Schizophrenia: The Mystery of the Missing Genes

By Neuroskeptic | August 17, 2009 2:00 pm

It’s a cliché, but it’s true – “schizophrenia genes” are the Holy Grail of modern psychiatry.

Were they to be discovered, such genes would provide clues towards a better understanding of the biology of the disease, and that could lead directly to the development of better medications. It might also allow “genetic counselling” for parents concerned about their children’s risk of schizophrenia.

Perhaps most importantly for psychiatrists, the definitive identification of genes for a mental illness would provide cast-iron proof that psychiatric disorders are “real diseases”, and that biological psychiatry is a branch of medicine like any other. Schizophrenia, generally thought of as the most purely “biological” of all mental disorders, is the best bet.

With this in mind, let’s look at three articles (1,2,3) published in Nature last month to much excited fanfare along the lines of ‘Schizophrenia genes discovered!’ All three were based on genome-wide association studies (GWAS). In a GWAS, you examine a huge number of genetic variants in the hope that some of them are associated with the disease or trait you’re interested in. Several hundred thousand variants per study is standard at the moment. This is the genetic equivalent of trying to find the person responsible for a crime by fingerprinting everyone in town.

The Nature papers were based on three seperate large GWAS projects – the SGENE-plus, the MGS, and the ICS. In total, there were over 8,000 schizophrenia patients and 19,000 healthy controls in these studies – enormous samples by the standards of human genetics research, and large enough that if there were any common genetic variants with even a modest effect on schizophrenia risk, they would probably have found them.

What did they find? On the face of it, not much. The MGS(1) “did not produce genome-wide significant findings…power was adequate in the European-ancestry sample to detect very common risk alleles (30–60% frequency) with genotypic relative risks of approximately 1.3 …The results indicate that there are few or no single common loci with such large effects on risk.” In the SGENE-plus(2), likewise, “None of the markers gave P values smaller than our genome-wide significance threshold”.

The ISC study(3) did find one significantly associated variant in the Major Histocompatability Complex (MHC) region on chromosome 6. The MHC is known to be involved in immune function. When the data from all three studies were pooled together, several variants in the same region were also found to be significantly associated with schizophrenia.

Somewhat confusingly, all three papers did this pooling, although they each did it in slightly different ways – the only area in which all three analyses found a result was the MHC region. The SGENE team’s analysis, which was larger, also implicated two other, unrelated variants, which were not found in other two papers.

To summarize, three very large studies found just one “schizophrenia gene” even after pooling their data. The variant, or possibly cluster of related ones, is presumably involved in the immune system. Although the authors of the Nature papers made much of this finding, the main news here is that there is at most one common variant which raises the relative risk of schizophrenia by even just 20%. Given that the baseline risk of schizophrenia is about 1%, there is at most one common gene which raises your risk to more than 1.2%. That’s it.

So, what does this mean? There are three possibilites. First, it could be that schizophrenia genes are not “common”. This possibility is getting a lot of attention at the moment, thanks to a report from a few months back, Walsh et al, suggesting that some cases of schizophrenia are caused by just one rare, high-impact mutation, but a different mutation in each case. In other words, each case of schizophrenia could be genetically almost unique. GWAS studies would be unable to detect such effects.

Second, there could be lots of common variants, each with an effect on risk so tiny that it wasn’t found even in these three large projects. The only way to identify them would be to do even bigger studies. The ISC team’s paper claims that this is true, on the basis of this graph:

They took all of the variants which were more common in schizophrenics than in controls, even if they were only slightly more common, and totalled up the number of “slight risk” variants each person has.

The graph shows that these “slight risk” markers were more common in people with schizophrenia from two entirely seperate studies, and are also more common in people with bipolar disorder, but were not associated with five medical illnesses like diabetes. This is an interesting result, but these variants must have such a tiny effect on risk that finding them would involve spending an awful lot of time (and money) for questionable benefit.

The third and final possibility is that “schizophrenia” is just less genetic than most psychiatrists think, because the true causes of the disorder are not genetic, and/or because “schizophrenia” is an umbrella term for many different diseases with different causes. This possibility is not talked about much in respectable circles, but if genetics doesn’t start giving solid results soon, it may be.

Edit: I missed it at the time but the great Prof. David Colhoun wrote an extremely good piece about this study.

ResearchBlogging.org
Purcell, S., & et Al (2009). Common polygenic variation contributes to risk of schizophrenia and bipolar disorder Nature DOI: 10.1038/nature08185

Shi, J., & et Al (2009). Common variants on chromosome 6p22.1 are associated with schizophrenia Nature DOI: 10.1038/nature08192

Stefansson, H., & et Al (2009). Common variants conferring risk of schizophrenia Nature DOI: 10.1038/nature08186

CATEGORIZED UNDER: genes, mental health, papers, schizophrenia
  • Anonymous

    Neuroskeptic,

    Doesn't the last possibility you suggest seem most likely?

    If so, what do you think about the positions of people like Ewald, Cochran, who argued in the late nineties (and still do, I believe) that many, if not most, of these confounding illnesses and disorders that exist at a percentage much higher than “rare” are likely the result of our battle with bugs?
    Haven't we learned that the CNS is not the formidable fortress we once thought it to be? Should more money be spent looking for pathogenic etiologies of such problems?

