View source for Monoamine oxidase A

{{Short description|Endogenous enzyme}}
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{{Infobox gene}}
[[File:MAOA Gene with ChrX Ideogram.svg|thumb|MAOA gene is located on the short (p) arm of the [[X chromosome]] at position 11.3.]]
'''Monoamine oxidase A''', also known as '''MAO-A''', is an [[enzyme]] ([[Enzyme classification|E.C.]] 1.4.3.4) that in [[human]]s is encoded by the ''MAOA'' [[gene]].<ref name="pmid1678250">{{cite 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 = August 1991 | pmid = 1678250 | pmc = 1683299 }}</ref><ref name="pmid2023912">{{cite 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 | bibcode = 1991PNAS...88.3637G | author-link5 = Jean Chen Shih | doi-access = free }}</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 [[norepinephrine]], [[serotonin]] and [[tyramine]]. 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>

== Structures ==

=== 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"/><ref name="pmid2023912"/> 
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 = July 2015 | pmid = 25810277 | doi = 10.1111/jnc.13099 | s2cid = 21044944 | doi-access = free }}</ref> This gene is adjacent to a related gene (''[[MAOB]]'') on the opposite strand of the [[X chromosome]].<ref name="pmid22377710">{{cite journal | vauthors = Eccles DA, Macartney-Coxson D, Chambers GK, Lea RA | title = A unique demographic history exists for the MAO-A gene in Polynesians | journal = [[Journal of Human Genetics]] | volume = 57 | pages = 294–300 | date = 10 January 2012 | issue = 5 | pmid=22377710 | doi = 10.1038/jhg.2012.19 | doi-access = free }}</ref>

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 all populations. The variants of the promoter have been found to appear at different frequencies in different ethnic groups in an American sample cohort.<ref name="pmid9799080">{{cite 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 = September 1998 | pmid = 9799080 | doi = 10.1007/s004390050816 | url = https://zenodo.org/record/1232725 | s2cid = 29954052 }}</ref>

The [[epigenetic]] modification of ''MAOA'' gene expression through methylation likely plays an important role in women. 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">{{cite journal | vauthors = Wong CC, Caspi A, Williams B, Craig IW, Houts R, Ambler A, Moffitt TE, Mill J | display-authors = 6 | title = A longitudinal study of epigenetic variation in twins | journal = Epigenetics | volume = 5 | issue = 6 | pages = 516–26 | date = August 2010 | pmid = 20505345 | pmc = 3322496 | doi = 10.4161/epi.5.6.12226 }}</ref><ref name="pmid19005036">{{cite journal | vauthors = Jiang Y, Langley B, Lubin FD, Renthal W, Wood MA, Yasui DH, Kumar A, Nestler EJ, Akbarian S, Beckel-Mitchener AC | display-authors = 6 | title = Epigenetics in the nervous system | journal = The Journal of Neuroscience | volume = 28 | issue = 46 | pages = 11753–9 | date = November 2008 | pmid = 19005036 | pmc = 3844836 | doi = 10.1523/JNEUROSCI.3797-08.2008 }}</ref>

