Is Mental Illness Good For You?


Mental illness is surprisingly common.  About 10% of the population is affected by it at any one time and up to 25% suffer some kind of mental illness over their lifetime.  This has led some people (many people in fact) to surmise that it must exist for a reason – in particular that it must be associated with some kind of evolutionary advantage.  Indeed, this is a popular and persistent idea both in scientific circles and in the general public.  (See the recent article “Depression’s Upside” from the New York Times Magazine, for example).

Such theories come in two main varieties – the first, that mental illness confers some specific advantage to those afflicted; and second, that the mutations which cause mental illness in one person’s genetic background may confer an advantage when they are in a different genetic background (balancing selection).  Both of these suffer from some misconceptions about how evolution by natural selection works.  The intuitive appeal of the “survival of the fittest” metaphor may have something to do with this – the actual mechanisms of natural selection are more nuanced.

Natural selection works by changing the frequencies of genetic variants in the population.  If a particular gene, gene X, comes in two varieties, X and X’, and one of these (say X’) tends to increase the evolutionary fitness of the people who carry it, this means they will have more offspring than people who do not carry that variant and the frequency of the X’ variant will increase in the next generation (at the expense of the X variant).  Variants that increase fitness a lot rapidly out-compete the alternative version and soon all copies of the gene will be of that type (it becomes “fixed” in the population).  In contrast, new variants that arise which seriously decrease fitness will tend to be rapidly weeded out of the population. 

We know that psychiatric disorders can be caused by such genetic variants (mutations). What are the likely effects of such mutations on fitness?  Is there any reason to think they may confer some kind of advantage on carriers?  Some examples of the types of advantages that have been postulated include that schizophrenics may have been seen as shamans in ancient societies, that people with bipolar disorder may be more creative (it is especially common among poets, for example), or that depressed people are actually more realistic and better able to concentrate on a problem.  The trouble with these theories is that natural selection doesn’t care whether you are good at poetry or solving problems through prolonged rumination.  Natural selection only cares how many children you have – more accurately, how many children you have who survive to breed themselves.

If it were true that people with mental illness live longer and have more surviving offspring than people without, then this kind of theory might be viable.  In fact, the evidence is overwhelmingly the opposite.  First, mortality rates before or during the reproductive period for depression and schizophrenia are two to three times higher than the general population.  Second, surviving patients with schizophrenia have only 1/3 the average number of children – this general trend seems to also hold for other psychiatric disorders.  Variants that increase risk of mental illness thus demonstrably and significantly decrease fitness and should be rapidly selected against; i.e., they would never rise to a high frequency.  (This is one of the major arguments against the so-called common disease/common variants hypothesis – see post of July 7th for more on this). 

But wait – maybe these disorders are deleterious in our current environment but conferred an advantage of some kind in primitive environments.  (Much as variants that predispose to obesity or diabetes in our current environment might have been adaptive in an environment where high-fat food was very scarce).  This is certainly conceivable, although there is no evidence or even good reason to think that this was the case.  In fact, through some simple modeling it can be shown that the current rates of mental disorders do not fit such a scenario (see Keller and Miller).

An alternative suggestion is that the variants that predispose to mental illness do so only in some genetic contexts – only in the presence of additional variants.  In other genetic backgrounds, perhaps they confer an increase in fitness which counterbalances the decreased fitness in mental illness sufferers.  This scenario of balancing selection is modeled on very rare cases like sickle-cell anemia, where a particular mutation causes a deleterious condition when present in two copies, but confers an advantage (increased resistance to malaria, in this case) when present in only one copy.  While this kind of model is difficult to disprove, there are strong arguments against it and no evidence that it applies – relatives of schizophrenics do not show increased fertility rates, for example.

So why is mental illness so common?  If it’s so bad and is caused by genetic variants, why hasn’t natural selection gotten rid of them all by now?  Well, the answer is it does – in fact, it’s very good at getting rid of them.  Unfortunately, new mutations keep arising all the time.  Rates of mental illness are higher than those of other genetic disorders because it takes the combined actions of thousands of different gene products to wire the staggeringly complex human brain.  If any one of a large number of these genes gets mutated, then development of the brain may be compromised and this may ultimately result in a psychiatric disorder.  There is thus no paradox to explain – common disorders like schizophrenia are really umbrella terms for lots of distinct genetic disorders, each of which is extremely rare, due to the efficient action of natural selection.  All of these theories are thus offering solutions to a problem that doesn’t exist. 


