Avshalom Caspi and Terrie Moffitt [interview with Moffitt here on npr] made quite a splash in 2002 when they published the paper “Role of Genotype in the Cycle of Violence in Maltreated Children” in Science. They reported that maltreated children would differ in the development of antisocial personality and violent behaviour depending upon whether or not their genotype conferred high or low levels of MAOA expression, a neurotransmitter-metabolizing enzyme. Thus, Caspi and Moffitt showed that a genetic variation may moderate the influence of environmental factors on behaviour in a rather dramatic manner, fueling the growing suspicion that the old nature/nurture dichotomy is much too simplistic. Behaviour is most probably not determined by either an innate genetic Bauplan or the ever changing forces of our surroundings. In Caspi and Moffitt’s study, at least, children with a low-level MAOA genotype only developed an antisocial personality if maltreated (if you happen not to be maltreated, a low-level MAOA polymorphism will not cause you to develop an antisocial personality); but, at the same time, maltreatment doesn’t affect children with a high-level MAOA polymorphism, so the maltreatment is not a cause in itself either. Genes and environmental factors interact to produce behaviour, and the real question is how they do so.
In the July issue of Nature Reviews Neuroscience Caspi and Moffitt discuss some important implications of their research. First of all, if you wish to understand how external pathogens can influence the brain, as is all-important for psychiatric treatment, you have to factor in the individual person’s genetic make-up. The ability of environmental factors to alter the nervous system and generate a disordered mind variates with genetic differences at the DNA sequence level. Say Caspi and Moffitt:
Heterogeneity of response characterizes all known environmental risk factorsfor psychopathology, including even the most overwhelming of traumas. Such response heterogeneity is associated with pre-existing individual differences in temperament, personality, cognition and autonomic physiology, all of which are known to be under genetic influence16. The hypothesis of genetic moderation implies that differences between individuals, originating in the DNA sequence, bring about differences between individuals in their resilience or vulnerability to the environmental causes of many pathological conditions of the mind and body.
Secondly, to really understand this interaction of genes and environmental risk factors and pathogens, more epidemiological cohort studies must integrate neuroscience measurements. As Caspi and Moffitt observe:
First, evidence is needed about which neural substrate is involved in the disorder. Second, evidence is
needed that an environmental cause of the disorder has effects on variables indexing the same neural substrate. Third, evidence is needed that a candidate gene has functional effects on variables indexing that same neural substrate. It is this convergence of environmental and genotypic effects within the same neural substrate that allows for the possibility of gene–environment interactions. At present, such evidence concerning environmental and genotypic effects in relation to neural substrate measures is sparse, and therefore gene–environment interaction hypotheses are likely to be circumstantial at best, and flimsy at worst. But this situation is steadily improving. When we were constructing our hypothesis regarding the genetic moderation of the depressogenic effects of stressful life events, we were aided by direct evidence linking the 5-HTT candidate gene to individual differences in physiological responsiveness to stress conditions in three different experimental paradigms, including knockout mice, stress-reared rhesus macaques and human functional brain imaging.
Of course, imaging genomics studies, such as those by Hariri and Weinberger, or Meyer-Lindenberg, give a good idea of how genetics, brain activity and behaviour can be related to each other, using avant-garde research techniques.
Finally, both perhaps most intriguing, Caspi and Moffitt suggest that findings such as theirs indicate that genes react to environmental influences more than cause brain activity and behaviour. This stance is captured in a quote like this one:
[The] gene–environment interaction approach differs fundamentally from the ‘main-effect approaches’,
with regard to the assumptions about the causes of psychiatric disorders. Main effect approaches assume that genes cause disorder, an assumption carried forward from early work that identified single-gene causes of rare Mendelian conditions. By contrast, the gene–environment interaction approach assumes that environmental
pathogens cause disorder, and that genes influence susceptibility to pathogens. In contrast to main-effect studies, there is no necessary expectation of a direct gene-to-behaviour association in the absence of the environmental pathogen.
Clearly, as such experimental work in greater detail furnish us with a more precise view of genes build the molecular structure of the brain, and how these structures underlie behaviour, we will also become better suited to settle long standing philosophical issues, such as what innateness actually is.
Caspi, A. & Moffitt, T. (2006): Gene-environment interactions in psychiatry: joining forces with neuroscience. Nature Reviews Neuroscience 7: 583-590.
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