The ultimate effect of the short SERT allele is that the part of the brain that is supposed to dampen down your fear responses doesn't seem to be able to do its job very well. Remember that serotonin provides a connection between two neurons. If something happens to that connection, problems are bound to occur—neurons aren't able to communicate clearly. It's like trying to speak (send out serotonin) in a room filled with people who are already talking loudly (serotonin is already in the space between the neurons). It's hard for important messages to get through. The short allele may produce depression simply because natural anxiety and fearfulness aren't restrained.
Fig. 3.5. This figure shows two vital, emotion-related organs—the amygdala and the cingulate cortex—that are affected by reduced serotonin transport.
Researchers are beginning to home in on how all this happens. Using functional magnetic resonance imaging, researchers have found that in normal and depressed people with one or two “shorts,” not only were the cingulate cortex and amygdala reduced in size, but the circuits that connected the two organs also appeared to be weakened.20 (The cingulate cortex is that part of the brain that helps us to focus our attention and “tune in” to thoughts, while the amygdala, again, is the “fight-or-flight” coordinator of the body's emotions.) You can see the weakened “speech” between the amygdala and the cingulate in the illustrations on the next page. The picture on the left shows a normal control loop for fear—the kind of loop that would be seen in a person with long/long SERT genes. The amygdala sends a signal to the lower part of the cingulate, and then on to the upper, and finally, a “calm down” signal is sent back to the amygdala. In real life, this process might relate to something like the fear you feel—due to the amygdala's response—as your plane suddenly begins jouncing up and down. This fear would be communicated by the amygdala to the cingulate cortex, which would turn back around and control the amygdala's response by communicating something like: “Calm down, it's okay—it's just turbulence as we're flying over the Rockies.”
The illustration on the right, however, shows the circuit response in people with at least one short SERT allele. Although the amygdala is activated, it can't send a strong signal out to the cingulate cortex because of all the other chatter going on. (Remember those serotonin transporters? There are fewer of them, so they don't transport very well—like stagehands who haven't bothered to clear the stage for the next act in the play.) Consequently, the controlling “whoa—take it easy” signal from the cingulate cortex back down to the amygdala is also weaker. The resulting thought pattern might go like this: “Calm down—it's just turbulence. I mean, I think it's just turbulence. But…the people on Flight 587 thought it was just turbulence, too. My God, that plane shook itself apart midair. Every one of the 260 people on board was killed! I'm going to die!!!” As you might imagine, this kind of negative thinking can lead to all sorts of problems—depression not the least of them.
Fig. 3.6. Those with the long/long genotype, as shown on the left, have a full feedback control system that damps down the aroused amygdala. This allows a person to relax after first being startled. Notice how much thinner some of the signaling arrows are in the image on the right. Those with one or two short carriers aren't able to take advantage of feedback—their amygdalae continue to be revved up even after the person has consciously realized there is nothing to feel threatened about.
Pleiotropy—The Naughty-Nice Aspects of “Evil Genes”
Given the many different negative aspects of the short version of the SERT allele on a personality, why hasn't the allele for the short version of the transporter molecule just died out? Surprisingly, it may be because the long version of the allele can also create problems—not necessarily with emotions, as the short allele does, but in other areas of the body. For example, primary pulmonary hypertension—a serious disorder that causes the heart to essentially overpump—appears to become a problem if a person has received long versions of the allele from both the mother and the father. This double mother-father dose allows for excessive serotonin that spurs the growth of pulmonary artery smooth muscle cells, which eventually blocks the blood's pipeline to the lungs.21
Remember, it is a single gene, the gene that produces the serotonin transporter molecule, that has all these varied effects on the body's neural, cardiac, and even the immune systems. The concept that one gene can affect many different areas of the body is so crucial that it even has a name: pleiotropy, from the Greek pleio, meaning “many,” and tropo, meaning “turning toward.”
An example of pleiotropy can be found in the APOE4 allele (short for apolipoprotein E 4). This allele, which is situated on chromosome 19, may have predisposed my father to Alzheimer's disease after his slip from the peaked roof of the covered bridge. Inflammation from his resulting concussion could have caused the allele's activation.22 (If my father had had a double set of APOE4 alleles, one from each of his parents, he would have been even more likely to have wound up with Alzheimer's, although a number of other genes undoubtedly also play a role.) If all of this wasn't bad enough, the APOE4 allele has another nasty effect. It seems to be associated with high cholesterol—from which my father also suffered.