For more on this topic see the extremely insightful article by Keller and Miller. 

 

Keller, M., & Miller, G. (2006). Resolving the paradox of common, harmful, heritable mental disorders: Which evolutionary genetic models work best? Behavioral and Brain Sciences, 29 (04) DOI: 10.1017/S0140525X06009095

Comments

  1. Of course mental illnesses in general are only partially heritable -- the phenotype only develops in interaction with the environment. And some diagnoses may have little or no heritability (and may not even be real entities). So some people who are diagnosed with mental illness have conditions with no meaningful genetic component at all.

    What we are really talking about here is schizophrenia and bipolar disorder. There is plenty of evidence that schizophrenia is associated with environmental factors including -- and this is a fact -- the month in which a person is born; and maternal malnutrition. So sporadic mutations probably have something to do with it but there are also plenty of people who carry genes that may be associated with schizophrenia under particular environmental conditions, who do not develop the disorder; and whose children who inherit said genes do not either.

    Just sayin'.

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    1. A simpler explanation might be to forget random-mutation-and-natural-selection. The organism posses an ability to organize responses when under stress. Not a supernatural, perfect ability, but a fallible ability similar to our own creative intelligence. Most mental illnesses, especially those that involve savant and other abilities, are merely nature's tentative, experimental, incomplete efforts to organize adaptations to changing environments.
      Berthajane Vandegrift
      http://30145.myauthorsite.com

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  2. Non-scientist warning; I'm full of it.
    I suspect the ability to diagnose mental illness is still too unscientific and the links to genetic information still too mysterious to say yet. How do you differ between Inherently Depressed and Just-Feeling-Shitty-Because-Life-Sucks? Tricky. There's probably a lot of hidden insanity in people who have the right genes but manage to fight off the diagnostic symptoms. If the rates of genetically-linked insanity are much higher than we currently detect and we find out, it may seem there is a selective pressure. When that theory is on the table again, I suggest this modification: Most mental illness is probably linked to multiple gene areas (or multiple changes within one area, whateva) and the prevalence of certain kinds of insanity derives from genetic advantage in SOME of the related genes. When they're all active, the person is liable to be a dead end. But maybe someone with 70% of the genes for depression survives better in miserable environments with minimal stimulus (Norway or Alaska), because their default state is apathy and they can deal with it. 60% paranoia would be useful for animals with a lot of cunning competition for resources, I imagine. I could make excuses for useful crazy all day long. My point: I don't think the information is strong enough just yet to rule out the possibility of advantage in the relatives of crazies.

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    1. One secret of success in life is for a man to be ready for his opportunity when it comes.avocats criminel

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  4. @Christopher: I don't see how depression can be a benefit in any situation. The idea that apathy can be beneficial is rather typical only in postindustrial societies where apathy is common. For instance, you mention Alaska. The Inuit have survived there for millenia. Do you think they would have done so if apathy was common among them? On the contrary, motivation is required to comfortably live in any environment, let alone extreme ones. As for others in Alaska, do you really think that those who don't care about doing anything have some sort of advantage over those that find the motivation to do things? How could that ever be beneficial? History and anthropology tells us that as far back as we know about, humans have told stories, made music and art. Children have found ways to play and explore and adults have helped them do so. I suppose if they knew that the only things worth doing were going to see a movie or something, they would have realized how pointless life was and how depressed they should be. Such is ignorance. Back to seriousness. Could we have made it to where we are with apathy?

    I have bipolar disorder and know many "crazies" as you say. The idea that we have some sort of advantage is frankly patronizing on the part of those with no mental illness and wishful thinking among those with. If you've known many mentally ill people, how have you remained completely unaware of how difficult it is for us to find and *keep* good relationships? Have you not noticed that many of us refuse to have children because we don't want to pass along what we've been through? Oh, and here's a small point to consider: we tend to *kill* ourselves. Please explain to me where the evolutionary advantages are. There's this idea growing among the "broad minded" that symptoms of mental illness are facets of humanity. I suppose they are... in the same way that predispositions to cancer and heart disease are. Unless you are of the other common and uninformed opinion that mental illnesses aren't "real" illnesses.

