Common Disease, Common Variant

Once upon a time, prominent geneticists put forth the notion that a given common disease was probably caused by a very limited number of alleles. If so, that would have made life easier: testing and drug development would have been simpler.  The argument was that the number of alleles at every locus should have been low way back in prehistory, since the effective population back then seems to have been small.   This model assumed that most of the common diseases under consideration had little selective impact.

A paper by David Reich and Eric Lander  (On the Allelic Spectrum of Human Disease)  discussed this about ten years ago.    They gave a number of examples of genetic diseases that are caused by one or a few alleles ( at least in some populations).  They mentioned cystic fibrosis,  Gaucher and Tay-Sachs disease (both common in Ashkenazi Jews, both affecting the same enzyme path, both stimulate neuron growth…), Wilson’s disease (in Sardinia), hemochromatosis, and beta-thalassemia.

The problem is that at least three of their examples (CF, hemochromatosis, and beta-thalassemia) and probably five (Gaucher and Tay-Sachs too)  are common because they confer selective advantage in heterozygotes.   Of course that makes sense: why would an allele whose main effect is deleterious ever be common?

The case in which such a simple allelic spectrum seems most likely (not counting strong heterozygote advantage) would be a disease that strikes in old age.  The reduction in fitness caused by an allele that messes you up at 85 is naturally small: it could easily be balanced by a teeny selective advantage earlier in life, and drift might be stronger than selection, allowing a weakly deleterious allele to reach high frequency.

The successes of this approach have been few: most have been in diseases of old age, such as Alzheimer’s,  macular degeneration, and exfoliation glaucoma.

In general the common disease-common variant strategy has been a bust, enough so that it’s hard to find anyone who admits to ever having believed in it.  I think many people who argued in favor of it did believe, though. I don’t think they lied for funding, although admittedly the prospect of serious funding does tend to cloud men’s minds. I remember Kari Stefansson reacting with surprise to his group’s finding that schizophrenia seems to be caused by many rare risk alleles, different ones in every family: “I would have thought the brain was a luxury organ when it comes to reproductive success. ” I think that the general feeling in the human genetics community at that time was that natural selection doesn’t really happen in humans.  Which is screwy as hell, but there it is.

Why would they have thought this?  My best guess is a combination of factors, not the same mix in every individual: dislike of some implications of continuing natural selection in humans,  misunderstood neutral theory, confused ideas received from anthropologists about how culture trumped selection, very limited educational exposure to evolutionary genetics, and mutational pressure.

Addendum: If David Reich ever had wrong ideas about human evolution, he got over it. He’s quality.

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25 Responses to Common Disease, Common Variant

  1. erica says:

    gcochran: “I think that the general feeling in the human genetics community at that time was that natural selection doesn’t really happen in humans. Which is screwy as hell, but there it is.

    “Why would they have thought this? My best guess is a combination of factors, not the same mix in every individual: dislike of some implications of continuing natural selection in humans….”

    I’m not a scientist, just a little ole former public school teacher. I am not surprised that many in the social sciences would let their “dislike of some implications of continuing natural selection in humans” cloud their thinking, but it distresses me greatly that those who’ve gone into the hard sciences have allowed such sentimentality to result in such mushy thinking and writing. Perhaps I have quite misjudged the type of person who goes into the field of genetics? Perhaps I don’t understand their courses of study? Or perhaps the state of education in the whole of the biological sciences of our universities is as bad as the state of things in K-12?

  2. dearieme says:

    “I think that the general feeling in the human genetics community at that time was that natural selection doesn’t really happen in humans.” If you don’t mind a foreigner saying so, I have decided that one of the big divides in American politics is just a matter of tense. Some on the Christian Right believe that humans didn’t evolve: many on the Left believe that humans don’t evolve.

  3. Henry Harpending says:

    Greg I think a big part of the answer is in our earlier post about eebers and robbers. No one of my eeber pals thought there was anything at all to the common-disease-common-variant model: they all immediately dismissed it. Unfortunately eebers and robbers don’t pay much attention to each other, and during this time robbers had all the money and visibility.

  4. Pingback: Perfect Health Diet » Around the Web: Bears in the Woods Edition

  5. J Pickrell says:

    Some context is important when dismissing genome-wide association studies as a “bust”. Next to the decades of linkage and candidate gene association studies that preceded them, they’ve been an incredible success! (Thousands of alleles identified over the last five years that contribute to disease risk compared to, like, five over the previous 15 years).

