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The New Zealand Medical Journal

 Journal of the New Zealand Medical Association, 02-March-2007, Vol 120 No 1250

Monoamine oxidase, addiction, and the “warrior” gene hypothesis
Rod Lea, Geoffrey Chambers
In August 2006, news broke that a “warrior” gene was linked to risk-taking, aggression, and criminality in Māori. The story sparked widespread controversy in New Zealand—with journalists, politicians, academics, scientists, and the general community all scrambling to publicly express their views on the matter. However, much of the controversy was unjustified because it stemmed from a combination of misquotes and misunderstandings printed in the original article released by the Australian Press Association.
Despite our sincere efforts to set the story straight through subsequent high-profile media interviews, the critical commentary continues in this issue of the Journal. We therefore welcome this opportunity to present the scientific rationale behind our monoamine oxidase gene research—including our findings to date and the relevance to medicine, ethics, and Māori.

The monoamine oxidase gene and behavioural traits

Monoamine oxidases (MAOs) are enzymes responsible for breaking down the neurotransmitters—serotonin, dopamine, and adrenalin—and are therefore capable of affecting mood. Indeed, MAO inhibitors (e.g. moclobemide) can effectively treat symptoms of depression and tobacco dependence. The activity of MAO enzymes can vary among individuals and is influenced by inherited genetic factors.1 Understanding the genetic variability of MAO activity and the linkage to drug response traits should assist in the design of more effective treatment options for certain clinical disorders.
The MAO genes are located on the X chromosome, thus males inherit only a single maternal copy. In 1997, Sabol et al reported that the MAO-A subtype contains a 30bp repeat polymorphism (MAO-A30bp-rpt) that is associated with transcriptional regulation (i.e. gene function).2 Hundreds of epidemiological studies of the MAO-A30bp-rpt variant have since been conducted and associations reported with psychiatric disorders including depression, anxiety, and addiction (e.g. tobacco dependence and alcoholism). Studies have also implicated the 3-repeat allele of MAO-A30bp-rpt, postulated to correspond to lower MAO-A activity and higher dopamine levels, with risk-taking3 and aggressive behaviour traits (see Merriman and Cameron’s article—Risk-taking: behind the warrior gene storyhttp://www.nzma.org.nz/journal/120-1250/2440). For the latter reason, Gibbons (2004) dubbed it a “warrior” gene.4
Since most neuropsychiatric and behavioural conditions are aetiologically complex (or multifactorial) it is not surprising that some of the reported associations to MAO-A30bp-rpt are significantly modified when considered in combination with non-genetic (environmental) factors.
In this issue of the Journal, Merriman and Cameron review the topic of MAO gene-by-environment interactions with relevance to aggressive behaviour. We note, however, that this diverges from our research agenda, which does not involve investigation of aggressive traits in Māori or any other population.

Ethnic differences in MAO-A allele frequencies

Ethnic variation in allele frequency (called population stratification by geneticists) is notorious for confounding genetic association studies and leading to false positive results. Therefore, it is sound research practice to identify and attempt to control for these effects prior to commencement of such studies, especially in ethnically and genetically mixed populations such as New Zealand.
MAO-A30bp-rpt allele frequencies appear to vary substantially between different worldwide ethnic groups (Table 1). For our studies of alcohol response traits in males, we estimated the population prevalence of the MAO-A30bp-rpt alleles for Māori by genotyping 46 unrelated male individuals. We found that the 3-repeat or “low activity” allele was present at a frequency of 56% (Table 1). Although the modest sample size places uncertainty around this statistic (95% CI:42–70), the frequency is almost two-fold higher then the Caucasian frequencies reported by Caspi et al, 20025 (P-value for Yates corrected χ2 test=0.002) and is consistent with the Pacific Islander data from Sabol et al (1997).2 Note that the highest frequency of the 3-repeat allele was observed in Chinese males (77%).6
Table 1. Estimates of MAO-A30bp-rpt (3-repeat) allele frequencies among ethnic groups
Ethnic Group
Allele frequency (%)
N (chromosomes)
Reference
3-repeat
95% CI
Caucasian (males)
Chinese (males)
African (male + female)
Hispanic (male + female)
Pacific Islander (male + female)
Māori males (at least 1 Māori parent)*
34
77
59
29
61
56
32–36
66–88
46–72
12–46
47–75
42–70
2382
55
52
27
50
46
Caspi et al, 2002
Lu et al, 2002
Sabol et al, 1998
Lea et al, 2005
CI=confidence interval; *Individuals were recruited from the general Wellington population and were affiliated with multiple iwi (tribes) and hapū (subtribes). Therefore we considered this to be a "fairly" random, albeit small, sample of the Māori population. All participants were informed about the nature of the research (to the best of our ability) and gave consent to participate in Dr Chamber’s studies of genetic markers and alcoholism at Victoria University (current ethics approval no. WEC 04/06/040).
The difference in MAO-A30bp-rpt allele frequency we observed for Māori males compared to Caucasians raises some scientific and medically relevant questions:
  • Do historical population genetic forces in Polynesia explain the differences?
  • Do these differences contribute to the differential patterns of alcohol and tobacco use seen between these groups?
and, more importantly...
  • Can this information be utilised for developing more appropriate treatments (e.g. smoking and drinking cessation) and lead to better health outcomes for Māori?