    The author of this entry is right on and I thank him for speaking logically.

    There are generally two extreme views of the mentally ill. Neither are very helpful. On the one hand, you have those who fear the mentally ill just as they fear criminals. On the other hand, you have those well meaning but ignorant folks who insist that we can overcome everything if we just try hard enough. The fact is that the mentally ill are mainly a danger to themselves and while the quality of life can be improved for some with a lot of hard work, there are those who simply will not get better to any significant degree. Those who say otherwise simply have not had the experience of knowing these people.

    By the way, about the paranoia: there is a lot of confusion about this. Many people don't realize that there's a difference between caution and paranoia. Paranoia is stifling, irrational and impedes social relationships. In a hunter or prey situation, it can cause hesitancy when action is needed, and action when hesitancy is needed. Paranoia is reactionary, caution and experience are not.

    As my people, the Greeks, say, the truth is always in the middle.

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    1. It's quite well established that the trait of lowering the body's activity evolved as a survival mechanism for the cold. http://www.ncbi.nlm.nih.gov/pubmed/22036090

      Your statement that "the mentally ill are mainly a danger to themselves" is utterly abhorrent and unrelated to reality. The majority of people with mental health conditions lead normal lives. Productivity, relationships and other aspects of life may be affected, but it is simply ridiculous to claim that most mentally ill people are "mainly a danger to themselves."

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    2. I think hypersexuality in manic episodes is a clear reproductive advantage!; when I am manic I certainly am not in a position to make the decision, as some people may (as you put it) 'Have you not noticed that many of us refuse to have children because we don't want to pass along what we've been through?' Plus, has it not occurred to you that up until recently abstinence was the only source of contraception and not one that is going to be in the ball park of somebody who is severely manic? Yes sure it's not great for exclusive relationships but given that it increases the possibility of multiple matings by 'killing off' those exclusive relationships this only increases the possibility for reproducing as much as possible. Let alone that some of us may have severe bipolar illnesses but consider it an illness that can be successfully managed in this day and age and is not a reason to forgo parenthood due to the passing on of bipolar genes.

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  5. Hi not High!
    Thanks!A little deep for me at the moment but in my non scientific way I usually get a grip on writings such as this because of direct personal experience and knowledge gained through age.
    I think my old line about "crazy" people is also applicable.
    "It,s not the crazy people you worry about...it,s the ones that don,t know It"
    The title of the post can say a lot to some people .Yes it can very good for you IF you understand you have "it".
    Or is it safe to flip the wording and say
    Not being mentally "ill" is bad for you.

    When I started to understand a few things about myself and that there may actually be real reasons for a lot of my little quirks and had I and many others known about some of the labels and names used in the phych. world
    I would have been labeled "CRAZY" many years ago even from adolescence if the modern labels were discovered and applied.
    But I would have been "mis-labeled"given the wrong types of medicine and even feared my many of my elders and siblings.
    Not long ago I could have been burned at the stake for a whole host of things I have done in my life that are very "normal" to me.
    (any guesses?)?
    I walk a fine line now in life that is I need to take medicine to control my brains actions BUT it also can remove a small piece of my everyday personality that I have come to not only enjoy but crave.
    And none of this is "madness" or "crazy"
    although when trying trying to explain them in print they sound like it.
    So in my rambling way I say and not in an offhanded manner but in a very personal one
    YES it can be good for us!
    If we are not trying to hard to figure "it" out or understand "it" somewhat when we do.
    Rick

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  6. Does “survival of the fittest” mean survival of an individual at a particular point in time, or survival of traits that are species adaptive over time? Perhaps being sane in an insane environment is maladaptive? If we pumped enough prozac into each person, maybe we'd all be happy and adjusted until the end? But maybe the end would come a lot sooner for the planet as a whole.

