Genetics and environment: Interaction in a different key

In previous posts, I wrote about PANDAS, the streptococcus related autoimmune disorder which involves obsessions, compulsions and perhaps more broad anxiety and movement problems. Discussion has been vigorous about the role of pathogens in creating mood and mental health issues.
Genetics as an influence is another biological factor often considered as a causal factor in mental health and behavior. Today, Brain Blogger discusses the influence of genetics and depression in a post with the provocative title, “Stressed by his short allele.” Brain Blogger is an interesting read in that he attempts to bring neurological research to a lay audience in a magazine format.
Regarding depression, stress and genetics, BB writes:

Individual differences in the genetic makeup of the serotonin system have been shown to increase one’s vulnerability to depression, anxiety and other psychiatric conditions, particularly if individuals are exposed to stressful events in their lives. Studies are showing that certain people (those that have the short allele of the serotonin transporter gene) have a greater biological reactivity to stressful events, including a larger hormonal response to stress and a greater brain reactivity to threat. In other words, both the hormonal and brain systems (amygdala) involved in fear and anxiety are more active in response to stress in those individuals who have a certain genetic makeup (short allele). This genetic difference may also account for individual differences in personality; those people who have a short allele for the serotonin transporter have been suggested to exhibit more “anxious” personality traits. This means our differences in gene function may bias our brains and our personalities to create a tendency to be more “negative,” “anxious” or reactive to stress.

Bringing together the PANDAS research with the observations regarding short serotonin gene alleles, one can envision several scenarios. A child with a stubby allele gets strep throat. This child is unfortunate in that the antibodies created to seek and destroy the strep bacteria find and bind with dopamine receptors in the basal ganglia. At that point, the cells designed to kill strep bacteria which are supposed to be hooked up with strep antibodies find this unholy alliance of strep antibody and dopamine receptors and launch their holy war of immunity. Dopamine cells fall in friendly fire thus sending the dopamine-serotonin balance into disarray. This child, being completely unaware of this of course, begins to feel nervous and irritable (mood change). This creates stress in the family and parents who may also have stubby alleles get stressed too. As BB notes, the short-allele brain already primed to be more reactive in the event of stress (the illness itself, the mood change and reaction of parents and sibs) goes into full fledged alert, generating lots of chemicals which basically provide that child with thoughts suggesting something is wrong here (anxiety and depression).
We can also imagine a child with a full sized allele going through the same thing. When the dopamine-serotonin balance is disrupted via an autoimmune disorder, one may see the typical rapid onset of PANDAS symptoms but these will likely not turn into a chronic problem. Furthermore, it is possible that the symptoms will be less intense or that the child will be more easily soothed with even modest parental inputs, thus preventing an escalation of panic.
Active readers will probably imagine a few hundred more scenarios.
I recently spoke with Susan Swedo at the NIMH who provided invaluable information regarding PANDAS. She agreed with me that we are at the beginning of this line of research and thinking. There is no doubt that psychological trauma is stressful and thus impacts mental health. However, the mechanisms of extended impact may be much different than psychodynamic theorists imagine.
The more of this kind of information we can get to patients the better in my view. It is helpful for people to understand the tricks their brain is playing on them when they get the intuition that they must engage in a compulsive action in order to relieve anxiety. Or when everything is really going well and they constantly fear the worst. Our active, monitoring minds play tricks on us and we are learning more about how those tricks are constructed in part via pathogens in the environment interacting with a genetically prepared host.

28 thoughts on “Genetics and environment: Interaction in a different key”

  1. Razib over on the Gene Expression blog has just put up a post on the monkeys. ( WEd. Jan 14 post). By tomorrow maybe there’ll be a lot of discussion on it there.
    I found a post by “neuroskeptic” who is a British neuroscientist with his own blog ( it was a fairly old post) and he spoke of these alleles for serotonin and their relation to biodiveristy, saying that if he remembered correctly 40% of Koreans had two short copies of the allele and Africans had the highest % of two longs.
    http://www.gnxp.com/

  3. Evan said,

    There doesn’t seem to be any germ that conks its brain and makes it fearful.