=== Protein ===

MAO-A shares 70% [[amino acid]] sequence identity with its homologue MAO-B.<ref name=pmid21971000>{{Cite book | vauthors = Binda C, Mattevi A, Edmondson DE | 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 | title = Monoamine Oxidase and their Inhibitors | chapter = Structural properties of human monoamine oxidases a and B }}</ref> Accordingly, both proteins have similar structures.  Both MAO-A and MAO-B exhibit an [[N-terminal]] [[protein domain|domain]] that binds [[flavin adenine dinucleotide]] (FAD), a central domain that binds the amine substrate, and a [[C-terminal]] [[alpha-helix|α-helix]] that is inserted in the [[outer mitochondrial membrane]].<ref name=pmid21971000 /><ref name=Iacovino>{{cite journal | vauthors = Iacovino LG, Magnani F, Binda C | title = The structure of monoamine oxidases: past, present, and future | journal = Journal of Neural Transmission | volume = 125 | issue = 11 | pages = 1567–1579 | date = November 2018 | pmid = 30167931 | doi = 10.1007/s00702-018-1915-z | s2cid = 52133633 }}</ref>  MAO-A has a slightly larger substrate-binding cavity than MAO-B, which may be the cause of slight differences in catalytic activity between the two enzymes, as shown in [[quantitative structure-activity relationship]] experiments.<ref name=Edmondson>{{cite journal | vauthors = Edmondson DE, Binda C, Mattevi A | title = Structural insights into the mechanism of amine oxidation by monoamine oxidases A and B | journal = Archives of Biochemistry and Biophysics | volume = 464 | issue = 2 | pages = 269–276 | date = August 2007 | pmid = 17573034 | doi = 10.1016/j.abb.2007.05.006 | pmc = 1993809 }}</ref> Both enzymes are relatively large, about 60 kilodaltons in size, and are believed to function as [[dimeric protein|dimers]] in living cells.<ref name=Iacovino />

== Function ==

Monoamine oxidase A catalyzes [[oxygen|O<sub>2</sub>]]-dependent oxidation of primary arylalkyl [[amines]], most importantly [[neurotransmitters]] such as [[serotonin]] and [[dopamine]]. MAO-A primarily catabolises dopamine peripherally, rather than in the brain, which is done by [[Monoamine oxidase B|MAO-B]].  This is the initial step in the breakdown of these molecules.  The products are the corresponding [[aldehyde]], [[hydrogen peroxide]], and [[ammonia]]:

:R{{chem|C|H|2}}-Amine + {{chem|O|2}} + {{chem|H|2|O}} → R-Aldehyde + {{chem|H|2|O|2}} + {{chem|N|H|3}}

This reaction is believed to occur in three steps, using FAD as an electron-transferring cofactor.  First, the amine is oxidized to the corresponding [[imine]], with reduction of FAD to FADH<sub>2</sub>.  Second, O<sub>2</sub> accepts two electrons and two protons from FADH<sub>2</sub>, forming {{chem|H|2|O|2}} and regenerating FAD.  Third, the imine is [[hydrolyzed]] by water, forming ammonia and the aldehyde.<ref name=Edmondson /><ref name=Binda>{{cite journal | vauthors = Binda C, Mattevi A, Edmondson DE | title = Structure-function relationships in flavoenzyme-dependent amine oxidations: A comparison of polyamine oxidase and monoamine oxidase | journal = Journal of Biological Chemistry | volume = 277 | issue = 27 | pages = 23973–23976 | date = July 5, 2002 | doi = 10.1074/jbc.R200005200 | pmid = 12015330 | doi-access = free }}</ref>

Compared to MAO-B, MAO-A has a higher specificity for serotonin and [[norepinephrine]], while the two enzymes have similar affinity for dopamine and [[tyramine]].<ref name=Kolla>{{cite journal | vauthors = Kolla NJ, Bortolato M | title = The role of monoamine oxidase A in the neurobiology of aggressive, antisocial, and violent behavior: A tale of mice and men | journal = Progress in Neurobiology | volume = 194 | pages = 101875 | date = June 2020 | doi = 10.1016/j.pneurobio.2020.101875 | pmid = 32574581 | pmc = 7609507 }}</ref>

