Can a Good Environment Beat Bad Genes?
To what extent do specific genes determine our behavior? Although the jury is still out, the answer for intricate illnesses like bipolar disorder seems to be much more complicated than originally anticipated. Often in studies in which researchers scan the whole genome looking for associations between genes and a neuropsychiatric illness, spirits flare when a risk gene pops up in a one study only to drop when many times the finding is not replicated in subsequent studies.
While some argue that the difficulty arises from studies being underpowered (having too small a pool of subjects), one interesting possibility is that these genes might be difficult to detect because they are only “activated” when exposed to a certain environment. For example, let’s take an analogy in which a person’s genes interact with the environment in a similar manner to the way a car’s parts interact with the road. If the car was put together with tires that have no tread (a risk gene), the car will drive just fine if the sun is out and the road is smooth and dry. However, if the car goes driving in a heavy rain or snow, all of a sudden the tread-less tires make it more likely than if it had treads that the car will get into an accident; the tread-less tire confers a risk for an accident only when exposed to a specific, adverse environment like hazardous weather.
Slowly, some evidence of gene environment interactions has piled up. Recently, much interest has been paid to a possible interaction with the serotonin transporter gene and stressful life events (for a very interesting discussion, see John McManamy’s article “The Gene-Environment Connection - Can We Change It?”).
If the importance of environmental interaction turns out to be a general rule with risk genes, then by controlling our environments we may be able to have more control over our “risky genes” than we previously thought. The best evidence that it takes an adverse environment to activate bad genes, however, comes from research on a fascinating Dutch family, a cohort of New Zealand school children, and a gene called MAOA.
Dutchmen and the Story of MAOA
Monoamine Oxidase-A, or MAOA, is an enzyme that is primarily involved in the turnover of serotonin. Mice without the MAOA protein, consequently, have increased levels of serotonin (Buckholtz et al. 2008a). MAOA first caught researchers’ interest with a study published in 1993. In a large Dutch family, Brunner and colleagues (1993) found the first evidence that a gene might be important in violence and aggression. Many of the men in this family exhibited a strange behavioral disorder characterized by antisocial behavior such as inappropriate aggression, assault, and other violent crime. In these men, Brunner and colleagues found that there was a point mutation in the MAOA gene which led to a complete absence of functional MAOA protein. It was hypothesized that without MAOA, these men would have trouble degrading the serotonin in their bodies. Because dysregulation of serotonin had been previously associated with violence (Moffit et al. 1998), a dysreglation of its turnover in these Dutch men was presented as a particularly attractive model for their violent behavior.
Moreover, the MAOA gene’s position on the X chromosome put men at greater risk for inheriting no functional copy. Men inherit a single X chromosome while females inherit two, therefore, women inheriting a mutated gene on one X chromosome can compensate with a functional copy on the second X chromosome while men cannot. This finding was interesting because violent crime and antisocial personality disorder is observed disproportionately in men.
Because this non-functional mutation in the MAOA gene is extremely rare in the rest of the population, however, the results of the Brunner study, while interesting, were of limited use.
MAOA’s Next Chapter: Insights from New Zealand
Subsequent research showed that the MAOA gene exists in two major variations in the general population, each with different lengths of a region that controls the expression efficiency of the gene called the promoter region. Approximately 30% of the general population posses a version with a short promoter region, which is expressed less efficiently in an in-vitro study than the version with the longer promoter region possessed by approximately 65% of the population (Kim-Cohen et al. 2006; Caspi et al. 2002).
Caspi and colleagues (2002) attempted to combine the expression data on these natural variations with the observations made on the Dutch family. In a landmark paper published in 2002, they tested the hypothesis that the low-expressing variant would correlate with antisocial behavior. In 1976, Caspi and colleagues began to track 1037 New Zealand children at regular intervals until the time of the 2002 study, at which point the children had reached 26 years of age. Antisocial behavior was measured by convictions for violent crime, diagnosis of adolescent conduct disorder, an end-point (i.e. at 26 years of age) psychological assessment of violence-acceptance, and antisocial personality disorder symptoms reported by an. When the children were genotyped for the low (short) and high (long) activity vin the MAOA gene, there was no significant correlation between MAOA activity and antisocial behavior.