    I’m certainly not saying there has to be a germ that causes these monkeys to behave this way, but considering how long it has taken for microbiologists to find the viruses involved in some mental illnesses, why should we think these researchers studying these alleles have eliminated that possibility? We may not even have the technology yet to find evidence of a long-gone pathogen. Looking around for a small population of neurons–where to look?
    Serotonin levels are crucial to feelings of emotional well being and passivity vs. aggressiveness, obviously in both humans and monkeys, but I wonder if it’s really the short allele that is the “problem” here, or if something else combined with that short allele is the problem. Might be pathogenic, might not be–could be another neurotransmitter not acting as it should in combo with the serotonin or another receptor problem somewhere.
    If it’s only the short allele that makes them that way—then either they do engage in reproductive activities in the wild or that short allele is a protection against something.
    I’ve a feeling it’s not just the short allele responsible for the behavior. Bet it’s a combo.

    1. Speaking of that scientists recently discovered a virus that causes Type 1 Diabetes in rats.
      Rats’ virus holds clues to diabetes

      The BioBreeding, or BB, rat naturally develops diabetes at about 2 months of age, and researchers have attributed the disease to genetics. The new findings suggest that there is indeed a genetic susceptibility but that the precipitating event is a viral infection.

      —
      It pretty much always works like that. In fact it couldn’t work any other way.

    1. It isn’t that genes don’t make us susceptible to disorders, they do. But the damage has to come from something else. It could be anything including socialization, but it’s not part of the original blueprint.

  5. Evan
    Ok, even simpler.
    If a gene is common it can’t harm young people. The number of exceptions to that rule is insignificant.

  6. Evan

    How does the allele remain in the gene pool if it’s counter-reproductive?

    If the gene is common there is a virtually 100% chance that it offers (or did offer) useful survival skills. Worst case scenario it has to be neutral. Rare genes are a different story, they can harm us.
    —
    Didn’t the scientists find this allele useful?

    “Heightened sensitivity to social threats may prove to be helpful in many ways, because success in a social group depends on seizing opportunities while avoiding any potential harmful, antagonistic interactions,” Watson said.

    —
    Except in the rarest cases scientists can’t explain disfunction by looking at common, nearly always useful genes. Correlation is another matter because genes correlate with just about everything.

  7. Drowssap,
    That study on monkeys was intriguing for two reasons: they’ve got the same genetic polymorphism as humans for that trait and they react comparably behaviourally. The male monkeys that have at least one short allele (for the serotonin transporter this topic is about) are averse to facing social situations. They avoid eye contact, seeing faces and they need reward to push through their fears and confront images of high-status males.
    I don’t see what use this function might have, considering that if the fearful monkey sees a dominant male first, it loses the determination to pursue a female. This trait makes the fearful monkey unlikely to reproduce. There doesn’t seem to be any germ that conks its brain and makes it fearful. How does the allele remain in the gene pool if it’s counter-reproductive?

  9. EVan said,

    In the meanwhile they have included projections until 2030. Unipolar depression still ranks second among the 15 leading disabling health conditions.

    My gosh, this is a very distressing picture painted, isn’t it? Mind boggling, really. Thanks for posting that.

  10. Drowssap said,

    There has to be a yin and yang on that. Ferraris are prone to burn a lot of fuel but they also go really fast. No common gene is perfectly bad or perfectly good. It all depends on if it’s being used properly and in the right environment.

    Great point.

  11. Here’s a very good article about the rising tide of research into infectious causation of all kinds of chronic diseases and that would include the kind about which we have been talking. I don’t know that this is the right thread on which to post it, Warren, but it does address the idea Susan Swedo shared with you about the trend in research.
    Here’s an excerpt:
    “

    Why are there unrecognized pathogens? Because of the completely unanticipated microbial diversity that was not known when we relied on culture-based methods,” said Stanford University assistant professor of medicine David Relman. He is referring to the classification of prokaryotes based on ribosomal RNA sequences and other molecular characteristics. “Of the 36 divisions of microbial life, seven are known to include animal pathogens. We don’t have a good handle yet on whether the other groups have pathogens,” he added.
    No longer does diagnosis depend on a series of infections and nurturing of the pathogen–genes do the trick. “Sequence-based molecular methods can detect the pathogen or the host’s response,” said Relman. The trend to look for molecular signatures will grow as genomics, proteomics, and DNA microarray technology mature.

