite2 journal |vauthors=Chen Sy, Wang J, Yu Gq, Liu W, Pearce D |title=Androgen and glucocorticoid receptor heterodimer formation. A possible mechanism for mutual inhibition of transcriptional activity |journal=The Journal of Biological Chemistry |volume=272 |issue=22 |pages=14087–92 |date=May 1997 |pmid=9162033 |doi=10.1074/jbc.272.22.14087}}</ref><ref name="pmid11920860">{{vcite2 journal |vauthors=Ono H, Shirakawa O, Nishiguchi N, Nishimura A, Nushida H, Ueno Y, Maeda K |title=No evidence of an association between a functional monoamine oxidase a gene polymorphism and completed suicides |journal=American Journal of Medical Genetics |volume=114 |issue=3 |pages=340–2 |date=Apr 2002 |pmid=11920860 |doi=10.1002/ajmg.10237}}</ref><ref name="pmid17007976">{{vcite2 journal |vauthors=Wang TJ, Huang SY, Lin WW, Lo HY, Wu PL, Wang YS, Wu YS, Ko HC, Shih JC, Lu RB |title=Possible interaction between MAOA and DRD2 genes associated with antisocial alcoholism among Han Chinese men in Taiwan |journal=Progress in Neuro-Psychopharmacology & Biological Psychiatry |volume=31 |issue=1 |pages=108–114 |date=Jan 2007 |pmid=17007976 |doi=10.1016/j.pnpbp.2006.08.010}}</ref><ref name="pmid20477771">{{vcite2 journal |vauthors=Lee SY, Hahn CY, Lee JF, Huang SY, Chen SL, Kuo PH, Lee IH, Yeh TL, Yang YK, Chen SH, Ko HC, Lu RB |title=MAOA interacts with the ALDH2 gene in anxiety-depression alcohol dependence |journal=Alcoholism: Clinical and Experimental Research |volume=34 |issue=7 |pages=1212–8 |date=Jul 2010 |pmid=20477771 |doi=10.1111/j.1530-0277.2010.01198.x}}</ref>

The [[epigenetic]] modification of ''MAOA'' gene expression through methylation likely plays an important role in women.<ref name="pmid19005036">{{vcite2 journal |vauthors=Jiang Y, Langley B, Lubin FD, Renthal W, Wood MA, Yasui DH, Kumar A, Nestler EJ, Akbarian S, Beckel-Mitchener AC |title=Epigenetics in the nervous system |journal=The Journal of Neuroscience |volume=28 |issue=46 |pages=11753–9 |date=Nov 2008 |pmid=19005036 |doi=10.1523/JNEUROSCI.3797-08.2008}}</ref> A study from 2010 found epigenetic methylation of ''MAOA'' in men to be very low and with little variability compared to women, while having higher heritability in men than women.<ref name="wong">{{vcite2 journal |vauthors=Wong CC, Caspi A, Williams B, Craig IW, Houts R, Ambler A, Moffitt TE, Mill J |title=A longitudinal study of epigenetic variation in twins |journal=Epigenetics |volume=5 |issue=6 |pages=516–26 |date=Aug 2010 |pmid=20505345 |pmc=3322496 |doi=10.4161/epi.5.6.12226}}</ref>

=== Protein ===

The gene encodes a [[monomeric]] protein which shares a 70% [[amino acid]] sequence identity, as well as conserved chain folds and [[flavin adenine dinucleotide]] (FAD)-binding site structures, with MAO-B. However, MAO-A has a monopartite cavity of approximately 550 [[angstrom]]s, compared to the 290-angstrom bipartite cavity in MAO-B. Nonetheless, both proteins adopt [[Protein dimer|dimer]]ic forms when membrane-bound. The [[C-terminal]] domain of MAO-A forms helical tails which are responsible for attaching the protein to the [[outer mitochondrial membrane]] (OMM). MAO-A contains loop structures at the entrance of its [[active site]].<ref name=pmid21971000>{{cite journal | vauthors = Binda C, Mattevi A, Edmondson DE | title = Structural properties of human monoamine oxidases A and B | journal = International Review of Neurobiology | volume = 100 | pages = 1–11 | date = 2011 | pmid = 21971000 | doi = 10.1016/B978-0-12-386467-3.00001-7 | series = International Review of Neurobiology | isbn = 9780123864673 }}</ref>

