Thursday, July 3, 2014

Monoamine Oxidase A: The War over the “Warrior Gene”

NOTE: This information was originally gathered for research related to a project that I was working on, but as it's become somewhat a nonessential due to the conclusions of the data collected, I decided to make it into a post for my site here instead. I thought that some might find it interesting. I will do more pieces like this in the future.


“A random pair of human haploid genomes differed at a rate of 1 bp per 1250 on average, but there was marked heterogeneity in the level of polymorphism across the genome. Less than 1% of all SNPs resulted in variation in proteins, but the task of determining which SNPs have functional consequences remains an open challenge.” [1]

The Department of Energy has long maintained some of the largest computing facilities in the world. Two of the most challenging problems in computer modeling are understanding weather patterns, and predicting the results of nuclear explosions under various starting conditions. Given the amount of money spent on such facilities, it is no surprise that other highly complex problems are sought out to keep these machines busy. Currently, genomic research also contributes to the development of biofuels to more efficiently replace nonrenewable energy sources.

The Human Genome Project (HGP) was a joint project of the Department of Energy and the National Institutes of Health, originally conceived in 1984, and fully underway and funded in 1987. The project was expected to take 15 years to complete, but the entry of private companies and international bodies, as well as advances in computing, allowed results to start emerging sooner than that.

Although the work was declared complete in 2003, as the quote above indicates, simply having a general idea of how the human genome is arranged, and fully understanding all of the ramifications of that arrangement, are two different things. Genes are not identically sized groups of molecules in our DNA strands. In fact, a major task of the HGP was to figure out the start and end points of our DNA for each functional unit. One initial finding (since it was brought into question) was that portions of our DNA do nothing useful at all. Other sections provide clues about human evolution; producing proteins or enzymes that might once have served some function, but do so no longer.

Recent discoveries have shown the possibility of overlaps in gene function, making the notion of a totally independent concept of a gene less useful than our simplifying minds might have liked. Those portions of the genetic material thought to do nothing (98% of it, in fact) are now believed to provide a “meta” function of controlling which parts of the 2% are turned on or off. Accordingly, the term “junk” that was originally applied to these regions is a misnomer.

The human genome has approximately 3.3 billion base pairs; on top of that is the fact that the results of a particular configuration at one location are not independent of all of the rest, but must act in cooperation with the whole. While it is human (as well as all other animal) nature to look for simplifying conclusions, such things can often elude even the most extensive analysis for years. The acrimony in scientific and general public writings over the significance of the gene which controls the production of monoamine oxidase A (MAOA) represents yet another tug-of-war between our desire to find simple explanations for things, and the reality that the operations of even simple living organisms are incredibly complex.

"The Warrior Gene"

MAOA is the name of a gene that encodes (or results in the production of) the enzyme monoamine oxidase A, which is referred to as maoA (or MAO-A). The original study that documented this gene/enzyme potential in humans was “Role of Genotype in the Cycle of Violence in Maltreated Children” by Avshalom Caspi, et al., done in 2002 [2], which built on a 1993 work by HG Brunner (et al.): “Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A.” [3]

The earlier study concerned a particular Dutch family with a history of antisocial behavior among its male members. The results led to the naming of this condition as the “Brunner Syndrome.” This is a rather rare condition wherein MAOA dysfunction is extreme. Men with this condition are typically somewhat retarded, in addition to overreacting to stressful situations.

The Caspi study followed more than a thousand children from birth until their late 20s and took into consideration whether they had been subject to abusive conditions or not. The main thrust of the study considered males, but about half of the more than one thousand subjects were female. The following footnote in the study explains why females are less likely to manifest antisocial behavior as a result of the same conditions that provoke it in males:

“This study focused on males because their single X chromosome yields two straightforwardly characterized MAOA genotypes: high activity (63% in this sample) and low activity (37%). Females, having two copies of the X chromosome, fall into two homozygous groups, high-high (42% in this sample), low-low (12%), and a third heterozygous group, low-high (46%), that cannot be characterized with certainty because it is not possible to determine which of the two alleles is inactivated for each female participant. Given the rarity in females of both the low-low genotype (12%) and severe antisocial outcomes, such as violent conviction (2%), our cohort of 481 females, 11% of whom were severely maltreated, was too small to support all of the analyses reported here for males.