    Here’s the link: http://www.canlyme.com/chronicinfect2.html

  12. carole

    The WHO position is very interesting. Is the major “stressor” thought to be the deterioration of the nuclear and extended families? Or is it poverty and disease and ill health? Have they broken it down as to continents, countries, geopolitical and geographic areas?

    I haven’t studied their entire report (it’s one big paper on all world health problems), but you can find the data in the Global Burden of Disease document. A shorter update which includes their conclusions is available here.
    In the meanwhile they have included projections until 2030. Unipolar depression still ranks second among the 15 leading disabling health conditions. On causes, I will quote from one article on the previous paper I referred to in my argument:

    The work of Murray and his colleagues suggests that the global burden of disease will undergo a process of dramatic change during these next two decades. Although epidemiological studies strive to assess the health of the entire world’s population, it is impossible to ignore the fact that four-fifths of the world’s people live in the developing regions. In these areas, noncommunicable diseases such as depression and heart disease are replacing problems such as infectious diseases and malnutrition as the leading causes of disability and premature death. While these problems remain huge sources of suffering in the developing world, it is clear that due to a number of factors, the prevalence of “adult” diseases that plague people for many years is increasing. Today, noncommunicable diseases account for less than half of the deaths in developing regions, but the GBD study estimates that by 2020, that percentage could rise to 70 percent.
    Several factors are at work in this epidemiological transition, which has outpaced public health policy. Perhaps most importantly, populations are aging. Improvements in health care have led to increased child survival, and diminished maternal morbidity and mortality. Higher literacy rates and better education have led to increased health awareness and a reduction in the birth rate. As a population’s birth rate falls, the number of adults relative to children increases, and the population’s most common health problems become those of adults. With life spans for both men and women on the rise globally, more and more people reach the at-risk ages for chronic diseases.
    Another key factor is the demographic shift that has the populations of developing countries moving to cities. In China, for example, more than half of the country’s 1.4 billion people live in urban areas. This urbanization, coupled with the advancement of technology and therefore more “sedentary” jobs, is leading to sharp reductions in physical activity. Today, fewer people are employed in manual labor jobs, more people are tethered to desks and computers, and more tasks are automated; more people are driving, rather than walking; conveniences are lightening the domestic labor load; and finally, in those hours when one might be on a bicycle or a jogging path, more people sitting on couches watching television, or playing computer games. All of these changes open the door to a multitude of risk factors related to noncommunicable diseases.
    Disease outlook for 2020
    The GBD study suggests that the burdens of mental illness, such as depression, alcohol dependence, and schizophrenia, have been seriously underestimated by epidemiological approaches that measure only deaths. Psychiatric conditions, while resulting in a little more than one percent of total deaths today, account for 10.5 percent of the global disease burden. By 2020, this could rise to 15 percent, a larger projected increase than that for cardiovascular diseases. Unipolar major depression is projected to rank second in DALYs [disability-adjusted life years] by 2020.

  13. The young girl who is prone to depression or at least to a great deal of anxiety and distress and whose environment she wishes to escape , this girl who “wants someone to love” is not likely to be picky.
    Youth, distress, the longing to be valued –all these conspire to make her “easy pickins” for someone who is not likely to offer her love, protection, and kindness. For this reason, maybe she winds up with a guy who offers her little.
    The WHO position is very interesting. Is the major “stressor” thought to be the deterioration of the nuclear and extended families? Or is it poverty and disease and ill health? Have they broken it down as to continents, countries, geopolitical and geographic areas?

    1. The young girl who is prone to depression or at least to a great deal of anxiety and distress and whose environment she wishes to escape

      There has to be a yin and yang on that. Ferraris are prone to burn a lot of fuel but they also go really fast. No common gene is perfectly bad or perfectly good. It all depends on if it’s being used properly and in the right environment.
      —
      Hemachromotosis is considered a “genetic disorder” because it encourages the body to store extra iron. But in the ancient world in cold environments it was advantageous. It’s sort of like the Indians who get Type II Diabetes in the modern world but in the ancient low calorie world they had the edge.