== Function ==

MAO-A is a key regulator for normal brain function. It is a [[flavoprotein|flavoenzyme]] which degrades amine [[neurotransmitter]]s, such as dopamine, norepinephrine, and serotonin, via [[oxidative]] [[deamination]]. It is highly expressed in [[neuron|neural]] and [[cardiomyocyte|cardiac cells]] and [[subcellular localization|localizes]] to the [[outer mitochondrial membrane]]. Its expression is regulated by the [[transcription factor]]s SP1, GATA2, and TBP via the [[Cyclic adenosine monophosphate|CAMP]] pathway in response to stress such as [[ischemia]] and [[inflammation]].<ref name=pmid25810277/>

== Clinical significance ==

=== Cancer ===

MAO-A 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.<ref name="pietrangeli">{{vcite2 journal | vauthors = Pietrangeli P, Mondovì B | title = Amine oxidases and tumors | journal = Neurotoxicology | volume = 25 | issue = 1–2 | pages = 317–24 | date = Jan 2004 | pmid = 14697906 | doi = 10.1016/S0161-813X(03)00109-8 }}</ref>  [[Cholangiocarcinoma]] suppresses MAO-A expression, and those patients with higher MAO-A expression had less adjacent organ invasion and better prognosis and survival.<ref name="huang">{{vcite2 journal | vauthors = 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 | title = Monoamine oxidase A expression is suppressed in human cholangiocarcinoma via coordinated epigenetic and IL-6-driven events | journal = Laboratory Investigation | volume = 92 | issue = 10 | pages = 1451–60 | date = Oct 2012 | pmid = 22906985 | doi = 10.1038/labinvest.2012.110 }}</ref>

=== Cardiovascular disease ===

MAOA activity is linked to [[apoptosis]] and cardiac damage during cardiac injury following ischemic-[[reperfusion injury|reperfusion]].<ref name=pmid25810277/>

=== Behavioral and neurological disorders ===
There is a link between low activities forms of the ''MAOA'' gene and [[autism]].<ref name="Cohen_2011">{{vcite2 journal |vauthors=Cohen IL, Liu X, Lewis ME, Chudley A, Forster-Gibson C, Gonzalez M, Jenkins EC, Brown WT, Holden JJ |title=Autism severity is associated with child and maternal MAOA genotypes |journal=Clinical Genetics |volume=79 |issue=4 |pages=355–62 |date=Apr 2011 |pmid=20573161 |doi=10.1111/j.1399-0004.2010.01471.x}}</ref> Mutations in the MAOA gene results in monoamine oxidase deficiency, or [[Brunner syndrome]].<ref name=entrez /> Other disorders associated with MAO-A include [[Alzheimer's disease]], [[aggression]], [[panic disorder]], [[bipolar affective disorder]], [[major depressive disorder]], and [[attention deficit hyperactivity disorder]].<ref name="pmid25810277" /> Effects of parenting on self-regulation in adolescents appear to be moderated by 'plasticity alleles', of which the 2R and 3R alleles of MAOA are two, with "the more plasticity alleles males (but not females) carried, the more and less self-regulation they manifested under, respectively, supportive and unsupportive parenting conditions."<ref name="pmid21039487">{{vcite2 journal |vauthors=Belsky J, Beaver KM |title=Cumulative-genetic plasticity, parenting and adolescent self-regulation |journal=Journal of Child Psychology and Psychiatry |volume=52 |issue=5 |pages=619–626 |date=May 2011 |pmid=21039487 |doi=10.1111/j.1469-7610.2010.02327.x |pmc=4357655}}</ref>