However, adolescent conduct disorder could be analyzed, revealing that girls with the low–MAOA activity genotype were more likely to develop conduct disorder by a significant odds ratio of 5.5 (95% CI: 1.0 to 32.0) if they were maltreated. In contrast, among girls with high MAOA activity, maltreatment did not confer significant risk for conduct disorder (OR 1.7, 95% CI: 0.75 to 4.2). This suggests that high MAOA activity exerts a protective influence against maltreatment for girls as well as boys, and raises the possibility that further research into X-linked genotypes may help to explain one of the least understood facts about serious antisocial behavior: the sex difference.” [2]

Most of the studies on this gene have been conducted on men due to the fact that the effects are more pronounced in men, and they seem to indicate that the MAOA-L variants, alone, are not sufficient to produce undesirable behaviors, but must be accompanied by some stress trigger(s) in early life. While the same compounds neutralized by MAOA-H variants can also have deleterious effects in females, the factors brought out above indicate, and research has confirmed, that the effects are less noticeable in females, and are also less frequently occurring due to their extra X chromosome.

Research continues around the world with the intent of understanding the psychological impacts of this gene. According to a study by McDermott, Tingley, Cowden, Frazzetto, and Johnson entitled “Monoamine oxidase A gene (MAOA) predicts behavioral aggression following provocation,” [18] those with the low activity form of monoamine oxidase A gene (MAOA-L) are more likely to react aggressively toward others, especially in response to the amount of environmental stimuli that they’re experiencing—specifically, in regard to their study, aggression of some sort from another party.

In the McDermott, et al. study, referenced above, the environmental spur was in the form of someone taking money from test subjects, which they had worked for in a game. The test was also of willingness to punish, even when there was little post-benefit in punishing the person that had wronged the subject.

MAOA-L individuals had a higher likelihood of administering more hot sauce to their opponents (the punishment), who were taking portions of their earnings from them, than MAOA-H individuals (or, those with a high activity form of MAOA). The difference was more significant between MAOA-L/MAOA-H individuals when 80% of their earnings were taken (MAOA-L being more aggressive and showing greater willingness to punish more severely), especially in the first round, than when only 20% of their earnings were taken.

Their findings suggest and expand upon the idea that MAOA does play a role in aggression, and that MAOA-L individuals are more likely to be aggressive and/or are more likely to punish severely as a form of revenge (out of “spite”) than MAOA-H individuals, particularly when also interacting with some forms of environmental stimuli that “aggravate them.”

MAOA, and a neighboring gene, MAOB (on the opposing DNA strand), are involved in the breakdown of the neurotransmitters dopamine, epinephrine, norepinephrine, and serotonin, some of which might be recognizable to the general public as being associated with a sense of well-being. In fact (for example), serotonin can play a part in a males desire to find a mate, as well as to a sense of satisfaction in eating. While the emphasis here is on the effects in the brain, these chemicals may express themselves in many ways depending upon which part of the body, and thus which cell type, they are contained in. (See Table 1 Below.)

Because in each organ of the body the actions of this gene can have different effects, a mutation of the gene can manifest itself in several different ways. Reference [15] contains a list of disorders that are thought to be related to MAOA. (See “List 1” Below.)

There are actually a number of variations in this gene based on the number of repetitions that exist along the DNA strands MAOA-R1, MAOA-R2, and so on, but a shorthand has come about related to how effectively the MAO-A enzyme produced is in doing its intended function. The notation generally used is MAOA-H, for what might be called the “normal” level of function, and MAOA-L (which, in the more detailed literature, is known as one of MAOA-2R or MAOA-3R) for the variations that are less effective. In the original Brunner study, the gene was absent entirely and higher levels of the named neurotransmitters could be detected in the urine of affected males.