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  7. A quick look for the definition of "sane" on Google gives me the two following definitions from Princeton's Wordnet:

    1. mentally healthy; free from mental disorder; "appears to be completely sane"
    2. reasonable: marked by sound judgment; "sane nuclear policy"

    So when someone calls an environment "insane", one has to wonder to what they refer to. If using the first definition, perhaps the implication is that the majority of people are mentally ill. What is there to suggest that a mentally ill person survives better among other mentally ill people than a mentally healthy person? What advantage does a mentally ill person have in this situation? I'm unable to foresee myself having any advantages were I to be in such a situation. In what way would I fare better?

    As to the second definition, I have personally been in situations where there was a lack of reason and sound judgment and I certainly didn't feel that I was any better off because of my own insanity. On the contrary, usually the reasons I did well in such situations was that I managed to keep a cool head. Thinking clearly and rationally allowed me to adapt. If I had been psychotic or even if I'd had an extreme mood swing, I certainly don't believe I would have done as well.

    But that's just conjecture. How might I benefit from my own mental illness in an irrational situation? Honestly, I can't see a way.

    As far as survival of the fittest, a man who sacrifices himself to save others is beneficial to the species. A man who leaps off a building because Cthulhu is chasing him is a help to no one. And one hopes he doesn't crush someone when he hits the ground.

    And if you put too much Prozac in my water, I will almost definitely become psychotic. In general, antidepressants are strictly for people suffering from major (or unipolar) depressive disorder, not bipolar disorder or schizophrenia. ADs can in fact cause psychosis in those disorders.

    Unless you work in the mental health field (which I doubt from those statements), the majority of mentally ill people you see, and there are many, are homeless people. It's a reality. It's one of my goals to not become that, but I have to face the possibility if I'm to avoid it.

    You know, I can understand why some mentally ill people want so badly to believe that there may be an evolutionary upside to it, but I wonder what the draw is for others. Is it simply that they have no idea what mental illness is or is it something else?

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    1. Actually it's well established that the evolutionary origin of bipolar disorder was in adapting to the seasons - lower mood during darker, colder weather and elevated mood during lighter, warmer months - http://www.ncbi.nlm.nih.gov/pubmed/22036090. The entire point of this article is very disingenous and frankly very misleading.

      "The hypothesis of the evolutionary origin of bipolar disorder (EOBD) synthesized ideas about the biological clock and seasonal shifts in mood (Rosenthal, Wehr) with theorizing that bipolar disorder descends from a pyknic (compact, cold-adapted) group (Kretchmer). The hypothesis suggested that bipolar behaviors evolved in the northern temperate zone as highly derived adaptations to the selective pressures of severe climatic conditions during the Pleistocene."

      Your statement that "the majority of mentally ill people you see...are homeless people" is also completely misleading, and you appear to be very sadly misinformed about a condition that you claim to have. The overwhelming majority of people with mental illness lead normal lives. Depression is one of the most common medical complaints in the developed world and likely will be the most common within a few years.

      Thirdly your statement that giving you antidepressants could lead to psychosis is exaggeration. Psychosis is an extremely rare occurrence in people with bipolar disorder - although you are correct that antidepressants have a risk of leading to a manic episode and are more suitable for people with unipolar depression.

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    2. Fourthly, on another note, you state that you managed to keep a cool head in stressful situations, but that a severe mood swing could have worsened these situations.

      That is not how bipolar disorder works. Episodes of high and low mood last for much longer time frames - there is no such thing as an instantaneous mood switch in bipolar disorder. You appear to be very alarmingly misinformed about your own condition, and I wonder why that is.

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  8. What all of this makes clear to me is that mental illness is almost exclusively environmentally caused. It is not genetic.

    Sanity and insanity are legal terms, not medical terms. Sanity means knowing right from wrong. An insane person does not know right from wrong.

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    1. People with depression actually have a difference in there brain chemicals. This is genetic, not environmental, that's why medication is necessary for such patents to help correct there biological depression.

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  9. @kurt9: There are legal definitions of sanity and insanity, but to say that they are legal terms is, at best, an ignorant jump to a conclusion. And that's giving the benefit of the doubt.

    To anyone else: if you're wondering if kurt9 has any idea what he's talking about, feel free to investigate the definition of insanity. Wikipedia has a good article on it, but if you don't trust that, there is plenty more.