MAO-A is a key regulator for normal brain function. In the brain, the highest levels of [[Transcription (biology)|transcription]] occur in the [[brain stem]], [[hypothalamus]], [[amygdala]], [[habenula]], and [[nucleus accumbens]], and the lowest in the [[thalamus]], [[spinal cord]], [[pituitary gland]], and [[cerebellum]].<ref name=Kolla /> Its expression is regulated by the [[transcription factor]]s SP1, GATA2, and TBP via [[Cyclic adenosine monophosphate|cAMP]]-dependent regulation.<ref name=pmid25810277/><ref name=Kolla />  MAO-A is also expressed in [[cardiomyocytes]], where it is induced 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">{{cite journal | vauthors = Pietrangeli P, Mondovì B | title = Amine oxidases and tumors | journal = Neurotoxicology | volume = 25 | issue = 1–2 | pages = 317–24 | date = January 2004 | pmid = 14697906 | doi = 10.1016/S0161-813X(03)00109-8 | bibcode = 2004NeuTx..25..317P }}</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">{{cite 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 | display-authors = 6 | title = Monoamine oxidase A expression is suppressed in human cholangiocarcinoma via coordinated epigenetic and IL-6-driven events | journal = Laboratory Investigation; A Journal of Technical Methods and Pathology | volume = 92 | issue = 10 | pages = 1451–60 | date = October 2012 | pmid = 22906985 | pmc = 3959781 | 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 some association between low activity forms of the ''MAOA'' gene and [[autism]].<ref name="Cohen_2011">{{cite journal | vauthors = Cohen IL, Liu X, Lewis ME, Chudley A, Forster-Gibson C, Gonzalez M, Jenkins EC, Brown WT, Holden JJ | display-authors = 6 | title = Autism severity is associated with child and maternal MAOA genotypes | journal = Clinical Genetics | volume = 79 | issue = 4 | pages = 355–62 | date = April 2011 | pmid = 20573161 | doi = 10.1111/j.1399-0004.2010.01471.x | s2cid = 24366751 }}</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 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">{{cite journal | vauthors = Belsky J, Beaver KM | title = Cumulative-genetic plasticity, parenting and adolescent self-regulation | journal = Journal of Child Psychology and Psychiatry, and Allied Disciplines | volume = 52 | issue = 5 | pages = 619–26 | date = May 2011 | pmid = 21039487 | pmc = 4357655 | doi = 10.1111/j.1469-7610.2010.02327.x }}</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">{{cite journal | vauthors = Meyer JH, Ginovart N, Boovariwala A, Sagrati S, Hussey D, Garcia A, Young T, Praschak-Rieder N, Wilson AA, Houle S | display-authors = 6 | 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 = November 2006 | pmid = 17088501 | doi = 10.1001/archpsyc.63.11.1209 | doi-access = free }}</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">{{cite 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 | display-authors = 6 | 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 = December 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">{{cite 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 = July 2002 | pmid = 12151768 | doi = 10.1097/00001756-200207020-00025 | s2cid = 19874514 }}</ref> major depression and sleep disturbance in males<ref name="pmid15486489">{{cite 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 = September 2004 | pmid = 15486489 | doi = 10.1097/00001756-200409150-00020 | s2cid = 39844598 }}</ref> and major depressive disorder in both males and females.<ref name="pmid15956990">{{cite 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 = September 2005 | pmid = 15956990 | doi = 10.1038/sj.npp.1300785 | doi-access = free }}</ref>