But it seems that there are several good aspects to the APOE4 allele. One is that, if this allele is switched on by nutritional stress, it may help children survive severe malnutrition early in life.23 (The trade-off, of course, comes at the other end of the life span.) Another nice aspect of APOE4 is that, although you may lose your memory when you get old, you may actually have a sharper memory when you're young.24
The flip side of pleiotropy is polygeny. Polygeny simply means that a single trait can be influenced by many genes. For example, even though Alzheimer's is associated with the APOE4 allele, other genes may ameliorate the errant allele's effect. This may be why many APOE4 carriers never succumb to Alzheimer's. Polygeny appears to underlie personality disorders that are related to some types of sinister behavior—behavior much like my sister Carolyn's.
Brain-Derived Neurotrophic Factor
Another gene related to mood and anxiety is the gene that produces BDNF—Brain-Derived Neurotrophic Factor. This factor helps support the survival of existing neurons and encourages the growth of new neurons and synapses. There are two common alleles for this gene, dubbed val (short for valine—an amino acid in the protein coded by the gene), and met (short for methionine—a different amino acid that is substituted for valine at the same spot in the protein). It turns out that people who have two versions of valine have exceptionally good memories—the double val alleles seem to have a stronger effect on memory than any other factor ever studied.25 Unfortunately, these people are also more neurotic—that is, they have more negative emotionality in regard to anxiety, low mood, and hostility.26 This instance of multiple effects of a single gene is another example of pleiotropy.
Daniel Weinberger believes the met allele may have evolved because a double dose (one from the father and another from the mother) of the met BDNF allele just can't “hear” serotonin very well—which could be a real advantage in ignoring the higher anxiety signal that results from short serotonin transporter genes. A double val dose, on the other hand, appears as if it may magnify the effect of the short serotonin transporter. Psychiatrist Jim Phelps relays an analogy from Weinberger:
Imagine that [val/val] BDNF alleles, with their memory-improving capacity, make your brain function like a 200 mile-per-hour race car. If you've got a hot rig like that, you'd better be a good driver who's capable of handling a fast, but temperamental car. In this analogy, that's the long/long allele pair for the SERT gene: the driver won't get over-anxious and allow the car to get out of control. That's important, because if you smash your car into the wall very often, your car won't run very well. In real life, if you take too many stress-hits, you end up depressed.
By comparison, if you inherit the short/short pair for SERT, and thus are less able to handle anxiety-producing situations such as conflict, trauma, and loss—yo
u are a more cautious and potentially distractible, frightenable driver. In this case, you might be better off with a slower but more crash-resistant car, one that you can smash up against the wall quite a few times without changing how it performs very much. In this analogy, that's the met/met allele pair for the BDNF gene.
By this analogy, perhaps the “slower” met allele was selected for (evolution-speak) in humans to help people with “two shorts” get through life better. If two shorts make you more cautious, and two met's make you less likely to worry about things, for some people that could make a durable, reliable combination that in dangerous times might be better than the high-performance but “higher-maintenance” val/val and long/long combination. Of course at this point that's almost entirely a guess, but it gives us a beginning of a model which might help us understand these genetic variations in humans.27
Certain alleles for BDNF receptors have been found to be strongly associated with bulimia and anorexia, which are in turn associated with such personality traits as anticipatory worry and pessimism.28 Some BDNF alleles are also associated with depression, bipolar disorder, and neuroticism.
Warrior or Worrier? The COMT Gene
Trade-offs—there are always trade-offs. And nowhere is that more clear than with the COMT gene (short for the ungainly catechol-O-methyltransferase), which is a key gene underlying our general intelligence. This gene works by serving as the blueprint for an enzyme that breaks down dopamine and other neurotransmitters. It turns out that the more slowly you metabolize dopamine, the smarter you are, so if you have versions of the COMT gene that don't metabolize dopamine well, chances are you have a higher IQ (other genes and the environment also play a role here, of course). Like the BDNF gene, COMT also has val and met versions, with the met being a slow metabolizer, and the val fast.29 People with val/val versions of the COMT gene can be a bit less intelligent—they may also have a slightly increased risk for schizophrenia. Val/vals are also at increased risk for antisocial behavior and hyperactivity. None of these detrimental, fast-metabolizing val effects are particularly surprising—after all, amphetamines and cocaine, which increase the transmission of dopamine, cause the psychotic, aggressive behavior that is so familiar to emergency room physicians. Compared to val/vals, met/mets can be smarter, and have a markedly better memory.30 People with mixed val/met versions of the alleles seem to be halfway in between.