==== Depression ====
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]].<ref name="pmid17088501">{{vcite2 journal |vauthors=Meyer JH, Ginovart N, Boovariwala A, Sagrati S, Hussey D, Garcia A, Young T, Praschak-Rieder N, Wilson AA, Houle S |title=Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression |journal=Archives of General Psychiatry |volume=63 |issue=11 |pages=1209–16 |date=Nov 2006 |pmid=17088501 |doi=10.1001/archpsyc.63.11.1209}}</ref> 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,<ref name="pmid11121185">{{vcite2 journal |vauthors=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 |title=Association between a functional polymorphism in the monoamine oxidase A gene promoter and major depressive disorder |journal=American Journal of Medical Genetics |volume=96 |issue=6 |pages=801–3 |date=Dec 2000 |pmid=11121185 |doi=10.1002/1096-8628(20001204)96:6<801::AID-AJMG21>3.0.CO;2-4}}</ref> depressed suicide in males,<ref name="pmid12151768">{{vcite2 journal |vauthors=Du L, Faludi G, Palkovits M, Sotonyi P, Bakish D, Hrdina PD |title=High activity-related allele of MAO-A gene associated with depressed suicide in males |journal=NeuroReport |volume=13 |issue=9 |pages=1195–8 |date=Jul 2002 |pmid=12151768 |doi=10.1097/00001756-200207020-00025}}</ref> major depression and sleep disturbance in males<ref name="pmid15486489">{{vcite2 journal |vauthors=Du L, Bakish D, Ravindran A, Hrdina PD |title=MAO-A gene polymorphisms are associated with major depression and sleep disturbance in males |journal=NeuroReport |volume=15 |issue=13 |pages=2097–101 |date=Sep 2004 |pmid=15486489 |doi=10.1097/00001756-200409150-00020}}</ref> and major depressive disorder in both males and females.<ref name="pmid15956990">{{vcite2 journal |vauthors=Yu YW, Tsai SJ, Hong CJ, Chen TJ, Chen MC, Yang CW |title=Association study of a monoamine oxidase a gene promoter polymorphism with major depressive disorder and antidepressant response |journal=Neuropsychopharmacology |volume=30 |issue=9 |pages=1719–23 |date=Sep 2005 |pmid=15956990 |doi=10.1038/sj.npp.1300785}}</ref>

Other studies failed to find a significant relationship between high-activity variants of the ''MAOA'' gene and major depressive disorder.<ref name="pmid11992558">{{vcite2 journal |vauthors=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 |title=Family-based association study of 5-HTTLPR, TPH, MAO-A, and DRD4 polymorphisms in mood disorders |journal=American Journal of Medical Genetics |volume=114 |issue=4 |pages=361–9 |date=May 2002 |pmid=11992558 |doi=10.1002/ajmg.10356}}</ref><ref name="pmid19224413">{{vcite2 journal |vauthors=Huang SY, Lin MT, Lin WW, Huang CC, Shy MJ, Lu RB |title=Association of monoamine oxidase A (MAOA) polymorphisms and clinical subgroups of major depressive disorders in the Han Chinese population |journal=The World Journal of Biological Psychiatry |volume=10 |issue=4 Pt 2 |pages=544–51 |year=2009 |pmid=19224413 |doi=10.1080/15622970701816506}}</ref> 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.<ref name="pmid19593178">{{vcite2 journal |vauthors=Leuchter AF, McCracken JT, Hunter AM, Cook IA, Alpert JE |title=Monoamine oxidase a and catechol-o-methyltransferase functional polymorphisms and the placebo response in major depressive disorder |journal=Journal of Clinical Psychopharmacology |volume=29 |issue=4 |pages=372–7 |date=Aug 2009 |pmid=19593178 |doi=10.1097/JCP.0b013e3181ac4aaf}}</ref>

==== Antisocial behavior ====
In humans, an association between the 2R allele of the [[variable number tandem repeat|VNTR]] region of the gene and an increase in the likelihood of committing serious crime or violence has been found.<ref name="pmid18212819" /><ref name="Guo_ Roettger_ Shih_2008">{{vcite2 journal |vauthors=Guo G, Roettger M, Shih JC |title=The integration of genetic propensities into social-control models of delinquency and violence among male youths |journal=American Sociological Review |volume=73 |issue=4 |pages=543–568 |date=August 2008 |doi=10.1177/000312240807300402 |url=http://www.asanet.org/galleries/default-file/Aug08ASRFeature.pdf |format=}}  {{webarchive |url=https://web.archive.org/web/20081202190216/http://www.asanet.org/galleries/default-file/Aug08ASRFeature.pdf |date=December 2, 2008}}</ref><ref name="beaver2012">{{cite journal  |vauthors=Beaver KM, etal |title=Exploring the association between the 2-repeat allele of the MAOA gene promoter polymorphism and psychopathic personality traits, arrests, incarceration, and lifetime antisocial behavior |journal=Personality and Individual Differences |year=2012 |doi=10.1016/j.paid.2012.08.014 |url=http://www.sciencedirect.com/science/article/pii/S0191886912004047 |volume=54 |issue=2 |pages=164–168}}</ref>