    I know that mental illness often runs in families, but Ewald points out that bugs can cluster/remain in a family and some genes protect better against one affliction than they do another, but that hardly means there are genes causing those afflictions.

    What do you think?

  • dearieme

    IQ gives material to ponder. Twin studies show that the genetic component outweighs the environmental component. But DNA studies seem, at best, to find evidence of lots of tiny contributions – nothing big sticks out. (So I understand – I write as a complete amateur here.)
    Perhaps genetics is trickier than people had hoped.

  • Jan Dirk Blom

    Dear Neuroskeptic and Anonymous,

    Perhaps we should not rule out the possibility that 'schizophrenia' is actually a heterogeneous collection of neuropsychological symptoms, arbitrarily bound together at the clinical level of conceptualization by an insufficiently validated concept. If so, it should not come as a surprise that the 'disease' we call schizophrenia resists our attempts to establish a final common pathway in terms of genetic or neurophysiological mechanisms.

    For some background literature, see

    • Bentall, R.P. (1992). The syndromes and symptoms of psychosis. Or why you can't play 'twenty questions' with the concept of schizophrenia and hope to win. In: Bentall, R.P., ed. Reconstructing schizophrenia. London: Routledge, pp. 23-60.
    • Boyle, M. (2002). Schizophrenia. A scientific delusion? Second edition. London: Routledge.
    • Blom, J.D. (2004). Deconstructing schizophrenia. An analysis of the epistemic and nonepistemic values that govern the biomedical schizophrenia concept. Amsterdam: Boom Publishers.

  • http://www.blogger.com/profile/05162735298576747474 Yigal Agam

    And don't get me started about autism genetics… similar issues.

  • Anonymous

    Are mental illnesses like what we call schiz and bi-polar uncommon among some populations?

    If so, which ones? Are island populations who aren't on the tourists' beaten path, for exmaple, afflicted with these at the rate of people in industrial, populated areas?

  • http://www.blogger.com/profile/06647064768789308157 Neuroskeptic

    Jan Dirk Blom: Thanks for your comment, you have an important point, although I think the concept of schizophrenia will stick with us until we find a more satisfying conceptual scheme – and I'm not sure we have one yet.

    I'd come across Deconstructing Schizophrenia & keep meaning to read it – with any luck I'll get round to it soon!

  • Anonymous

    Schizophrenia as an umbrella term for heterogeneous disorders with several possible causes is certainly discussed in “respectable ” research circles.
    However, this kind of genetic work needs to be done first, to rule out the possibility of simple causes and allow us to begin to unpick the pathways to disease.

  • http://www.blogger.com/profile/06647064768789308157 Neuroskeptic

    I think that's fair – certainly this research is valuable, because “negative” results are still results. We now know, with some certainty, that there are no common variants with a relative risk of more than 1.2 or so, which is important.

    Respectable people do talk about the possibility that schizophrenia is a heterogeneous collection of diseases, but my impression is that that's where the discussion ends. People nod their heads at the idea – but then go away and research (and treat) “schizophrenia” even so.

  • Anonymous

    “Schizophrenia as an umbrella term for heterogeneous disorders”

    I don't really understand this argument. The same thing is said about cancer, but frankly, most diseases are heterogeneous disorders. But there is something called cancer and it's very different from diabetes. Likewise, schizophrenia is not APD.

  • Anonymous

    There is the reason for everything; one only. Sciences liking for genes causing schizophrenia. So far no luck to pinpoint one. Gluten is plague of human race. Dr Fasano discovered the answer for neurological and other health problem cause by gluten. In my humble opinion, it is most significant discovery since bacteria. That time was a joke for medical community as is now zonulin.
    I am not a doctor, however I can read. It makes me surprise why many of sciences are not able to read results of researches, instead they do it all over again. Anybody who would deserve Nobel Prize that would be team of Dr Fasano
    http://jccglutenfree.googlepages.com/zonulin

  • Jan Dirk Blom

    The heterogeneity remark refers to the lack of a common denominator among 'schizophrenia patients'. Diabetes is an umbrella term for a heterogeneous group of diseases, but all types and sybtypes have something to do with carbohydrate metabolism. Cancer is an umbrella term for a heterogeneous group of diseases due to uncontrolled cell division. Although admittedly heterogeneous, the diseases belonging to such nosological categories are bound together by a common – conceptual – denominator. But what is the common denominator – at a clinical, psychological, anatomic, physiologic, neuropharmacological, electrophysiological, or molecular biological level – of (1) a person experiencing command hallucinations, (2) a person with paranoid delusions, (3) a person with catatonic features, and (4) a person with formal thought disorder? Why do all four persons tend to be diagnosed similarly? Please don't say that the common denominator is 'psychosis', or I'll ask for a definition.

  • Anonymous

    Yes, well, the term “psychosis” is almost as big an umbrella as “schizophrenia”.

    Honestly, I think they persist with the terminology because no-one has come up with a more useful grouping for research. Although some people do sort by symptom classes in their studies. “Auditory hallucinators” vs “non” or “predominately negative symptoms” etc. Or do dimensional analysis on negative or positive symptom scores.