Given the advantages of met, it would seem that val would have died out. Instead, it is common in many human populations, with increases of met being balanced by decreases in val, and vice versa, in a sort of yin-yang relationship.31 Why? Val versus met has been aptly described as “warrior” versus “worrier.”32 It seems that although vals may not be as smart on average and they have the mixed blessing of increased aggressivity, they can handle stress better than mets. Additionally, val cognition, although perhaps not as quick or deep, is more flexible—vals can more easily adapt when the rules of the game suddenly change.33 Conversely, the met allele is instead associated with more anxiety or, in research-speak: “lower emotional resilience against negative mood states.”34 It is more frequently seen in individuals with obsessive compulsive disorder, which is characterized by distressing intrusive thoughts and the compulsive performance of rituals. Met is also associated with feeling pain more strongly and reacting more negatively to prolonged pain—people with met alleles simply don't get the same natural soothing opiates that vals get.35 Although met COMT enhances intelligence and memory, it can also add to the effects of a short SERT allele, making a person even more anxious and neurotic.36 You might think of this as the Woody Allen of genes—producing brilliance coupled with deep neuroticism.
Monoamine Oxidase A
Monoamine oxidase A—MAO-A for short—is a term for an enzyme that helps break down neurotransmitters like serotonin and dopamine so they don't continuously build up inside neurons. As with the SERT gene, it seems that low-functioning versions of the MAO-A gene have been linked to problematic personality traits. These traits involve both impulsive and aggressive behavior, as well as depression, substance abuse, criminal behavior, attention deficit disorder, and social phobias.37 One recent study has linked the low-functioning versions of the MAO-A gene to those with the dramatic, emotional, and erratic personalities known as “Cluster B” disorders (which include antisocial and narcissistic personality disorders).38 Differences in neural behavior in those with different versions of the gene have been spotted even in those with mild intermediate phenotypes—that is, in normal or relatively normal people who would fly under the radar of clinical significance for diagnosis of a personality disorder.39
One study analyzed one hundred normal volunteer men and women to see whether they carried the high- or low-efficiency versions of the MAO-A gene.40 These volunteers were then imaged. The upshot was that those with the low-efficiency MAO-A alleles had smaller limbic organs, such as the amygdala and cingulate gyrus. The amygdala reacted strongly when these subjects were given a very mild scare, but the increased amygdala reaction was accompanied by an unexpected decreased reaction in the orbitofrontal and cingulate cortices (generally the amygdala would activate these two cortices, which would in turn send signals back to the amygdala to calm it down). These are the types of neurological reactions that are associated with impulsive violence. These reactions display the same sort of tamped down neural control circuitry between the amygdala and the cingulate cortex that we saw earlier in the individuals with short serotonin transporter alleles. It's just that in this case, not only is there a damped connection between the cingulate cortex and the amygdala, there's also a damped connection between the orbitofrontal cortex and the amygdala. Weakening this latter circuit means someone might have trouble with stimulus-reinforcement learning. A typical example of this type of behavior might be the knuckleheaded kid who continues to saunter in late for classes even though he knows he'll get detention.
The low-efficiency MAO-A allele appears to be particularly associated with impulsive violence, as opposed to violence as a purposeful means toward an end. The effects of MAO-A genes were, in fact, first discovered in a Dutch family in which certain males had inherited an unusual mutation that did not allow their MAO-A to metabolize serotonin or other neurotransmitters. Generations of family members had shown bizarre aggressive behavior, such as an attempt to run an employer over with a car; stabbing a warden in the chest with a pitchfork; or entering sisters’ rooms at night, armed with a knife, and forcing them to undress.41
The MAO-A system is interesting, too, because it was the first neurotransmitter system to reveal how the same environment might have a different effect on people with different genetics. In 2002, Avshalom Caspi and his colleagues gave evidence that indicated why some children who are maltreated grow up to develop antisocial behavior, whereas others do not.42 The key to the differences, it turned out in this study, lay in the children's genotype. Children who grew up in positive environments generally had no developmental difficulties, whatever their genotype. But those children who grew up being maltreated showed significant differences depending on whether they had high- or low-efficiency MAO-A alleles. Maltreated kids with efficient MAO-A activity weathered the storms of their youth relatively well. However, those with inefficient MAO-A activity developed significant antisocial problems—85 percent of those with a low-activity MAO-A genotype who were severely maltreated developed some form of antisocial behavior. That result was twice as high as the high-activity group under severely maltreated conditions. It was thought that deficient MAO-A activity disposes the kids toward neural hyperreactivity to threat.
How, precisely, might the genes operate differently under different environmental conditions? As mentioned earlier, stress might cause an increase in certain chemicals that in turn cause the DNA copiers to jump their tracks and begin copying from different parts of the DNA strand. This makes slightly different proteins, which in turn cause the properties of the synapses to subtly shift.43 This type of effect, where a particular
allele is problem-free unless the environment (or another gene) kicks it off track, might happen with many different personality-related genes.44
Other Moody Genes
Evil Genes Page 7