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    1. Speaking as a law student and former medical student, sanity and insanity *are* legal terms, not medical or psychological ones. Cheers

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  10. kurt9: thanks for your comments. Your impression is mistaken. The evidence that mental illness has a very large genetic component is overwhelming and we now know the identities of many genes which are involved - when these genes are mutated, the risk of disorders like autism or schizophrenia or bipolar disorder increases drastically. In contrast, while some environmental factors have been identified and likely play some role in the emergence of the disorders, none of them causes a dramatic increase in risk.

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    1. The most recent research I read is that it is a 50-50 breakdown between genetics and environment.

      As for environment, look at the effects of poverty on the brain.

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  11. Considering only depression, how about a model in which depression is a fitness drag in the present environment but not in pre-1700 human history? The two most debilitating effects of depression are listlessness and self-isolation, while hard work and strong social engagement commonly alleviate depression (e.g. Darwin's observation about work). In modern societies depression itself causes a negative cycle because it is possible not to work and to self-isolate. But subsistence farmers in small villages and hunter-gatherers in small tribes seem to me not likely to have had an option in either case. In which case perhaps depression, which has a potential virtuous cycle in compelling hard work and more prosocial (moral) behavior resulting from more realistic self-assessment (at least that's what I think the psych findings suggest), might be a fitness enhancer, either simply for the individual or similarly to altruism. Does the research address this possibility?

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  12. Thanks to all of you for your comments. George, you asked whether there was any research addressing a potential advantage for depression in terms of a work ethic - that is the first time I've ever heard that suggestion and I would be very surprised if it were true. While hard work may alleviate depression that does not mean depressed people tend to work harder.

    Cervantes, you raise an important point about environmental factors but overestimate their importance. It is true that various environmental factors such as winter birth increase one's risk of schizophrenia. The effect is very small, however, (risk goes from 1% to 2%) and nowhere near strong enough to explain the overall prevalence of the disorder. The evidence is extremely strong that variation in genes is by far the largest determinant of risk. It is quite likely, however, that environmental conditions can modify the effects of genetic variants.

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  13. Kevin, thank you for the interesting and provocative post, I'll have to read the Keller/Miller article. I have one minor quibble. You mention "variants that predispose to mental illness do so only in some genetic contexts," which sounds fascinating, and I wish you had written about interactions between different genes. Instead, you only mention heterozygote advantage (which involves interations between different alleles of the same gene). For folks interested in that topic, I recommend the book Survival of the Sickest. Again, thanks for the post and for your fascinating blog.

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  14. Thanks Ernie for your comments. I haven't read that book, but had a quick glance at the blurb. Sounds like it may be attempting to explain the persistence of illness by supposing some evolutionary advantage to it or to the variants that can predispose to it. (Similar to the arguments above). There may indeed be some cases where variants persist because they are deleterious in some genetic contexts and advantageous in others. As far as a general explanation for why common genetic illnesses persist, however, there is no evidence that that kind of scenario (balancing epistatic interactions) is widespread, nor is there any need, a priori, to posit it in order to explain the prevalence of disorders - ongoing mutation can explain why they persist.

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  17. Might there be group evolutionary advantages -- crazy war leaders, explorers, inventors -- which would favor more rather than fewer "mutations" in the developmental pathways -- or, rather, a Goldilocks mean? What about obsession -- is that a mental illness? Still, your overall point is well-taken: the new mutants just keep on coming.

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  18. It's an interesting question whether there might be group evolutionary advantages. Perhaps it is good to have a certain frequency of slightly mad folks in your tribe or clan. (I'm using "mad" in the colloquial Irish sense of the word, to mean someone who would do anything - your "war leaders, explorers, inventors"). There are some theoretical difficulties with group selection, though I am not convinced by the arguments against its possibility. The argument here would be that genetic variants predisposing to slightly different behaviour would be selected for and might in some circumstances (say in combination with each other) cause more serious mental illness. It's a nice idea, but there is really no evidence to support it and also no need to invoke it. New mutations that are really just frankly deleterious are arising all the time, causing illness and pretty rapidly being selected against. The prevalence of these disorders can be explained by the very large number of genes required to build a human brain.

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  23. I think mental illness is not normal, and we can't think it is good for us. The problems is we are trying to make this disease a part of our lives, and for that reason there are persons who are looking for a "nice" way to convince us this is normal, but it isn't, and we can't be stupid and believe what they say.
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  24. Mental illness could be the human condition. The reason why the other 75% aren't included is they haven't been observed...yet.