    My understanding is that common alleles do contribute considerably to disease risk. Maybe more or less than any individual investigator was expecting 10 years ago. And rare alleles contribute too. Also maybe more or less than someone 10 years ago was expecting. But people 10 years ago had no actual data (and arguing about what’s obvious given evolutionary theory is unfair, because things are only “obvious” given a set of parameters that are unknowable a priori). This paper (“the false dichotomy between common and rare variant hypotheses”) is a good discussion of these issues in the context of psychiatric disorders, where there’s been strong resistance to doing large association studies.

  6. Peter Frost says:

    As late as the 1960s, most geneticists had a solid grounding in evolutionary theory. Theodosius Dobzhansky and Ernst Mayr, perhaps the leading American geneticists of their day, argued that natural selection had shaped the human brain, like any other organ. That view was fairly typical … in the 1960s.

    The retreat from evolutionary thinking took place in the 1970s and 1980s, but it was not a product of anything internal to the community of human geneticists. It was a case of people falling into line with the zeitgeist. In some cases, the change was generational — professors retired and were replaced with people who had an anti-evolutionary bias. In other cases (as with Cavalli-Sforza), the same geneticist suddenly “discovered” that the human brain was an exception to the rule of evolution.

    • gcochran9 says:

      Mayr was usually wrong. For example, he seems to have completely dismissed mathematical population genetics. On the other hand, I never had the feeling he was a liar. Just clueless.

  7. gcochran says:

    I said that you weren’t going to find common variants playing a big role in things like schizophrenia ten years ago and I kept saying it. Henry tells me that _no_ population geneticists thought CD-CV made sense – but no one listened to them. Their reasoning was the same as mine: it is hard for any allele with such negative fitness consequences to remain common. It can happen if the allele in question has lots of heterozygote advantage – and you see that, mostly in malaria defenses. You could see this happening in old age, when the amount of fitness to be lost is already tiny. Let me quote a fairly recent article (Genetic Heterogeneity in Human Disease, Jon McClellan and Mary-Claire King, Cell 2010): “We further suggest that age at onset and severity of the illness are excellent predictors of allelic heterogeneity at each locus. ” I said that in the 90s. I said more: allelic heterogeneity goes up with prevalence as well. Basically. the strength of the selection acting against the syndrome is the decrease in population fitness it causes – which is the individual loss of fitness (related to age of onset and severity) multiplied by the prevalence.

    By the way, if fitness loss for a syndrome gets too big, it’s not going to be genetic at all. When you see villages in Africa with half the population blind by 40, it’s onchocerciasis, not mutation.

    There were grey areas, things we didn’t know, in 2001. But there were also things we did know. We knew that trouble at 85 had a tiny impact on fitness, we knew that trouble at 17 had a large impact. It was hard to be sure about the evolutionary impact of disease syndromes in late midlife, CVD for example. But we knew that schizophrenia (onset in late adolescence) cuts reproductive fitness by at least half and exists at the percent level: obviously it is strongly pruned by selection, and equally obviously it would be difficult for common variants to play much of a role. To the extent that it is genetic (which unfortunately seems large), you have to invoke mutational pressure at many loci. Lots of rare variants. It was obvious to me but it sure wasn’t obvious to Kari Stefansson. I rack my brain trying to understand how anyone could think that being fucking crazy would be invisible to natural selection. But then, lots of prominent figures in human genetics didn’t believe in selection acting on humans. Neil Risch didn’t then and still does not : he doesn’t believe that lactose tolerance was selected and appears to have doubts about sickle cell ! In other words, he’s nuts.

    As for the utility of these approaches in human disease, it doesn’t look to me that there has been much, particularly on the big problems like cancer and cardiovascular disease and mental illness. Others have the same impression (again quoting from McClellan and king 2010): “To date, genome-wide association studies (GWAS) have published hundreds
    of common variants whose allele frequencies are statistically correlated with various illnesses and traits. However, the vast majority of such variants have no established biological relevance
    to disease or clinical utility for prognosis or treatment. For example, a recently published 12 year follow-up study of cardiovascular disease (CVD) in more than 19,000 women found that the 101 SNPs identified by GWAS as risk variants for CVD did not predict cardiovascular outcomes (Paynter et al., 2010). ”

    If there’s a well-thought-out theory – neodarwinism in this case – that says a particular pattern of events is very unlikely, essentially impossible – if the practitioners of that theory make that prediction in advance of the test, and the test bears them out, it is hardly unfair to say I told you so. With great good luck, maybe someone at NIH will listen to the theoreticians when the next big funding question comes along. They won’t, though: biologists and biomedical types don’t really believe in theory.