A connection between the MAO-A gene 3R version and several types of [[anti-social behaviour]] has been found: Maltreated children with genes causing high levels of MAO-A were less likely to develop antisocial behavior.<ref name="pmid12161658">{{vcite2 journal |vauthors=Caspi A, McClay J, Moffitt TE, Mill J, Martin J, Craig IW, Taylor A, Poulton R |title=Role of genotype in the cycle of violence in maltreated children |journal=Science |volume=297 |issue=5582 |pages=851–4 |date=Aug 2002 |pmid=12161658 |doi=10.1126/science.1072290 |laysummary=http://www.eurekalert.org/pub_releases/2002-08/uow-gmp072602.php |laydate=2002-08-01 |laysource=eurekalert.org}}</ref>  Low MAO-A activity alleles which are overwhelmingly the 3R allele in combination with abuse experienced during childhood resulted in an increased risk of aggressive behaviour as an adult,<ref name="pmid17534436">{{vcite2 journal |vauthors=Frazzetto G, Di Lorenzo G, Carola V, Proietti L, Sokolowska E, Siracusano A, Gross C, Troisi A |title=Early trauma and increased risk for physical aggression during adulthood: the moderating role of MAOA genotype |journal=PLOS ONE |volume=2 |issue=5 |pages=e486 |year=2007 |pmid=17534436 |pmc=1872046 | doi = 10.1371/journal.pone.0000486}}</ref> and men with the low activity MAOA allele were more genetically vulnerable even to punitive discipline as a predictor of antisocial behaviour.<ref name="doi10.1177/2167702613518046">{{vcite2 journal |vauthors=Choe DE, Shaw DS, Hyde LW, Forbes EE|title=Interactions Between Monoamine Oxidase A and Punitive Discipline in African American and Caucasian Men’s Antisocial Behavior |journal=Clinical Psychological Science |volume=2 |issue=5 |pages=591–601 |date=September 2014 |doi=10.1177/2167702613518046 |url=http://cpx.sagepub.com/content/2/5/591}}</ref> High testosterone, maternal tobacco smoking during pregnancy, poor material living standards, dropping out of school, and low IQ predicted violent behavior are associated with men with the low-activity alleles.<ref name="pmid22297589">{{vcite2 journal |vauthors=Fergusson DM, Boden JM, Horwood LJ, Miller A, Kennedy MA |title=Moderating role of the MAOA genotype in antisocial behaviour |journal=The British Journal of Psychiatry |volume=200 |issue=2 |pages=116–23 |date=Feb 2012 |pmid=22297589 |doi=10.1192/bjp.bp.111.093328}}</ref><ref name="pmid17429405">{{vcite2 journal |vauthors=Sjöberg RL, Ducci F, Barr CS, Newman TK, Dell'osso L, Virkkunen M, Goldman D |title=A non-additive interaction of a functional MAO-A VNTR and testosterone predicts antisocial behavior |journal=Neuropsychopharmacology |volume=33 |issue=2 |pages=425–30 |date=Jan 2008 |pmid=17429405 |pmc=2665792 |doi=10.1038/sj.npp.1301417}}</ref> The low-activity 3-repeat allele variant of the MAOA gene has also been found to occur frequently in men who join gangs.<ref>[http://europepmc.org/abstract/MED/24361183/reload=0;jsessionid=MEhqhPcx8wL15VZ6HSkU.18 The role of gene-gene interaction in the prediction of criminal behavior.]</ref>According to a large meta-analysis in 2014, the 3R allele had a small main effect on aggression and antisocial behavior, even in the absence of other interaction factors.<ref name="pmid24902785">{{vcite2 journal |vauthors=Ficks CA, Waldman ID |title=Candidate genes for aggression and antisocial behavior: a meta-analysis of association studies of the 5HTTLPR and MAOA-uVNTR |journal=Behavioral Genetics |volume=44 |issue=5 |pages=427–44 |date=Sep 2014 |pmid=24902785 |doi=10.1007/s10519-014-9661-y}}</ref>