Other studies failed to find a significant relationship between high-activity variants of the ''MAOA'' gene and major depressive disorder.<ref name="pmid11992558">{{cite 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 | display-authors = 6 | 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">{{cite 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 | s2cid = 30281258 }}</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">{{cite 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 = August 2009 | pmid = 19593178 | doi = 10.1097/JCP.0b013e3181ac4aaf | s2cid = 29200403 }}</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. The VNTR 2R allele of MAOA has been found to be a risk factor for violent delinquency, when present in association with stresses, i.e. family issues, low popularity or failing school.<ref>{{cite web | vauthors = Garcia-Arocena D | title = The Genetics of Violent Behavior |url=https://www.jax.org/news-and-insights/jax-blog/2015/december/the-genetics-of-violent-behavior# |website=The Jackson Laboratory |access-date=2021-03-23}}</ref><ref name="pmid18212819">{{cite 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><ref name="Guo_ Roettger_ Shih_2008">{{cite 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 |s2cid=30271933 }}</ref><ref name="beaver2012">{{cite journal | vauthors = Beaver KM, Wright JP, Boutwell BB, Barnes JC, DeLisi M, Vaughn MG |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 |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">{{cite journal | vauthors = Caspi A, McClay J, Moffitt TE, Mill J, Martin J, Craig IW, Taylor A, Poulton R | display-authors = 6 | title = Role of genotype in the cycle of violence in maltreated children | journal = Science | volume = 297 | issue = 5582 | pages = 851–4 | date = August 2002 | pmid = 12161658 | doi = 10.1126/science.1072290 | s2cid = 7882492 | bibcode = 2002Sci...297..851C}}
*{{cite press release |date=2002-08-01 |title=Gene may protect abused kids against behavior problems |website=EurekAlert! |url=http://www.eurekalert.org/pub_releases/2002-08/uow-gmp072602.php}}</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">{{cite journal | vauthors = Frazzetto G, Di Lorenzo G, Carola V, Proietti L, Sokolowska E, Siracusano A, Gross C, Troisi A | display-authors = 6 | 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 | date = May 2007 | pmid = 17534436 | pmc = 1872046 | doi = 10.1371/journal.pone.0000486 | bibcode = 2007PLoSO...2..486F | doi-access = free }}</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">{{cite 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 | pmid = 27014508 | pmc = 4802365 | doi = 10.1177/2167702613518046 }}</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">{{cite 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 = February 2012 | pmid = 22297589 | pmc = 3269651 | doi = 10.1192/bjp.bp.111.093328 }}</ref><ref name="pmid17429405">{{cite 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 = January 2008 | pmid = 17429405 | pmc = 2665792 | doi = 10.1038/sj.npp.1301417 }}</ref> According to a large meta-analysis in 2014, the 3R allele had a small, nonsignificant effect on aggression and antisocial behavior, in the absence of other interaction factors. Owing to methodological concerns, the authors do not view this as evidence in favor of an effect.<ref name="pmid24902785">{{cite 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 = Behavior Genetics | volume = 44 | issue = 5 | pages = 427–44 | date = September 2014 | pmid = 24902785 | doi = 10.1007/s10519-014-9661-y | s2cid = 11599122 }}</ref>

The ''MAO-A'' gene was the first candidate gene for antisocial behavior and was identified during a "molecular genetic analysis of a large, multigenerational, and notoriously violent, Dutch kindred".<ref name="Dorfman_2014">{{cite book | vauthors = Dorfman HM, Meyer-Lindenberg A, Buckholtz JW | title = Neuroscience of Aggression | chapter = Neurobiological mechanisms for impulsive-aggression: the role of MAOA | series = Current Topics in Behavioral Neurosciences| volume = 17 | pages = 297–313 | date = 2014 | pmid = 24470068 | doi = 10.1007/7854_2013_272 | isbn = 978-3-662-44280-7 }}</ref> A study of Finnish prisoners revealed that a MAOA-L (low-activity) genotype, which contributes to low dopamine turnover rate, was associated with extremely violent behavior.<ref name="Tiihonen_2015">{{cite journal | vauthors = Tiihonen J, Rautiainen MR, Ollila HM, Repo-Tiihonen E, Virkkunen M, Palotie A, Pietiläinen O, Kristiansson K, Joukamaa M, Lauerma H, Saarela J, Tyni S, Vartiainen H, Paananen J, Goldman D, Paunio T | title = Genetic Background of Extreme Violent Behavior | journal = Molecular Psychiatry | volume = 20 | issue = 6 | pages = 786–92 | date = June 2015 | pmid = 25349169 | pmc = 4776744 | doi = 10.1038/mp.2014.130 }}</ref> For the purpose of the study, "extremely violent behavior" was defined as at least ten committed homicides, attempted homicides or batteries.