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  31. Hi Kevin, I came to your blog after reading your article in Genome Biology. I believe that some cases of mental illness are caused by very rare mutations of large effect, but that in the main, a polygenic model involving a large number of genes explains genetic predisposition to mental illness. I think the recent Lee et al paper in Nature Genetics goes some way to demonstrating that a polygenic model fits for schizophrenia.

    Under such a model, the increase in risk attributed to any specific locus is small and therefore the negative selection on the specific variant will be very small. For instance, the genes that have come out of GWAS for SCZ and BPD in the main have been the major allele at that locus, implying they're more common in the population than the protective allele. So the majority of people in the population carry those alleles yet don't get mental illness. It's only the people who carry 100s or even 1000s of risk alleles who are most predisposed to the illness, therefore the selection pressure is small at each locus.

    One could imagine a scenario whereby those people who don't carry sufficient risk alleles get the disorder, there may be positive selection on the risk alleles that they do carry. As you say in your post, there is some evidence that people with bipolar disorder show increased creativity. In a scenario where one carries 75 or 80 bipolar risk alleles out of the 100 necessary to get the disorder, creativity, intelligence, or some other measure of cognitive functioning could be increased, leading to a fitness advantage in the absence of disease. This fitness advantage and/or genetic drift owing to the negative selection at each locus being small, could explain why these alleles persist in the population.

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  32. Hi Enda,

    Thanks very much for your comments. It is nice to hear from you.

    You give a very clear explanation of the polygenic model and the argument that balancing selection can account for the persistence of disease-causing alleles at high prevalence. I fully understand the model. I don’t agree with it.

    What would be required to convince me that it is right or even plausible is not more explanation but evidence. My main argument is that the polygenic model was invented for statistical convenience, relies on a massive and completely unsupported assumption (of continuously and normally distributed liability to disease) and has led to the construction of a body of literature that is arguably internally consistent in its mathematical abstractions but never reality-tested against known biological principles or facts.

    Given that we have a perfectly reasonable (though still complicated) general explanation for the genetic architecture of complex disorders like schizophrenia or autism using known and proven genetic mechanisms (the same ones that apply to mental retardation or inherited forms of blindess or deafness), I see no reason why the made-up polygenic model should be taken in the field as the default position and simply accepted without justification. It is an extraordinary claim that requires extraordinary evidence, not no evidence.

    To answer your specific points, first on balancing selection – this has so far been proven for only a handful of celebrated cases. There is no evidence that it is a widespread mechanism. It could be, but simply invoking it does not get proponents of the common disease-causing variants off the hook – I will believe it when it is demonstrated to exist. (And natural selection does not care how “creative” you are, unless what you are creating is more children).

    Cont'd...

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  33. Second, I find the recent paper by Lee et al and other similar ones using aggregate scores of vast numbers of SNPs or genome partitioning of variance to be deeply unsatisfying and unconvincing. The main reason is that they are highly abstract and also circular – assuming an underlying, normally distributed liability (even when the actual data are produced from discrete sets of cases and controls) and modelling the amount of variance explained in risk across the population (i.e., the simulations assume the model they claim to prove).

    In the Lee et al paper for SZ, they clearly get some kind of signal – by computing a genome-wide similarity matrix across all SNPs, they see that cases are more similar to each other than to controls and vice versa. However, the lack of detail in the paper on methodology or specifics of the results leave me very unsure of what the signal actually is, what is driving it and what that means. How much more similar? Are they identical by state or by descent? Can these be distinguished? Is population stratification really sufficiently controlled for? Wouldn’t the differing numbers of cases and controls from different geographic regions lead to some such effects?

    The inference is that cases are more similar in genome-wide profile because they share more risk alleles (exactly what GWAS should pick up, but the argument is that there are so many of them that GWAS cannot pick up individual ones at statistically significant levels with current sample sizes). The stated implication is that larger GWAS need to be funded to find these minuscule effects. Even assuming the signal is real and not caused by stratificiation, going from an increased genome-wide similarity signal (of unspecified magnitude) to a “proportion of variance explained” requires a set of assumptions that are not made fully clear – the most basic of these is that schizophrenia really is a unitary disorder (as opposed to an umbrella term for many hundreds of genetically distinct disorders that lead to similar symptoms) and that measures of population-wide variance have any meaning at all. (This approach would not be used for mental retardation, for example, because it’s clear it would be meaningless).