==== {{anchor|Warrior gene}}Aggression and the "Warrior gene" ====
A version of the [[monoamine oxidase]]-A gene has been popularly referred to as the ''warrior gene''.<ref name=Hogenboom>{{cite news |last=Hogenboom |first=Melissa |url=http://www.bbc.com/news/science-environment-29760212 |title=Share this pageEmail Print Share this page |publisher=BBC News |date=28 October 2014 |accessdate=2014-11-01 |name-list-format=vanc}}</ref> 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]]).<ref name="maoa">{{OMIM|309850|MONOAMINE OXIDASE A; MAOA.}}</ref> In the variant, the allele associated with behavioural traits is shorter (30 [[base pair|bases]]) and may produce less MAO-A enzyme.<ref name="pmid9799080">{{vcite2 journal |vauthors=Sabol SZ, Hu S, Hamer D |title=A functional polymorphism in the monoamine oxidase A gene promoter |journal=Human Genetics |volume=103 |issue=3 |pages=273–9 |date=Sep 1998 |pmid=9799080 |doi=10.1007/s004390050816}}</ref> This gene variation is in a regulatory [[promoter (biology)|promoter]] region about 1,000 [[nucleobase|bases]] from the [[start codon|start]] of the region that [[translation (genetics)|encodes]] the MAO-A enzyme.

When faced with social exclusion or ostracism, individuals with the low activity ''MAOA'' gene showed higher levels of aggression than individuals with the high activity ''MAOA'' gene.<ref>{{vcite2 journal |vauthors=Gallardo-Pujol D, Andrés-Pueyo A, Maydeu-Olivares A |title=MAOA genotype, social exclusion and aggression: an experimental test of a gene-environment interaction |journal=Genes, Brain, and Behavior |volume=12 |issue=1 |pages=140–145|date=Feb 2013 |pmid=23067570 |doi=10.1111/j.1601-183X.2012.00868.x}}</ref>  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.<ref name="pmid19168625">{{vcite2 journal |vauthors=McDermott R, Tingley D, Cowden J, Frazzetto G, Johnson DD |title=Monoamine oxidase A gene (MAOA) predicts behavioral aggression following provocation |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=106 |issue=7 |pages=2118–23 |date=Feb 2009 |pmid=19168625 |pmc=2650118 |doi=10.1073/pnas.0808376106}}</ref>

"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".<ref name=Hook_2009>{{vcite2 journal |vauthors=Hook GR|title="Warrior genes" and the disease of being Māori |journal=MAI Review |year=2009 |issue=2 |pages=1–11 |url=http://www.review.mai.ac.nz/index.php/MR/article/view/222/243}}</ref> 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 (MAO-A) has been shown to be associated with aggressive behaviour in men of a Dutch family".<ref name="pmid7792602">{{vcite2 journal |vauthors=Cases O, Seif I, Grimsby J, Gaspar P, Chen K, Pournin S, Müller U, Aguet M, Babinet C, Shih JC |title=Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA |journal=Science |volume=268 |issue=5218 |pages=1763–6 |date=Jun 1995 |pmid=7792602 |pmc=2844866 |doi=10.1126/science.7792602}}</ref>

===== 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.<ref name="url_Psychology_Today">{{cite web |url= http://www.psychologytoday.com/blog/the-human-beast/201007/pity-the-poor-murderer-his-genes-made-him-do-it |title= Pity the poor murderer, his genes made him do it |author= Barber N |date= 2010-07-13 |id= Blog: "The Human Beast: Why we do what we do" |work= Psychology Today |accessdate= 2010-10-17}}</ref><ref name="url_NPR">{{cite web |url= http://www.npr.org/templates/story/story.php?storyId=128043329 |title= Can Your Genes Make You Murder? |author= Hagerty BB |date= 2010-07-01 |work=News > Science > Inside The Criminal Brain |publisher= National Public Radio |accessdate= 2010-10-17}}</ref> The results showed the effects of the 4-repeat allele of MAOA promoter polymorphism on physical aggressive behavior for women. It seems that there is an interaction between the 3-repeat allele of MAOA promoter polymorphism and emotional abuse experiences on aggressive behavior for women.<ref name="url_Psychology_Today" />