    Which reminds me of a story. A friend of a friend dropped out of particle physics and decided to become a veterinarian. That meant taking courses in chemistry. The lecturer was talking about the chemistry of urine, and wrote equations on the blackboard about various ionic species – but the poor physicist noticed that the charges didn’t balance. Which would mean that taking a piss generated a shower of lightning bolts (my favorite superpower). The physicist pointed this out. The irritated lecturer said that charges may have to balance in physics, but not in biology.

    • J Pickrell says:

      It’s fair to say that genome-wide association studies were overhyped and technology-driven (rather than theory-driven). The next stage of sequencing studies is also overhyped and technology-driven, and that McClellan and King article is what people will be citing in 10 years when they ask “What the hell were people thinking back then?”.

      As for schizophrenia, imagine you’re a researcher a decade ago with thousands of subjects. You can take a chance on trying a GWAS, or you can wait a decade for sequencing technology to get better (for all the talk of rare variants, finding them will involve sequencing of thousands of individuals, which is only now even starting to be feasible). It’s hard to blame people for trying. 15 years ago people tried linkage studies and found nothing. Five years ago people tried GWAS and found some things (e.g., http://www.ncbi.nlm.nih.gov/pubmed/21926974). Are the 8-10 loci identified from GWAS so far going to help people understand schizophrenia? It remains to be seen; but it’s a lot better than not knowing anything.

    • Sean says:

      In ‘Mad to be normal: conversations with R.D. Laing’ RD recalled that the 2 leading medical geneticists of the 70s said they were in agreement with him; there was no evidence for what psychiatry said was the genetic causation of schizophrenia. In the same book Laing also comes out with this: “If it’s a virus, as the Russians have been trying to say every other year …”

      Having a schizophrenia spectrum disorder is unlikely to be an advantage in reproductive terms, but there are a lot of eccentrics among the truly great scientists. Like the parasite that makes the shell of its host thicker a virus could be augmenting some capability in its human host for some reason of its own. Creativity might be a rare side effect of that.

      Is group selection an issue in relation to the fitness cost of schizophrenia; could the benefit be reaped by the non schizophrenic?

    • Anonymous says:

      A very entertaining/interesting comment, top to bottom

  8. erica says:

    gcochran, a question:

    “To the extent that it is genetic (which unfortunately seems large), you have to invoke mutational pressure at many loci. Lots of rare variants.”

    So, if the collection of symptoms and behaviors which we have termed schizophrenia is the result of many different rare variants, different in each family, (” Lots of rare variants”), why don’t you think this is likely to be the case also for male homosexuality? Both occur at levels greater than 1% and are thus not rare from an evolutionary perspective as are fitness-reducing conditions that result from a single rare mutation. Don’t both conditions have twin concordance figures that are relatively similar? Doesn’t male homosexuality also show up in some families much more frequently over the generations than in other families as does schiz? (Maybe I’m wrong about this).

    I know you favor the germ hypothesis as the explanation for homosexuality. Why not the common disease/rare variants that you seem to favor for schiz? I’m missing something here.

  9. gcochran says:

    Schizophrenia is more like half a percent: homosexuality is considerably more common than that. The MZ twin concordance numbers are noticeable lower in homosexuality than schizophrenia -: around 20%, in Bailey’s Australian twin-registry study. Lower than MZ twin concordances in autism, too. It also seems that fitness is depressed more in homosexual men than in schizophrenics, although I wouldn’t want to bet the farm on that,

    Next, if a syndrome is caused by many individually rare deleterious mutations, you expect at least some of them will be syndromic – that is, cause characteristic changes in other aspects of the phenotype. There are many kinds of genetic mental retardation – some make you look funny in a particular way, like fragile X syndrome. Some kinds of genetic deafness are syndromic (about 15%): like Waardenburg syndrome, where there is a white streak in the hair along with deafness.
    I know of at least one syndromic form of schizophrenia – DiGeorge syndrome, caused by a deletion on chromosome 22, account for about 1% of schiz. I’ll bet that there are more. There are also indications that schiz is associated with lower IQ.

    I don’t know of any syndromic form of male homosexuality, although there might be a very rare one somewhere. I don’t see any signs of IQ depression in homosexuals.

    Maybe most important, the brain is extremely complicated, probably the most complex of human adaptations. More than half of all genes are expressed in the brain. This means that general brain function is a big mutational target, and the incidence of various kinds of brain dysfunction should be high. There are lots of ways to go wrong. On the other hand, it doesn’t seem to me that triggering an interest in the opposite sex would be nearly as complicated. After all, birds do it. Bees do it. Even educated fleas do it.