  14. carole —

    I asked myself how the short homozygous alleles that make depression most likely have survived since those who are depressed often don’t work steadily or at all, are prone to other illnesses, often stay home, eat, sleep, show interest or a passion in very little etc. This alone would limit the kind of partner who might be interested in them.

    The small picture: until recently marriages were fixed; more recently, women still come under pressure to find a mate as long as they are young and to have children (other women are doing it, maternal instincts are pressing, insecurity, emotional needs etc); more women are at risk for this type of problems but that does not take from their chances of finding someone (it’s harder for men actually, if they carry vulnerable traits, but fewer men than women are affected). Risk for depression is not tantamount to sure outcome in mental health problems: most people are probably carriers of risky alleles.
    The big picture: The pace of changes in environmental stressors must be the hefty factor here. This is why the WHO (the institution) predicted that major depression will be the world’s second-most debilitating disease by 2020. The pressure is rising in the mental realm. I imagine that primeval humans lived in small groups, were physically very active and had very few reasons to ruminate about.

  15. Drowssap said,

    My point is that in nearly every case the genes we posess are just fine. This is particularly true in young people. It takes environmental input to get trouble brewing.

    Well put. The simplest concept is (and I know you know who said it) “Genes optimize function” and there are not that many exceptions– mutations which are rare and usually quite bad and a few genes thrown in as defenses against killer diseases, even if those defenses aren’t w/out their own problems if you get two of them–that’s the crapshoot that evolution hasn’t yet taken care of yet.
    So, the short alleles of 5-HTT: I suppose further research one day will show either it has survived because it is good for something, or it has survived because those who have it reproduce before the negative consequences of it kick in too much (like the Huntington’s gene, for example.)
    My bet is it’s been retained because it offers something good since there are few genes in the genome like Huntington’s.
    Yes, the environment screws things up–problem is, the environment can be so many things for so many people with so many variant genetic lines. Where to start? Gotta admire the people who try to figure all this out.

    1. If any gene exists in great numbers it’s got a positive use. We think of stress as bad because in a lot of ways it is. But if stress was ENTIRELY bad we wouldn’t have it at all.

  16. One thing I feel compelled to add.
    —
    Ok so there is a Long-allele and a Short-allele. But would we also expect to find a common “ultra-mini-allele” that produces a feeling of constant stress in any environment?
    Nope.

    1. Maybe I cut that one a little short.
      —
      My point is that in nearly every case the genes we posess are just fine. This is particularly true in young people. It takes environmental input to get trouble brewing.

  17. The Brain Blogger article does not mention how does age play into this, but most of the research on the serotonine-amygdala-depression/anxiety link was done on adults. Apparently, age matters a lot in already affected people. A recent study on teenagers found that:

    in healthy adolescents who have at least one copy of the short version of the [serotonin transporter] gene, the amygdala reacts more than it does in healthy adolescents who have two copies of the long version. This result is the same in healthy adults. However, in anxious or depressed adolescents, the opposite results were found. In affected adolescents who have at least one copy of the short version, the amygdala reacts less than it does in affected adolescents who have two copies of the long version.
    This finding in affected teens with two long version genes is the opposite of that observed in anxious or depressed adults. It is surprising because anxiety and depression during adolescence tend to predict these disorders during adulthood.

    So it works inversely for already affected teenagers: the long variants carriers are more stressed than the short ones. Rarely one gene works on its own, probably.

  18. Evan,
    Yes, more numbers on the racial correlates, partner selection, etc. will be interesting and hopefully helpful.
    At first I asked myself how the short homozygous alleles that make depression most likely have survived since those who are depressed often don’t work steadily or at all, are prone to other illnesses, often stay home, eat, sleep, show interest or a passion in very little etc. This alone would limit the kind of partner who might be interested in them.
    So, given all the negatives, why hasn’t this allele been weeded out? Is it conferring another advantage? That seems unlikely unless something else is going on here.
    Then, I realized– the eldest daughter’s experience is very much what I saw in my work–the child who is distressed and who comes from such a backgroud such as she did, is likely to seek loveand protection in the form of a mate (yes, often one who abuses her or at least is not a very strong and supportive one) at a very early age. Such people often do have children, lots of children sometimes, as a way of trying to form a family that will supply love.
    Look carefully at girls who bear children in their early teens (at least in this country) and you are most likely, I’ll bet, to see a history of this abuse at a rate greater than in girls who do not bear kids at an early age. Thus, the depression that might one day make a person disinterested in sexual relations has not yet occurred in the teen or young adult. They have kids and those alleles get passed on.
    Boy, have I heard a lot of young people who had kids when they were very young tell me just what that eldest girl told the writer–“I wanted a baby so someone would love me.”