Of the children evaluated, 8% had experienced severe maltreatment between the age of three and eleven years. Consistent with previous studies, there was a significant positive correlation between maltreatment and later antisocial behavior. Strikingly, boys who had been maltreated AND possessed the low expression form of MAOA were significantly more likely to exhibit later antisocial behavior than were maltreated boys with the high expression form. Amazingly, only 12% of the boys in the cohort were maltreated and possessed the low MAOA genotype, but these boys were responsible for 44% of convictions for violent crime. Because there was no correlation between MAOA genotype and maltreatment, moreover, it did not seem like genotype predisposed the boys for maltreatment and this exciting gene x environment interaction was still seen after correction for socioeconomic status and several other environmental variables. Thus the low MAOA variant seemed to confer sensitivity to maltreatment while the high MAOA conferred a sort of protection. This was the first example of a gene x environment interaction correlating with a behavioral phenotype and the first time such an interaction was shown to predispose anyone to criminal violence.
Several other groups similarly confirmed and expanded this gene x environment interaction over the next five years (Taylor et al. 2007). Although some groups were not able to repeat the findings of Caspi et al. 2002 with their own sample groups, this may have been due to differences in definition of maltreatment or aggression or in lack of statistical power. Several meta-analyses, which pooled the sample data from up to 8 studies, thereby increasing statistical power, confirmed the predisposition of maltreated boys with the low MAOA genotype to aggression and violence (Taylor et al. 2007, Kim-Cohen 2006).
Beating Your Genes with a Good Environment?
One important message to take away from the MAOA story is that the “risky” version of the MAOA gene became a risk only when combined with the adverse environment. If looked at from the opposite angle, this could be restated by saying the risk gene had no effect if the boys were raised in positive environments. This is the KEY statement, because it suggests that by surrounding ourselves and our loved ones with positive, supportive environments, we might avoid activating many of the “bad” or risky genes present in that genetic witch’s brew that is dealt at birth. If your car tires have no tread, you may be more likely to avoid an accident if you try to drive on sunny roads. We may not be able to change the genes we were dealt, but perhaps we can trump their effects with a positive environment.
Alia-Klein N, Goldstein RZ, Kriplani A, Logan J, Tomasi D, Williams B, Telang F, Shumay E, Biegon A, Craig IW, Henn F, Wang G, Volkow ND, Fowler JS (2008) Brain monoamine oxidase A activity predicts trait aggression. J Neurosci 28:5099-5104.
Brunner HG, Nelen M, Breakefield XO, Ropers HH, Oost BAv (1993) Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Science 262:578-580.
Buckholtz JW, Meyer-Lindenberg A (2008a) MAOA and the neurogenetic architecture of human aggression. Trends Neurosci 31:120-129.
Buckholtz JW, et al. (2008b) Genetic variation in MAOA modulates ventromedial prefrontal circuitry mediating individual differences in human personality. Mol. Psyc. 13: 313-324.
Kim-Cohen J, Caspi A, Taylor A, Williams B, Newcombe R, Craig IW, Moffitt TE (2006) MAOA, maltreatment, and gene-environment interaction predicting children’s mental health: New evidence and a meta-analysis. Mol Psychiatry 11:903-913.
Moffitt TE, Brammer GL, Caspi A, Fawcett JP, Raleigh M, Yuwiler A, Silva P (1998) Whole blood serotonin relates to violence in an epidemiological study. Biol Psychiatry 43:446-457.
Taylor A, Kim-Cohen J (2007) Meta-analysis of gene-environment interactions in developmental psychopathology. Dev. and Pyschopath. 19:1029-1037.