Positive selection at the MAO-A gene

In a high-profile study, Gilad et al (2002) re-sequenced the entire MAO-A gene from globally diverse groups of males and found additional polymorphisms spanning the entire 90kb of MAO-A DNA sequence.7 Analysis of this data provided evidence that MAO allele frequencies were influenced by positive selection perhaps acting on behavioural traits. The authors concluded by saying:
“This finding should motivate further studies of this region as a candidate in genetic association studies”
The findings of Gilad and colleagues, coupled with the unusual migratory history of the Māori population, prompted us to investigate the MAO-A locus further before testing it as a candidate for alcohol and tobacco-use traits.
To date, we have characterised and published associations among polymorphisms spanning the entire MAO-A gene (including MAO-A30bp-rpt) and identified two additional polymorphisms that are suitable for scoring the most common haplotype (AGCCG).8 This haplotype was present in 70% of the Māori we tested (n=46) compared to 40% of the global (non-Māori) sample tested by Gilad et al.7 In a sub-sample of 17 Māori males (selected because they had 8 Māori great grandparents and thus reduced European admixture), the AGCCG haplotype frequency was increased in carriers of the “functional” 3-repeat allele compared to non-Māori carriers (p<0.014).7,8
This finding in itself is evidence of positive (natural) selection acting at the MAO-A gene. It suggests to us that Polynesian males who embark on long, dangerous canoe voyages and engaged in (and survived) war with other islander tribes carried the AGCCG haplotype, coupled with the 3-repeat allele of MAO-A30bp-rpt, to Aotearoa (New Zealand) where they both increased in frequency due to rapid population growth. More importantly, these results emphasise that researchers conducting case-control studies of MAO-A gene variants and drug response or disease traits in New Zealand cohorts need to exercise extreme caution when interpreting allele frequencies so as not to declare false positive associations.

The “warrior” gene hypothesis and Māori

The Māori population of Aotearoa (New Zealand) represents the final link in a long chain of island-hopping voyages stretching across the South Pacific—“the last of the great human migrations.”9
“Kupe had monumental courage and a huge sense of adventure, to go where no man had ever gone before” (From Alan Duff’s Māori Heroes)
It is well recognised that historically Māori were fearless warriors. Indeed, reverence for the “warrior” tradition remains a key part of Māori cultural structure today and one that many New Zealanders take an obvious pride in, especially in the sporting context.
In an effort to explain the significance of our research findings we reason that the MAO-A gene may have conferred some selective advantage during the canoe voyages and inter-tribal wars that occurred during the Polynesian migrations and may have influenced the development of a substantial and sophisticated culture in Aotearoa (New Zealand).
It is important that the incidental formation of this “warrior gene hypothesis” is interpreted for what it is—a retrospective, yet scientifically plausible explanation of the evolutionary forces that have shaped the unique MAO-A gene patterns that our empirical data are indicating for the Māori population.
As alluded to by Merriman and Cameron, the extrapolation and negative twisting of this notion by journalists or politicians to try and explain non-medical antisocial issues like criminality need to be recognised as having no scientific support whatsoever and should be ignored.