However, a large genome-wide association study has failed to find any large or statistically significant effects of the MAOA gene on aggression.<ref>{{cite journal | vauthors = Vassos E, Collier DA, Fazel S | title = Systematic meta-analyses and field synopsis of genetic association studies of violence and aggression | journal = Molecular Psychiatry | volume = 19 | issue = 4 | pages = 471–7 | date = April 2014 | pmid = 23546171 | doi = 10.1038/mp.2013.31 | pmc = 3965568 | s2cid = 13936647 }}</ref> A separate GWAS on antisocial personality disorder likewise did not report a significant effect of MAOA.<ref>{{cite journal | vauthors = Rautiainen MR, Paunio T, Repo-Tiihonen E, Virkkunen M, Ollila HM, Sulkava S, Jolanki O, Palotie A, Tiihonen J | display-authors = 6 | title = Genome-wide association study of antisocial personality disorder | journal = Translational Psychiatry | volume = 6 | issue = 9 | pages = e883 | date = September 2016 | pmid = 27598967 | pmc = 5048197 | doi = 10.1038/tp.2016.155 }}</ref> Another study, while finding effects from a candidate gene search, failed to find any evidence in a large GWAS.<ref name="Tiihonen_2015" /> A separate analysis of human and rat genome wide association studies, Mendelian randomization studies, and causal pathway analyses likewise failed to reveal robust evidence of MAOA in aggression.<ref>{{cite journal | vauthors = Zhang-James Y, Fernàndez-Castillo N, Hess JL, Malki K, Glatt SJ, Cormand B, Faraone SV | title = An integrated analysis of genes and functional pathways for aggression in human and rodent models | journal = Molecular Psychiatry | volume = 24 | issue = 11 | pages = 1655–1667 | date = November 2019 | pmid = 29858598 | pmc = 6274606 | doi = 10.1038/s41380-018-0068-7 }}</ref> This lack of replication is predicted from the known issues of candidate gene research, which can produce many substantial false positives.<ref>{{cite journal | vauthors = Sullivan PF | title = Spurious genetic associations | journal = Biological Psychiatry | volume = 61 | issue = 10 | pages = 1121–6 | date = May 2007 | pmid = 17346679 | doi = 10.1016/j.biopsych.2006.11.010 | s2cid = 35033987 }}</ref>

==== {{anchor|Warrior gene}}Aggression and the "Warrior gene" ====
{{Further|Genetics of aggression}}
Low-activity variants of the VNTR promoter region of the ''MAO-A'' gene have been referred to as the ''warrior gene''.<ref name=Hogenboom>{{cite news | vauthors = Hogenboom M |url=https://www.bbc.com/news/science-environment-29760212 |title=Two genes linked with violent crime |work=BBC News |date=28 October 2014 |access-date=2014-11-01 }}</ref>  When faced with [[social exclusion]] or ostracism, individuals with the low activity ''MAO-A'' variants showed higher levels of aggression than individuals with the high activity ''MAO-A'' gene.<ref>{{cite 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 = 140–5 | date = February 2013 | pmid = 23067570 | doi = 10.1111/j.1601-183X.2012.00868.x | s2cid = 4830611 }}</ref>  Low activity MAO-A could significantly predict aggressive behaviour in a high provocation situation: Individuals with the low activity variant of the ''MAO-A'' gene were more likely (75% as opposed to 62%, out of a sample size of 70) to retaliate, and with greater force, as compared to those with a normal ''MAO-A'' variant if the perceived loss was large.<ref name="pmid19168625">{{cite 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 = February 2009 | pmid = 19168625 | pmc = 2650118 | doi = 10.1073/pnas.0808376106 | bibcode = 2009PNAS..106.2118M | doi-access = free }}</ref>

