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| Journal of the New Zealand Medical Association,
02-March-2007, Vol 120 No 1250
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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 traitsMonoamine 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 story—http://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 frequenciesEthnic 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
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:
and, more
importantly...
Positive selection at the MAO-A geneIn 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 MāoriThe 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 commentsIn 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:
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