In humans, there is a 30-baserepeat sequence repeated several different numbers of times in thepromoter 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.[10]
Theepigenetic modification ofMAOA gene expression through methylation likely plays an important role in women. A study from 2010 found epigenetic methylation ofMAOA in men to be very low and with little variability compared to women, while having higher heritability in men than women.[11][12]
MAO-A shares 70%amino acid sequence identity with its homologue MAO-B.[13] Accordingly, both proteins have similar structures. Both MAO-A and MAO-B exhibit anN-terminaldomain that bindsflavin adenine dinucleotide (FAD), a central domain that binds the amine substrate, and aC-terminalα-helix that is inserted in theouter mitochondrial membrane.[13][14] 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 inquantitative structure-activity relationship experiments.[15] Both enzymes are relatively large, about 60 kilodaltons in size, and are believed to function asdimers in living cells.[14]
Monoamine oxidase A catalyzesO2-dependent oxidation of primary arylalkylamines, most importantlyneurotransmitters such asserotonin anddopamine. MAO-A primarily catabolises dopamine peripherally, rather than in the brain, which is done byMAO-B. This is the initial step in the breakdown of these molecules. The products are the correspondingaldehyde,hydrogen peroxide, andammonia:
RCH 2-Amine +O 2 +H 2O → R-Aldehyde +H 2O 2 +NH 3
This reaction is believed to occur in three steps, using FAD as an electron-transferring cofactor. First, the amine is oxidized to the correspondingimine, with reduction of FAD to FADH2. Second, O2 accepts two electrons and two protons from FADH2, formingH 2O 2 and regenerating FAD. Third, the imine ishydrolyzed by water, forming ammonia and the aldehyde.[15][16]
Compared to MAO-B, MAO-A has a higher specificity for serotonin andnorepinephrine, while the two enzymes have similar affinity for dopamine andtyramine.[17]
MAO-A produces an amine oxidase, which is a class of enzyme known to affect carcinogenesis.Clorgyline, an MAO-A enzyme inhibitor, preventsapoptosis inmelanoma cells, in vitro.[18]Cholangiocarcinoma suppresses MAO-A expression, and those patients with higher MAO-A expression had less adjacent organ invasion and better prognosis and survival.[19]
There is some association between low activity forms of theMAOA gene andautism.[20] Mutations in the MAOA gene results in monoamine oxidase deficiency, orBrunner syndrome.[7] Other disorders associated with MAO-A includeAlzheimer's disease,aggression,[clarification needed]panic disorder,bipolar disorder,major depressive disorder, andattention deficit hyperactivity disorder.[8] 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."[21]
MAO-A levels in the brain as measured usingpositron emission tomography are elevated by an average of 34% in patients withmajor depressive disorder.[22] Genetic association studies examining the relationship between high-activityMAOA variants and depression have produced mixed results, with some studies linking the high-activity variants to major depression in females,[23] depressed suicide in males,[24] major depression and sleep disturbance in males[25] and major depressive disorder in both males and females.[26]
Other studies failed to find a significant relationship between high-activity variants of theMAOA gene and major depressive disorder.[27][28] 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 ofplacebo response than those with other genotypes.[29]
In humans, an association between the 2R allele of theVNTR 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.[30][31][32][33]
A connection between theMAO-A gene 3R version and several types ofanti-social behaviour has been found: Maltreated children with genes causing high levels of MAO-A were less likely to develop antisocial behavior.[34] 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,[35] and men with the low activity MAOA allele were more genetically vulnerable even to punitive discipline as a predictor of antisocial behaviour.[36] 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.[37][38] 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.[39]
TheMAO-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".[40] 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.[41] 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.[42] A separate GWAS on antisocial personality disorder likewise did not report a significant effect of MAOA.[43] Another study, while finding effects from a candidate gene search, failed to find any evidence in a large GWAS.[41] 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.[44] This lack of replication is predicted from the known issues of candidate gene research, which can produce many substantial false positives.[45]
Low-activity variants of the VNTR promoter region of theMAO-A gene have been referred to as thewarrior gene.[46] When faced withsocial exclusion or ostracism, individuals with the low activityMAO-A variants showed higher levels of aggression than individuals with the high activityMAO-A gene.[47] Low activity MAO-A could significantly predict aggressive behaviour in a high provocation situation: Individuals with the low activity variant of theMAO-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 normalMAO-A variant if the perceived loss was large.[48]
The effects of MAOA genes on aggression have also been criticized for being heavily overstated.[49] Indeed, the MAOA gene, even in conjunction with childhood adversity, is known to have a very small effect.[50] The vast majority of people with the associated alleles have not committed any violent acts.[51][52]
In a 2009 criminal trial in the United States, an argument based on a combination of "warrior gene" and history ofchild abuse was successfully used to avoid a conviction offirst-degree murder and the death penalty; however, the convicted murderer was sentenced to 32 years in prison.[53][54] 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.[55] Judges in Germany are more likely to sentence offenders to involuntary psychiatric hospitalization on hearing an accused's MAOA-L genotype.[56]
Studies have linked methylation of theMAOA gene with nicotine and alcohol dependence in women.[57] A secondMAOA VNTR promoter, P2, influences epigenetic methylation and interacts with having experienced child abuse to influence antisocial personality disorder symptoms, only in women.[58] A study of 34 non-smoking men found that methylation of the gene may alter its expression in the brain.[59]
A dysfunctionalMAOA gene has been correlated with increased aggression levels in mice,[60][61] and has been correlated with heightened levels of aggression in humans.[62] In mice, a dysfunctionalMAOA gene is created through insertional mutagenesis (called 'Tg8').[60] Tg8 is a transgenic mouse strain that lacks functional MAO-A enzymatic activity. Mice that lacked a functionalMAOA gene exhibited increased aggression towards intruder mice.[60][63]
Some types of aggression exhibited by these mice were territorial aggression, predatory aggression, and isolation-induced aggression.[61] 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.[64] There is research in both humans and mice to support that a nonsense point mutation in the eighth exon of theMAOA gene is responsible for impulsive aggressiveness due to a complete MAO-A deficiency.[60][62]
^abIacovino LG, Magnani F, Binda C (November 2018). "The structure of monoamine oxidases: past, present, and future".Journal of Neural Transmission.125 (11):1567–1579.doi:10.1007/s00702-018-1915-z.PMID30167931.S2CID52133633.