    But let’s assume, for argument’s sake, that the value that Lee et al obtain of 23% of variance attributable to common variants is correct. What does that actually mean in individuals? Does it mean some cases are caused by rare, single mutations and others completely by this massive polygenic effect? A much more plausible scenario would be that the effects of rare mutations are modified by the polygenic background. We know that even classically Mendelian disorders like cystic fibrosis or Huntington’s disease can be strongly modified by genetic background. (As it happens, though, there is no evidence that even this modification is due to thousands of SNPs of small effect, as opposed to a small number of strong modifiers).

    I argue, based on principles of robustness of biological systems (more on that soon), as well as on the growing list of causative rare mutations, that to push the system into a pathogenic state you need a large perturbation (either environmental or genetic). Actually, to be very precise, what I am arguing is that that should be the default model, which can be modified as more complexities arise. (Such as the growing evidence for a two-hit model for some cases of intellectual disability or autism).

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  34. Hi Kevin,

    thanks a lot for your response. There's a lot of points there to discuss, so I can only deal with a handful here. With regards to balancing selection, I agree that there's not a whole lot of evidence for it, but I don't think one even needs to invoke balancing selection in this case. If the purifying selection on individual variants is small, genetic drift could then explain why risk alleles could rise to an appreciable frequency in the population. I don't particularly want to get in to evolutionary psychology as I think it's a field in which there's a lot of theorising, with not much testing of models or replication of results, but many studies show that creativity is a much desired trait in partners, particularly in females choosing male partners, and hence could lead to more children. So I can't dismiss the idea that creativity could have been selected for.

    I don't see what is abstract about the Lee et al paper beyond the liability threshold model. It's simply the extension of classical twin and family studies that have always been used to estimate heritability in population samples. In a twin study, we assume that the DZ twins share 50% of their genome IBD and from there partition variance into genetic and environmental factors. This assumption is of course not always accurate as due to Mendelian segregation, the number can range from ~37-63%. This method is simply removing the assumptions by directly testing how much of the genome cases share IBS (which is actually a very good estimate of IBD), and then just like a twin or family study, estimating how much more sharing there is among cases relative to controls. Essentially, it's showing that cases are more "related" to each other than controls. I think that that is clear evidence of polygenic liability. You can choose to estimate the relatedness using any type of SNPs that you want e.g. only SNPs with MAF >10% etc and then estimate how much those SNPs contribute to the polygenic liability. Even taking out the liability threshold model, showing that cases are more similar than controls is evidence of polygenic liability. The liability threshold model is primarily used in this case to compensate for the prevalence of the disorder in calculating the heritability.

    That might seem like an unsatisfactory explanation, but when they took genes that were expressed in the central nervous system, they showed that a disproportionate amount of the liability could be explained by those genes versus picking genic regions of similar physical length and with similar numbers of SNPs at random from the genome. This implies that what they're picking up is real biology as opposed to random noise from the genome or population stratification. There's clear clustering of the many risk alleles in systems that are disrupted in disease.

    I think this also agrees with your theory about the robustness of systems. I completely agree with you that large perturbations are needed for disease. This is why the polygenic model makes sense. Many genes are involved in each biological system, and if a mutation causes a problem somewhere, the system has safeguards built-in to compensate. This is sensible from an evolutionary point of view. But when the number of mutations in a system reaches 100s or 1000s, the system can't adapt anymore and disease onset occurs. The mutations that build up will be both common and rare, not just rare mutations. So I would argue, that your ideas of robustness are correct, but could also be explained by the polygenic model.

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    1. Estimating heritability from twins is NOT a population-based method - it is family-based and then averaged across the population. In contrast, the method of Lee et al looks for cryptic relatedness at much greater distances. But as you say: "Essentially, it's showing that cases are more "related" to each other than controls. I think that that is clear evidence of polygenic liability." I think it is clear evidence of population stratification. (In fact, that would be my definition).