To give some idea of how varied the roles of these genes are, studies have not only shown increased levels of aggression, but a predisposition to alcoholism, gambling, and other undesirable behaviors. But at the same time, MAOA-L can result in beneficial behaviors regarding risk-taking; for instance, in selection of investment products. [16]

Numbers on the worldwide prevalence of the MAOA-L mutations are not fully documented. Within historically isolated population groups, there may be a greater or lesser number than the world-wide norm. And while there have been studies of fairly large numbers of men (over 600 in the case of [2]), these studies are not widespread geographically, and in many parts of the world, access to DNA testing is limited (and expensive). For example, references to the percentages of MAOA-L among “Africans” does not actually include samples from Africa, but rather “African Americans,” most of which include European genetic traits as well. While it would be inaccurate to state that studies to date are inconclusive due to this, correcting these issues would be helpful in the future in regard to clearing up some of the holes in the current data.

Based on independent studies [references 5-14], we can draw some approximate numbers as to which groups carry the low effect version of MAOA:

For the 3R variant: 58% of Black men, 56% of Maori men, 54% of Chinese men, and 36% of Caucasian men.

For the 2R variant: 5.5% of Black men, 0.9% of Caucasian men, and 0.00067% of Asian men.

Care should be taken, however, to avoid reaching hasty conclusions regarding the differences in MAOA among various populations. It may yet be discovered that other genetic differences in these populations compensate for the actions of MAOA in each of its forms.

As already mentioned, in our hurry to draw conclusions, it is easy to get the facts wrong, as demonstrated in this blog post at Science Blogs (the error was corrected in the comments):

“But back to the Maori, what seems to be suggested is that they have an increased incidence of MAO genes resulting in more MAO produced as compared to other populations. As the researcher himself notes, the gene may exert some influence but behavior is complex—it results from environment as well. Perhaps the Maori are overlooking a really useful bit of information here: MAOs can be inhibited. If it is shown to be true that MAOs can increase aggressiveness, depression, etc, high-risk individuals could be treated with MAO blockers.” [17]

List of conditions for which MAOA might play a role (List 1 [15]):

antisocial personality disorder, avoidant personality disorder, maoa-related behavior disorders, monoamine oxidase a deficiency, social phobia, brunner syndrome, personality disorder, paranoid schizophrenia, substance abuse, serotonin syndrome, anxiety disorder, conduct disorder, exhibitionism, melancholia, borderline personality disorder, postpartum depression, hepatic encephalopathy, specific phobia, norrie disease, agoraphobia, severe pre-eclampsia, chronic fatigue syndrome, lesch-nyhan syndrome, pathological gambling, generalized anxiety disorder, post-traumatic stress disorder, mood disorder, major depressive disorder, endogenous depression, panic disorder, early-onset schizophrenia, bulimia nervosa, drug dependence, exudative vitreoretinopathy, eclampsia, heroin dependence, obsessive-compulsive disorder, pre-eclampsia, attention deficit hyperactivity disorder, headache, restless legs syndrome, vitiligo, substance dependence, bipolar disorder, nonalcoholic steatohepatitis, fibromyalgia, relapsing-remitting multiple sclerosis, sudden infant death syndrome, tardive dyskinesia, anorexia nervosa, idiopathic generalized epilepsy, fragile x syndrome, developmental disabilities, alcohol dependence, migraine, toxic encephalopathy, schizoaffective disorder, eating disorder, frontotemporal dementia, turner syndrome, obesity, association with nicotine dependence, parkinson's disease, pick's disease, dementia, traumatic brain injury, schizophrenia, autism spectrum disorder, gout, temporal lobe epilepsy, neuroendocrine tumor, intellectual disability, hypotonia, blindness, narcolepsy, prostate adenocarcinoma, hypertension, mental retardation, multiple sclerosis, neuronitis, pheochromocytoma, alzheimer's disease, vascular disease, lung cancer susceptibility, lateral sclerosis, amyotrophic lateral sclerosis, labyrinthitis, prostatitis, huntington's disease, osteosarcoma, cholangiocarcinoma, hepatitis, liver disease, prostate cancer, ischemia, neuroblastoma, breast and colorectal cancer, cerebritis, renal cell carcinoma, atherosclerosis, tuberculosis, pancreatitis, adenocarcinoma, hypoxia, cervicitis, tonsillitis, lung cancer, thyroiditis, colorectal cancer, myeloma, multiple myeloma, endotheliitis
Table 1: MAOA factors in other body tissues [4]

Author: Krista Milburn [@Femitheist]
NOTE II: References not numbered are for general background information.