The effects of MAOA genes on aggression have also been criticized for being heavily overstated.<ref name=Horgan>{{cite web | title = Code rage: The "warrior gene" makes me mad! (Whether I have it or not) | vauthors = Horgan J | date = 26 April 2011 | work = Scientific American | url = https://blogs.scientificamerican.com/cross-check/code-rage-the-warrior-gene-makes-me-mad-whether-i-have-it-or-not/ }}</ref> Indeed, the MAOA gene, even in conjunction with childhood adversity, is known to have a very small effect.<ref>{{cite web | title = Chasing the 'warrior gene' and why it looks like a dud so far | vauthors = Hovet K | date = 20 February 2018 | work = Genetic Literacy Project | url =  https://geneticliteracyproject.org/2018/02/20/chasing-warrior-gene-looks-like-dud-far/ }}</ref> The vast majority of people with the associated alleles have not committed any violent acts.<ref>{{cite web | title = Do the MAOA and CDH13 'human warrior genes' make violent criminals—and what should society do? | vauthors = Powledge TM | date = 29 July 2016 | work = Genetic Literacy Project | url = https://geneticliteracyproject.org/2016/07/29/does-the-human-warrior-gene-make-violent-criminals-and-what-should-society-do/ }}</ref><ref>{{cite web | title = MAOA and CDH13 genes linked to violent crime, but can they explain criminal behavior? | work = Genetic Literacy Project| date = 29 October 2014| url = https://geneticliteracyproject.org/2014/10/29/genes-linked-to-violent-crime-but-can-they-explain-criminal-behavior/ }}</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 | vauthors = Barber N |date= 2010-07-13 |id= Blog: "The Human Beast: Why we do what we do" |website= Psychology Today |access-date= 2010-10-17}}</ref><ref name="url_NPR">{{cite news |url= https://www.npr.org/templates/story/story.php?storyId=128043329 |title= Can Your Genes Make You Murder? | vauthors = Hagerty BB |date= 2010-07-01 |newspaper=NPR.org |publisher= National Public Radio |access-date= 2010-10-17}}</ref> In a second case, an individual was convicted of second-degree murder, rather than first-degree murder, based on a genetic test that revealed he had the low-activity MAOA variant.<ref>{{cite journal | vauthors = Scurich N, Appelbaum PS | title = ''State v. Yepez:'' Admissibility and Relevance of Behavioral Genetic Evidence in a Criminal Trial | journal = Psychiatric Services | volume = 72 | issue = 7 | pages = 853–855 | date = July 2021 | pmid = 34074149 | doi = 10.1176/appi.ps.202100226 | s2cid = 235298342 }}</ref> Judges in Germany are more likely to sentence offenders to involuntary psychiatric hospitalization on hearing an accused's MAOA-L genotype.<ref>{{cite journal | vauthors = McSwiggan S, Elger B, Appelbaum PS | title = The forensic use of behavioral genetics in criminal proceedings: Case of the MAOA-L genotype | journal = International Journal of Law and Psychiatry | volume = 50 | pages = 17–23 | date = January 1, 2017 | pmid = 27823806 | doi = 10.1016/j.ijlp.2016.09.005 | pmc = 5250535 }}</ref>

==== Epigenetics ====
Studies have linked methylation of the ''MAOA'' gene with nicotine and alcohol dependence in women.<ref name="pmid18454435">{{cite 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, Neuropsychiatric Genetics | volume = 147B | issue = 5 | pages = 565–70 | date = July 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">{{cite 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 = July 2011 | pmid = 21554924 | pmc = 3134149 | doi = 10.1016/j.biopsycho.2011.04.007 }}</ref> A study of 34 non-smoking men found that methylation of the gene may alter its expression in the brain.<ref>{{cite journal | vauthors = Shumay E, Logan J, Volkow ND, Fowler JS | title = Evidence that the methylation state of the monoamine oxidase A (MAOA) gene predicts brain activity of MAO A enzyme in healthy men | journal = Epigenetics | volume = 7 | issue = 10 | pages = 1151–1160 | date = October 2012 | pmid = 22948232 | pmc = 3469457 | doi = 10.4161/epi.21976 }}</ref>