      Regarding the "CNS" genes, I am unconvinced. The vast majority of genes are expressed in the CNS (>85%).

      On robustness, it's funny how it can be seen both ways - the right way and the wrong way. The question is whether the cumulative effect of many very tiny changes can push the system into an altered state. The definition of robustness is that it cannot. Developmental systems must be robust to environmental perturbations and especially to internally generated noise - the normal fluctuations in gene expression that happen on a moment-to-moment basis all the time. In fact, these may help to buffer the system - if the functional operating parameters were too narrowly set it would not tolerate any changes. Your argument that "when the number of mutations in a system reaches 100s or 1000s, the system can't adapt anymore and disease onset occurs" thus does not fit with my understanding of developmental systems. I also know of no case that demonstrates such an effect but am prepared to be proved wrong.

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  35. I find it easier to think about more common disorders because in this case the adjustment in the heritability estimate from threshold models due to the prevalence is negligible. Take major depression as an example. The prevalence is around 16%. I don't think that the genetic liability to major depression in the population will be explained by rare variants modified by a polygenic background. Again linkage studies have been unsuccessful (so have GWAS), so I don't think that every case of major depression is caused by individual rare variants in the population. If some of the rare variants were shared, they would have been picked up by linkage studies. Unipolar depression is also more common in families with bipolar or schizophrenia, implying that there is a shared genetic etiology. I find a rare variants explanation completely unsatisfactory in this case. A polygenic model of many variants with small effect makes much more sense here.

    I do believe that rare variants contribute to schizophrenia. I think that they contribute to the overall polygenic liability, and that in some cases where there are large CNVs etc, that they can be the direct cause. But in the population at large, genetic predisposition to disease is caused by the variants from across the spectrum of frequency.

    I understand your criticisms of the theory. It's only really now that we have such large genetic datasets that we can begin to test different models of genetic liability properly. Once sequencing becomes the primary method in genetic epidemiology, we will be able to test even more models. But I think that Lee et al paper goes some way to showing that many genetic variants explain a decent proportion of the variance of schizophrenia, but clearly not all. There is much more to be found. Your theory of rare variants modified by genetic background is an interesting model. Is there some way that you can test it?

    ReplyDelete
  36. The "theory of rare variants modified by genetic background" is not MY theory - it's standard genetics. That is why I argue that it should be our starting point when thinking about the genetics of complex disorders. It is based on thousands of examples of Mendelian disorders.

    As for the argument that if rare variants really caused these psychiatric disorders, they would have been found by linkage, I don't buy it. We know they have incomplete penetrance for specific clinical categories (even in MZ twins), that their effects on fitness are large, meaning big pedigrees are rare and that if the disorders are highly heterogeneous then lumping families together for a linkage study defeats the purpose.

    This comes back to the central assumption of studying "the genetics of schizophrenia" (or any other complex disorder) - if our ability to distinguish phenotypes is extremely limited, because our criteria are very superficial (such as psychological symptoms), then we are likely to fool ourselves into thinking such categories are unitary. If they are not, then population-based methods (like genetic epidemiology) are not likely to be productive in identifying causal variants. (Or particularly meaningful actually on a broader level - if SZ is really a symptom arising as a consequence of several hundred genetically distinct disorders, then studying its overall "heritability" is not that useful - it's nice to know it's largely genetic, but the precise value carries little information (and partitioning it into different bits even less).

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  37. A parallel to your argument is nonspecific learning disability (previously termed mental retardation). Can be caused by lots of rare genetic conditions, and clearly not advantageous.

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  38. Yes, exactly. Many specific forms of learning disability can be recognised by their other symptoms (typical facial morphology for example). That is not the case for most genetic conditions leading to psychiatric disorders (with a few examples like Fragile X and Velocardio-Facial syndrome). But no reason to think the architecture differs significantly. And no one is arguing that the currently unexplained cases of intellectual disability require a whole new genetic mechanism (massively polygenic effects) to account for them - just that we haven't found the responsible mutations yet.

    Again, I am not saying the genetic will not have complexities, with huge heterogeneity, modifiers, oligogenic interactions likely. But I am unconvinced by mathematical simulations claiming to show major effect of common variants, when based on flawed assumptions and circular logic.

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