  19. carole,
    From your NYT article, one piece of statistics caught my attention:
    About one-third of the white population have two copies of the protective long allele. About one-half have one long allele and one short one. And about 17 percent have two short alleles. (African-Americans are less likely to have a short allele; Asians are more likely.)
    If that’s true then prevalence of depression or PTSD should reflect distribution of 5-HTT allelic variants according to race. If I recall well, the intervals of prevalence in different parts of the world are not very different. There must be more factors at work here; or maybe those statistics are scrambled by something. The number of scenarios must increase by interference with other risk factors. Someone who has two short versions of the 5-HTT allele (homozygous for the short allele) may chose some types of play environments, some types of playmates and develop particular task abilities. This would influence their interest in some topics and further influence their social networking and skills. As they reach puberty, the vulnerable type may have a hard time finding friends or getting into a relationship. It’s more likely that they will settle with a partner that either is equally or more vulnerable (especially for men) or is more confident (especially for women). Anyway, it would be interesting to see how married couples are patterned according to this factor. If more often than not vulnerable men seek equally vulnerable women to marry, then whatever children come out of their marriage must share their parents’ weak spots.
    ############
    One more thought on that story. The mother’s boyfriend who enticed or forced the girls to interact with him sexually must had had some social deficits himself. This begs the question what kind of woman — their mother — would want to be with him. Pedophilia was found related with some brain abnormalcies (Schiltz et al, Brain Pathology in Pedophilic Offenders, Evidence of Volume Reduction in the Right Amygdala and Related Diencephalic Structures, Arch Gen Psychiatry. 2007; 64:737-746). These interactions between people with different vulnerable spots and traumatic histories paint an obscure picture right now, but many intersections appear. Was the mother even more vulnerable than her boyfriend and therefore unable to do a better job at gatekeeping her girls? That would be another one factor to know that would put the story into a holistic perspective.

  20. @Drowssap: Dr. Swedo is a scholar and quite interested in improving mental health care.

    Not only is trauma emotionally scaring but the stress can trigger physical/mental illness because it lowers the immune system and lets in nasty bugs. There is no telling what this might do to the brains of infants.

    What I am working on here some way to describe how trauma is emotionally scarring. Knowing more about how trauma prepare a person for the future might help us be better about addressing such situations. I feel fairly sure mental health professionals frequently flail around trying things until something seems to work which might really be until the brain heals itself

  21. Warren

    I recently spoke with Susan Swedo at the NIMH who provided invaluable information regarding PANDAS. She agreed with me that we are at the beginning of this line of research and thinking. There is no doubt that psychological trauma is stressful and thus impacts mental health. However, the mechanisms of extended impact may be much different than psychodynamic theorists imagine.

    You talked to Swedo? RIGHT ON!!!
    —
    As an aside…
    Not only is trauma emotionally scaring but the stress can trigger physical/mental illness because it lowers the immune system and lets in nasty bugs. There is no telling what this might do to the brains of infants.

  22. the short-allele brain already primed to be more reactive in the event of stress (the illness itself, the mood change and reaction of parents and sibs) goes into full fledged alert, generating lots of chemicals which basically provide that child with thoughts suggesting something is wrong here (anxiety and depression).

    Lack of a deep “reservoir” is another reason why genes corelate with illness. It may take a lot of damage before someone with a LONG-allele starts to feel stressed. People with a short-allele have no slack to lose. But the short-allele isn’t defective. No doubt it proves useful in different types of environments, not the least of which where Strep Throat might not be common.

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