==== Epigenetics ====
Studies have linked methylation of the ''MAOA'' gene with nicotine and alcohol dependence in women.<ref name="pmid18454435">{{vcite2 journal |vauthors=Philibert RA, Gunter TD, Beach SR, Brody GH, Madan A |title=MAOA methylation is associated with nicotine and alcohol dependence in women |journal=American Journal of Medical Genetics Part B |volume=147B |issue=5 |pages=565–70 |date=Jul 2008 |pmid=18454435 |pmc=3685146 |doi=10.1002/ajmg.b.30778}}</ref>  A second ''MAOA'' VNTR promoter, P2, influences epigenetic methylation and interacts with having experienced child abuse to influence antisocial personality disorder symptoms, only in women.<ref name="philibert">{{vcite2 journal |vauthors=Philibert RA, Wernett P, Plume J, Packer H, Brody GH, Beach SR |title=Gene environment interactions with a novel variable Monoamine Oxidase A transcriptional enhancer are associated with antisocial personality disorder |journal=Biological Psychology |volume=87 |issue=3 |pages=366–71 |date=Jul 2011 |pmid=21554924 |pmc=3134149 |doi=10.1016/j.biopsycho.2011.04.007}}</ref>

== Animal studies ==

A dysfunctional ''MAOA'' gene has been correlated with increased aggression levels in mice,<ref name="Novel">{{vcite2 journal | vauthors = Scott AL, Bortolato M, Chen K, Shih JC | title = Novel monoamine oxidase A knock out mice with human-like spontaneous mutation | journal = NeuroReport | volume = 19 | issue = 7 | pages = 739–43 | date = May 2008 | pmid = 18418249 | pmc = 3435113 | doi = 10.1097/WNR.0b013e3282fd6e88 }}</ref><ref name="pmid17441000">{{vcite2 journal | vauthors = Vishnivetskaya GB, Skrinskaya JA, Seif I, Popova NK | title = Effect of MAO A deficiency on different kinds of aggression and social investigation in mice | journal = Aggressive Behavior | volume = 33 | issue = 1 | pages = 1–6 | year = 2007 | pmid = 17441000 | doi = 10.1002/ab.20161 }}</ref> and has been correlated with heightened levels of aggression in humans.<ref name="Abnormal">{{vcite2 journal | vauthors = Brunner HG, Nelen M, Breakefield XO, Ropers HH, van Oost BA | title = Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A | journal = Science | volume = 262 | issue = 5133 | pages = 578–80 | date = Oct 1993 | pmid = 8211186 | doi = 10.1126/science.8211186 }}</ref> In mice, a dysfunctional ''MAOA'' gene is created through insertional mutagenesis (called ‘Tg8’).<ref name="Novel" /> 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.<ref name="Novel" /><ref>{{vcite2 journal | vauthors = Vishnivetskaya GB, Skrinskaya JA, Seif I, Popova NK | title = Effect of MAO A deficiency on different kinds of aggression and social investigation in mice | journal = Aggressive Behavior | volume = 33 | issue = 1 | pages = 1–6 | date = 1 January 2007 | pmid = 17441000 | doi = 10.1002/ab.20161 }}</ref>

Some types of aggression exhibited by these mice were territorial aggression, predatory aggression, and isolation-induced aggression.<ref name="pmid17441000" /> 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.<ref name="pmid7649563">{{vcite2 journal | vauthors = Hebebrand J, Klug B | title = Specification of the phenotype required for men with monoamine oxidase type A deficiency | journal = Human Genetics | volume = 96 | issue = 3 | pages = 372–6 | date = Sep 1995 | pmid = 7649563 | doi = 10.1007/BF00210430 }}</ref> 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.<ref name="Novel"/><ref name="Abnormal"/>