NOTE III: If you liked this piece, feel free to share it, and if you have any thoughts on it or the general subjects discussed within, or even purely semi-related topics, please leave them in the comments below. I always enjoy reading the feedback of others whether they liked and agreed with what I had to say or not.
References (Last Accessed on July 3, 2014):

[1] The Sequence of the Human Genome
J. Craig Venter et al
Science 291, 1304 (2001);
DOI: 10.1126/science.1058040

[2] Role of Genotype in the Cycle of Violence in Maltreated Children
Avshalom Caspi, Joseph McClay, Terrie E. Moffitt, Jonathan Mill, Judy Martin, Ian W. Craig, Alan Taylor, and Richie Poulton
Science 2 August 2002: 297 (5582), 851-854. [DOI:10.1126/science.1072290]

[3] Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A
HG Brunner, M Nelen, XO Breakefield, HH Ropers, and BA van OostScience 22 October 1993: 578-580. [DOI:10.1126/science.8211186]

[4] MAOA Expression data (how it manifects itself in variousl parts of the body);g=ENSG00000189221;r=X:43515467-43606068

[5] 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.

[6] 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.

[7] Lea R, Chambers G (2007). "Monoamine oxidase, addiction, and the "warrior" gene hypothesis". N. Z. Med. J. 120 (1250): U2441.PMID 17339897.

[8] 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.

[9] 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 MAO-A gene polymorphism". Dev Sci 14 (5): 1059–65. doi:10.1111/j.1467-7687.2011.01047.x.PMID 21884321.

[10] 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:10.1037/0012-1649.43.2.369. PMC 1832154. PMID 17352545.

[11] 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.

[12] 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.doi:10.1002/ajmg.10237. PMID 11920860.

[13] 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 MAO-A 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.

[14] 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.

[15] Disorders / Diseases for MAOA gene

[16] MAOA-L carriers are better at making optimal financial decisions under risk.
Proc Biol Sci. 2011 Jul 7;278(1714):2053-9. doi: 10.1098/rspb.2010.2304. Epub 2010 Dec 8.
Frydman C1, Camerer C, Bossaerts P, Rangel A.

[17] The Maori, MAO Inhibitors, and the “Warrior Gene”
Posted in Science Blogs by Shelley Batts on August 10, 2006

[18] "Monoamine oxidase A gene (MAOA) predicts behavioral aggression following provocation" (2009) - Proceedings of the National Academy of Sciences of the United States of America - Rose McDermotta, Dustin Tingleyb, Jonathan Cowdenc, Giovanni Frazzettod andDominic D. P. Johnsone,
Supplementary Resources (Last Accessed on July 3, 2014):

1) Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A

2) MAOA - monoamine oxidase A Homo sapiens

3) Increased stress response and beta-phenylethylamine in MAOB-deficient mice.

4) American Now - The Warrior Gene: Aggressive traits

5) Genetic Susceptibility for Individual Cooperation
Preferences: The Role of Monoamine Oxidase A Gene
(MAOA) in the Voluntary Provision of Public Goods

6) Scientists Rediscover the Violence Gene, MAOA-2R

7) Containing a two-part video:

8) Hyperbolic, but possibly correct video, also from above blog:

9) The Genetic Science Learning Center at The University of Utah

10) The Tech Museum of Innovation

11) Cloning of the maoA gene that encodes aromatic amine oxidase of Escherichia coli W3350 and characterization of the overexpressed enzyme

Other science-related posts that I've done: Click Here