    • erica says:

      gcochran,

      Thanks for the response. I didn’t realize schiz occurred at less than 1%, nor that it may be associated with lower IQ.
      I am assuming that the winter/spring birth numbers of schizophrenics is still part of the picture, leaving open the possibility that at least in some cases, early infection may be in play.

  10. Justin Loe says:

    With respect to gene studies, my intuition is that the complexity of various illnesses and traits has turned out to be far greater than was anticipated. Additionally, the progress of drug research has slowed, not quickened, in the past ten years.

    It doesn’t matter if more genes are found that are associated with a particular illness, if the pace and success of drug research has fallen.

    As can be seen in Derek Lowe’s post, here: http://pipeline.corante.com/archives/2009/07/17/drug_approvals_natural_and_unnatural.php, has been lower since 2000 than in the previous years, with the exception of 2005.

    See also: http://www.forbes.com/sites/matthewherper/2011/06/27/the-decline-of-pharmaceutical-researchmeasured-in-new-drugs-and-dollars/

    • erica says:

      From your toxo link (and a “thanks” for that as I haven’t read about updates on toxo in a while)

      “Recently, it has been recognized that different genotypes of Toxoplasma have distinct neuropathogenic potential. The objective of this study was to investigate whether parasite genotype is a contributing factor to disease risk. ”

      Wow–the genotype. Wonder where all this will lead.

      • Justin Loe says:

        @Erica,
        Yolken and his team have done a lot of work on this subject. E. Fuller Torrey, one of their collaborators, has been heavily involved in that research, and is a psychiatrist well-known for his advocacy of the viral/infectious disease contributions to schizophrenia.

        Yolken is probably one of the leading infectious disease specialists in the world doing research in this area.

  11. Justin Loe says:

    As I mentioned in another post, and as Derek Lowe of In the Pipeline has highlighted in his blog, http://pipeline.corante.com/archives/2009/07/17/drug_approvals_natural_and_unnatural.php, it doesn’t really matter how many new genes are discovered for schizophrenia in the short term if the rate of new drug discovery continues to decrease.

    As Lander mentioned in a recent Harvard panel discussion on the human genome, the payoffs from this sequencing are probably going to be realized 40-50 years down the road. It’s possible that this prediction is too pessimistic but that prediction seems more likely given the rate of confirmed gene discoveries and the rate of new drug development.

  12. Sean says:

    “The reduction in fitness caused by an allele that messes you up at 85 is naturally small: it could easily be balanced by a teeny selective advantage earlier in life, and drift might be stronger than selection, allowing a weakly deleterious allele to reach high frequency.”

    I am puzzled by what Michael Rose, a professor of evolutionary biology at the University of California, is saying here. “One possibility is that there are genes that are advantageous early on but damaging to health later in life — an effect called “antagonistic pleiotropy.” We are making progress on this, but in any case the fruit fly experiments tell us that the effect is real.”

    “In 1939, British statisticians Major Greenwood and J.O. Irwin published a little-noticed article in the journal Human Biology that contained a profoundly unexpected discovery. Greenwood and Irwin were studying mortality figures for women 93 and older. They expected to see the death rate rising with age, as it does throughout adult life.[…], between age 93 and 100, the acceleration in death rates came to a screeching stop. Little old ladies who were 99 were no more likely to die than those who were 93.[…]
    n Hamilton reasoned that, in early life, any gene that kills an organism before it can reproduce will be ruthlessly weeded out by natural selection, since that individual will fail to leave offspring. But genes that kill later in life are not weeded out as rigorously, so they can hang around in the population. By this reckoning, aging evolved as a result of “declining forces of natural selection” as individuals get older.

    OK, Here is the bit I don’t understand.

    “What if aging was actually caused by the declining forces of natural selection? If so, once these forces bottomed out, the aging process too would stop.”

  13. JediWonk says:

    THIS JUST IN:
    http://www.nytimes.com/2016/05/26/health/alzheimers-disease-infection.html?smprod=nytcore-ipad&smid=nytcore-ipad-share

    Alzheimer’s is a response to a pathogen (probably herpes simplex).

  14. JediWonk says:

    I had dinner with Dr. E. Fuller Torrey a year before this post was published, and privately, he stated as fact that schizophrenia was a result of toxoplasma gondii infection. Dr. Torrey recounted how he had realized by 1974 that schizophrenia had to have as its root cause an infection, but in all that time NIMH had never put a dime into directly researching that hypothesis.

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