Final comments

In summary, our research involves analysis of the MAO-A gene as a genetic marker for alcohol and tobacco response traits with a view to improving the health of New Zealanders. In this article we have provided statistically significant evidence that allele frequencies of the “functional” variant (MAO-A30bp-rpt) are different in Māori compared to Caucasian. We have provided further evidence supporting the notion that MAO-A in Māori has been shaped by ancient episodes of positive selection and genetic bottlenecks, and we suggest this was due to both environmental pressures during the migrations and behavioural characteristics of Polynesian voyagers. Through studying the evolutionary history of MAO-A we have gained valuable knowledge for conducting large-scale, robust association studies of drug response traits in New Zealanders with the aim of developing more personalised disease treatments based on MAO-A genotype.
In this issue of the Journal, Crampton and Parkin (Warrior genes and risk-taking science; http://www.nzma.org.nz/journal/120-1250/2439) convey their ethical concerns surrounding the “warrior gene” story. In terms of our research, we assure readers that we have taken all reasonable steps over the years, including extensive consultation with Māori and ethics committees, to ensure that our genetic studies comply with the expectations of participants.
We do not see how our revealing evidence of positive selection at the MAO gene in Māori (and our suggested reasons for why this might have occurred) as transcending ethical boundaries, but rather as logical scientific interpretation. With this in mind, it was surely our obligation as ethical researchers to disseminate findings to key stakeholders including the general public through media engagement. Of course, when engaging the media, scientists can only do their best to convey (often technical) findings and hope that journalists accurately report the scientific interpretations. If the media distorts the story, as was the case here, then the investigators have an extended social responsibility to engage in subsequent debate and try to ensure that correct interpretation prevails.
The publicity surrounding the “warrior gene” story has taught us some valuable lessons and has led to the establishment of an ESR policy working group, which is comprised of Māori academics, iwi members, researchers, and scientists. The goal of the group is to develop best practice procedures for genetic research involving Māori including informing participants, use of data, and dissemination of findings.10 We expect the group’s developments will also be helpful to other researchers and ethics committees regarding genetic studies involving Māori.
In conclusion, the “warrior gene” controversy, although largely based on negative media hype and misconception, has catalysed important social and scientific debate about genetic screening in human populations. It has highlighted the point that complex human characteristics (such as behavioural traits) mostly confer potential rather than setting an inescapable fate. We feel that continued debate and public education on this topic is a positive move forward that should ultimately lead to informed and sensible policies for the appropriate use of genetic information, thus minimising risk of data misuse for mischievous ends.
There is mounting evidence that individuals respond differently to environmental exposures, including medicines, based partly on differences at key genes. There is also evidence that people with Māori ancestry inherit such genes (e.g. MAO-A) with a different likelihood compared to their European counterparts.9
It is important that biomedical and public health researchers, clinicians, drug companies acknowledge genetic differences in Māori since some of these may contribute to drug response differences and/or disease disparities in New Zealand. Indeed, ignoring evolutionary forces (such as gene selection), and assuming that all population subgroups have the same genetic background when designing diagnostic, prevention, and treatment regimes, is both unscientific and unethical and destined to do minority groups such as Māori a disservice in terms of health care.
Conflict of interest statement: There are no conflicts of interest.
Author information: Rod A Lea, Genetic Epidemiologist, Institute of Environmental Science and Research Ltd, Porirua; and Adjunct Research Associate, Victoria University of Wellington; Geoffrey K Chambers, Reader, School of Biological Sciences, Victoria University of Wellington, Wellington.
Correspondence: Dr Rod A Lea, Environmental Science and Research Ltd, 34 Kenepuru Drive, PO Box 50-348, Porirua. Email: Rod.Lea@esr.cri.nz
References:
  1. Pedersen NL, Oreland L, Reynolds C, McClearn GE. Importance of genetic effects for monoamine oxidase activity in thrombocytes in twins reared apart and twins reared together. Psychiatry Res. 1993;46:239–51.
  2. Sabol SZ, Hu S, Hamer D. A functional polymorphism in the monoamine oxidase A gene promoter. Hum Genet. 1998;103:273–9.
  3. Ibanez A, de Castro IP, Fernandez-Piqueras J, et al. Pathological gambling and DNA polymorphic markers at MAO-A and MAO-B genes. Mol Psychiatry. 2000;5:105–9.
  4. Gibbons A. American Association of Physical Anthropologists meeting. Tracking the evolutionary history of a “warrior” gene. Science. 2004;304:818.
  5. Caspi A, McClay J, Moffitt TE, et al. Role of genotype in the cycle of violence in maltreated children. Science. 2002;297:851–4. Abstract at URL: http://www.sciencemag.org/cgi/content/abstract/297/5582/851
  6. Lu RB, Lee JF, Ko HC, et al. No association of the MAOA gene with alcoholism among Han Chinese males in Taiwan. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26:457–61.
  7. Gilad Y, Rosenberg S, Przeworski M, et al. Evidence for positive selection and population structure at the human MAO-A gene. Proc Natl Acad Sci USA. 2002;99:862–7.
  8. Lea RA, Hall D, Green M, Chambers GK. Tracking the evolutionary history of the warrior gene in the South Pacific. Presented at the Molecular Biology and Evolution Conference in Auckland, Jun 2005, and the International Congress of Human Genetics, Brisbane Aug, 2006.
  9. Lea RA and Chambers GK. Pharmacogenetics in Admixed Polynesian Populations. In: Pharmacogenetics in Admixed Populations, edited by Guilherme Suarez-Kurtz. Austin, TX: Landes Bioscience; 2007. URL: http://www.eurekah.com/
  10. Hudson M, Ahuriri-Driscoll A, Lea MG, Lea RA. Whakapapa – a foundation for genetic research? Bioethical Enquiry (in press).
     
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