^Cohen IL, Liu X, Lewis ME, Chudley A, Forster-Gibson C, Gonzalez M, et al. (April 2011). "Autism severity is associated with child and maternal MAOA genotypes".Clinical Genetics.79 (4):355–62.doi:10.1111/j.1399-0004.2010.01471.x.PMID20573161.S2CID24366751.
^Schulze TG, Müller DJ, Krauss H, Scherk H, Ohlraun S, Syagailo YV, et al. (December 2000). "Association between a functional polymorphism in the monoamine oxidase A gene promoter and major depressive disorder".American Journal of Medical Genetics.96 (6):801–3.doi:10.1002/1096-8628(20001204)96:6<801::AID-AJMG21>3.0.CO;2-4.PMID11121185.
^Du L, Faludi G, Palkovits M, Sotonyi P, Bakish D, Hrdina PD (July 2002). "High activity-related allele of MAO-A gene associated with depressed suicide in males".NeuroReport.13 (9):1195–8.doi:10.1097/00001756-200207020-00025.PMID12151768.S2CID19874514.
^Du L, Bakish D, Ravindran A, Hrdina PD (September 2004). "MAO-A gene polymorphisms are associated with major depression and sleep disturbance in males".NeuroReport.15 (13):2097–101.doi:10.1097/00001756-200409150-00020.PMID15486489.S2CID39844598.
^Serretti A, Cristina S, Lilli R, Cusin C, Lattuada E, Lorenzi C, et al. (May 2002). "Family-based association study of 5-HTTLPR, TPH, MAO-A, and DRD4 polymorphisms in mood disorders".American Journal of Medical Genetics.114 (4):361–9.doi:10.1002/ajmg.10356.PMID11992558.
^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".The World Journal of Biological Psychiatry.10 (4 Pt 2):544–51.doi:10.1080/15622970701816506.PMID19224413.S2CID30281258.
^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".Journal of Clinical Psychopharmacology.29 (4):372–7.doi:10.1097/JCP.0b013e3181ac4aaf.PMID19593178.S2CID29200403.
^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.S2CID30271933.
^Beaver KM, Wright JP, Boutwell BB, Barnes JC, DeLisi M, Vaughn MG (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.54 (2):164–168.doi:10.1016/j.paid.2012.08.014.
^Ficks CA, Waldman ID (September 2014). "Candidate genes for aggression and antisocial behavior: a meta-analysis of association studies of the 5HTTLPR and MAOA-uVNTR".Behavior Genetics.44 (5):427–44.doi:10.1007/s10519-014-9661-y.PMID24902785.S2CID11599122.
^Dorfman HM, Meyer-Lindenberg A, Buckholtz JW (2014). "Neurobiological mechanisms for impulsive-aggression: the role of MAOA".Neuroscience of Aggression. Current Topics in Behavioral Neurosciences. Vol. 17. pp. 297–313.doi:10.1007/7854_2013_272.ISBN978-3-662-44280-7.PMID24470068.
^Gallardo-Pujol D, Andrés-Pueyo A, Maydeu-Olivares A (February 2013). "MAOA genotype, social exclusion and aggression: an experimental test of a gene-environment interaction".Genes, Brain and Behavior.12 (1):140–5.doi:10.1111/j.1601-183X.2012.00868.x.PMID23067570.S2CID4830611.
^Scurich N, Appelbaum PS (July 2021). "State v. Yepez: Admissibility and Relevance of Behavioral Genetic Evidence in a Criminal Trial".Psychiatric Services.72 (7):853–855.doi:10.1176/appi.ps.202100226.PMID34074149.S2CID235298342.
^abBrunner 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.Bibcode:1993Sci...262..578B.doi:10.1126/science.8211186.PMID8211186.
^Hebebrand J, Klug B (September 1995). "Specification of the phenotype required for men with monoamine oxidase type A deficiency".Human Genetics.96 (3):372–6.doi:10.1007/BF00210430.PMID7649563.S2CID33294633.
^van Diermen D, Marston A, Bravo J, Reist M, Carrupt PA, Hostettmann K (March 2009). "Monoamine oxidase inhibition by Rhodiola rosea L. roots".Journal of Ethnopharmacology.122 (2):397–401.doi:10.1016/j.jep.2009.01.007.PMID19168123.
Rehan W, Sandnabba NK, Johansson A, Westberg L, Santtila P (October 2015). "Effects of MAOA genotype and childhood experiences of physical and emotional abuse on aggressive behavior in adulthood".Nordic Psychology.67 (4):301–12.doi:10.1080/19012276.2015.1026922.S2CID146577097.