== Interactions ==

=== Transcription factors ===

A number of [[transcription factor]]s that the bind to the [[promoter (genetics)|promoter]] of MAO-A and thereby [[up regulate]] its expression. These include:[[Sp1 transcription factor]], [[GATA2]], [[TATA Binding Protein|TBP]].<ref name=pmid25810277/>

=== Inducers ===

Synthetic compounds that up-regulate the expression of MAO-A include [[Valproic acid]] (Depakote)<ref name="mao-a-depakote">{{vcite2 journal | vauthors = Wu JB, Shih JC | title = Valproic acid induces monoamine oxidase A via Akt/forkhead box O1 activation | journal = Molecular Pharmacology | volume = 80 | issue = 4 | pages = 714–723 | date = Oct 2011 | pmid = 21775495 | pmc = 3187529 | doi = 10.1124/mol.111.072744 }}</ref>

=== Inhibitors ===

{{Main article|Reversible inhibitor of monoamine oxidase A|Monoamine oxidase inhibitor}}

Substances that inhibit the enzymatic activity of MAO-A include:
{{div col|colwidth=25em}}
*Synthetic compounds
** [[Befloxatone]] (MD370503)
** [[Brofaromine]] (Consonar)
** [[Cimoxatone]]
** [[Clorgyline]] (irreversible)
** [[Methylene Blue]]
** [[Minaprine]] (Cantor)
** [[Moclobemide]] (Aurorix, Manerix)
** [[Phenelzine]] (Nardil)
** [[Pirlindole]] (Pirazidol)
** [[Toloxatone]] (Humoryl)
** [[Tyrima]] (CX 157)
** [[Tranylcypromine]] (nonselective and irreversible)
*Natural products
** [[Incarviatone A]]
*Herbal sources
** [[Curcumin]] ([[Turmeric]])
** [[Garlic]] ([[Garlic]])
** [[Harmala alkaloid|Harmala Alkaloid]]s ([[Syrian Rue]], [[Passion Flower]], [[Banisteriopsis caapi|Ayahuasca]])
*** [[Harmine]]
*** [[Harmaline]]
{{Div col end}}

== See also ==
* [[Monoamine oxidase B]]

== References ==
{{reflist|2}}
Rehan W., Sandnabba N.K., Johansson A., Westberg L., & Santtila P. (2015). Effects of MAOA genotype and childhood experiences of physical and emotional abuse on aggressive behavior in adulthood. Nordic Psychology. DOI:10.1080/19012276.2015.1026922.

== Further reading ==
{{refbegin|2}}
* {{cite web |url=http://www.sciencedaily.com/releases/2009/01/090121093343.htm |title={{-'}}Warrior Gene' Predicts Aggressive Behavior After Provocation |date=2009-01-23 |work=Science News |publisher=Science Daily}}
* {{vcite2 journal | vauthors = McDermott R, Tingley D, Cowden J, Frazzetto G, Johnson DD | title = Monoamine oxidase A gene (MAOA) predicts behavioral aggression following provocation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 7 | pages = 2118–23 | date = Feb 2009 | pmid = 19168625 | pmc = 2650118 | doi = 10.1073/pnas.0808376106 }}
* {{vcite2 journal | vauthors = Edmondson DE, Binda C, Mattevi A | title = The FAD binding sites of human monoamine oxidases A and B | journal = Neurotoxicology | volume = 25 | issue = 1–2 | pages = 63–72 | date = Jan 2004 | pmid = 14697881 | doi = 10.1016/S0161-813X(03)00114-1 }}
* {{vcite2 journal | vauthors = Craig IW | title = The importance of stress and genetic variation in human aggression | journal = BioEssays | volume = 29 | issue = 3 | pages = 227–36 | date = Mar 2007 | pmid = 17295220 | doi = 10.1002/bies.20538 }}
{{refend}}

{{Commons category|Monoamine oxidase A}}

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{{Mitochondrial enzymes}}
{{Neurotransmitter metabolism enzymes}}
{{CH-NH2 oxidoreductases}}
{{Enzymes}}
{{Monoamine metabolism modulators}}
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{{DEFAULTSORT:Monoamine Oxidase A}}
[[Category:Aggression]]
[[Category:EC 1.4.3]]
[[Category:Human proteins]]

[[de:Warrior Gene]]