== Animal studies ==

A dysfunctional ''MAOA'' gene has been correlated with increased aggression levels in mice,<ref name="Novel">{{cite 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">{{cite 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 | doi-access = free }}</ref> and has been correlated with heightened levels of aggression in humans.<ref name="Abnormal">{{cite 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 = October 1993 | pmid = 8211186 | doi = 10.1126/science.8211186 | bibcode = 1993Sci...262..578B }}</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>{{cite 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 | doi-access = free }}</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">{{cite 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 = September 1995 | pmid = 7649563 | doi = 10.1007/BF00210430 | s2cid = 33294633 }}</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 bind to the [[promoter (genetics)|promoter]] region of MAO-A and [[upregulate]] 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">{{cite 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 = 714–23 | date = October 2011 | pmid = 21775495 | pmc = 3187529 | doi = 10.1124/mol.111.072744 }}</ref>

=== Inhibitors ===

{{Main|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 (herbal sources)
** [[Incarviatone A]] (''[[Incarvillea delavayi]]'')
** [[Garlic]] ([[Garlic]])
** [[Harmala alkaloid|β-Carboline alkaloid]]s ([[Syrian Rue]], [[Passion Flower]], [[Tobacco smoke]], [[Banisteriopsis caapi|Ayahuasca]])
*** [[Harmine]]
*** [[Harmaline]]
** [[Isoquinoline alkaloids]]
** [[Piperine]] ([[Black pepper]])<ref>{{cite journal | vauthors = Lee SA, Hong SS, Han XH, Hwang JS, Oh GJ, Lee KS, Lee MK, Hwang BY, Ro JS | display-authors = 6 | title = Piperine from the fruits of Piper longum with inhibitory effect on monoamine oxidase and antidepressant-like activity | journal = Chemical & Pharmaceutical Bulletin | volume = 53 | issue = 7 | pages = 832–5 | date = July 2005 | pmid = 15997146 | doi = 10.1248/cpb.53.832 | doi-access = free }}</ref>
** [[Rosiridin]]<ref>{{cite journal | vauthors = van Diermen D, Marston A, Bravo J, Reist M, Carrupt PA, Hostettmann K | title = Monoamine oxidase inhibition by Rhodiola rosea L. roots | journal = Journal of Ethnopharmacology | volume = 122 | issue = 2 | pages = 397–401 | date = March 2009 | pmid = 19168123 | doi = 10.1016/j.jep.2009.01.007 }}</ref> (''in vitro'')
{{Div col end}}

== See also ==
* [[Monoamine oxidase B]]
* [[Monoamine oxidase inhibitor]] - a class of antidepressant drugs that block or inactivate one or both MAO isoforms

== References ==
{{reflist}}

== Further reading ==
{{refbegin|30em}}
* {{cite journal | vauthors = Rehan W, Sandnabba NK, Johansson A, Westberg L, Santtila P | title = Effects of MAOA genotype and childhood experiences of physical and emotional abuse on aggressive behavior in adulthood. | journal = Nordic Psychology | date = October 2015 | volume = 67 | issue = 4 | pages = 301–12 | doi = 10.1080/19012276.2015.1026922| s2cid = 146577097 }}
* {{cite 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 = February 2009 | pmid = 19168625 | pmc = 2650118 | doi = 10.1073/pnas.0808376106 | bibcode = 2009PNAS..106.2118M | doi-access = free }}
* {{cite 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 = January 2004 | pmid = 14697881 | doi = 10.1016/S0161-813X(03)00114-1 | bibcode = 2004NeuTx..25...63E }}
* {{cite 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 = March 2007 | pmid = 17295220 | doi = 10.1002/bies.20538 | s2cid = 46059787 }}
{{refend}}

== External links ==
* {{PDBe-KB2|P21397|Human Monoamine oxidase A}}

{{Commons category|Monoamine oxidase A}}

{{PDB Gallery|geneid=4128}}
{{Mitochondrial enzymes}}
{{Neurotransmitter metabolism enzymes}}
{{CH-NH2 oxidoreductases}}
{{Enzymes}}
{{Monoamine metabolism modulators}}
{{Portal bar|Biology|border=no}}

{{DEFAULTSORT:Monoamine Oxidase A}}
[[Category:Aggression]]
[[Category:Criminology]]
[[Category:EC 1.4.3]]
[[Category:Human proteins]]

[[de:Warrior Gene]]