    The DSM-V will be interesting. I dunno how useful, but interesting.

  • http://www.blogger.com/profile/06647064768789308157 Neuroskeptic

    dearieme: Yes, that's true. In fact this story is more or less true of the least 10 years of genetics research into IQ, personality, bipolar, autism, obesity, and much else – “Population genetics found it to be at least 50% heritable but molecular genetics hasn't found the genes”.

  • bks

    It may also be that they have good data and were honest about their statistics. Genome Wide Association Studies are prone to finding the Man-in-the-Moon (i.e. patterns where there is no pattern).

    –bks

  • http://www.zippy-health.com/fda-approves-novel-drug-for-schizophrenia-and-bipolar-disorder/ Schizophrenia

    A new-fangled drug, Saphris, has received the approval of the FDA for treatment of adult schizophrenia and bipolar disorder I. Bipolar I disorder is an unremitting, vicious, intermittent psychiatric disorder that leads to sporadic episodes of despair, agitation and reduced sleeping patterns. The general side effects in schizophrenics are restlessness or staying totally stock-still, reduced oral sensation and sleepiness.

  • http://www.blogger.com/profile/04154200709776051635 Jhon

    I think the concept of schizophrenia will stick with us until we find a more satisfying conceptual scheme.


    Jhon
    Wireless Home Alarm Security Systems

  • http://www.blogger.com/profile/11886591104850968752 Andrei

    My mother suffers from paranoid schizophrenia. She acquired it after 20 years of physical abuse and humiliation at the hands of my father, as well as persistent hostility on the part of our neighbours. She was always subordinate to my father and accepting of his commands, violence and derision, (cf. commanding/derisive voices) even when it went against her best interests. Well before her first episode, she had been in denial over this abuse and willing to ultimately blame it on individuals outside our family. (cf. delusions of persecution) She had also, incidentally, been beaten regularly as a child. I don't think she needed any special SNPs, thank you very much.

    Read et al, 2005 makes a good case that my mother's situation was not isolated. It seems the majority of people with schizophrenia were known to have been victims of abuse before developing the condition. Incidentally, some (other) PTSD victims hallucinate and experience paranoid delusions; they turn to drugs and exhibit depression, much like schizophrenics.

    My mother's hallucinations have always been very tightly correlated with past events – she often reported hearing the specific insults with which my father had addressed her in the previous several months, for example. Of course, it has taken psychiatrists decades to catch up with the facts that a) the content of hallucinations is meaningful, and b) they are actually the patient's own thoughts. I realized this after a few months simply because I spent far more time with my mother than most psychiatrists spend with their patients.

    The unfortunate truth is that no amount of random research into the biological correlates of schizophrenia is going to compensate for most researchers' lack of insight into the individual patients' lives. It will, at best, provide support for basic research, and at worst perpetuate the stigma against people with schizophrenia.

  • My_Voices

    In response to Andrei:

    I wasn't abused as a child and I have paranoid schizophrenia. I don't believe the content of what my voices say is actually my own thoughts. If the content is my own thoughts, I'm a sick and twisted individual who needs to find a really good therapist!

    Maybe for some people that might be the case, but I don't believe that to be the case for everyone who has schizophrenia. I'm not a doctor, so I have no scientific basis to support my claim. If you have a source for your claim, I'd like to see it.

  • Catch33

    In response to My_Voices:

    I was diagnosed with paranoid schizophrenia after I'd spent a period of time intensely devoting myself to a particular religion. My symptoms did not begin prior to that period of excessive religious practice.

    I can't speak for you, but I know that in my case the causes of my symptoms were caused by psychological factors. My symptoms went away when I realised my beliefs weren't realistic. For instance, one of my symptoms was that I believed that I could predict things with my mind, but so many of my predictions turned out to be false that I couldn't believe that I had predictive powers anymore. Unfortunately these symptoms lasted for more than six months before I realised this so I'm permanently labelled “schizophrenic” despite the absense of symptoms for a long period of time.

    In my case this wasn't caused by trauma, but we are all unique individuals with different life histories and social and psychological experiences. We “schizophrenics” also have a variety of different types and degrees of symptoms.

    We should be looked at as individuals with different personal issues that need to be addressed. It is so fustrating that I have never felt as though I can speak to a psychiatrist about why I believe my symptoms occured, because I don't want to get into an argument about the non-biological causes of my so-called illness otherwise I'd in psychiatric terms lose insight into the nature of my illness. This, in my opinion makes a person labelled mentally ill powerless and forces them to repress their true feelings and opinions, which I believe is dangerous and unhealthy.

    Despite years of research there is scant evidence that schizophrenia is a genetic or biological disease. And the notion that people never recover from it is contradicted by evidence of people who do.

    There has been some reasearch that suggests that a large number of cases of schizophrenia are caused by trauma. And for such people and other people who hear voices or have “strange” beliefs there is information about psychological methods of dealing with this. For instance, some people learn to change and have more control over what their voices say to them. Others learn different coping strategies to deal with their voices. For one example go to Intervoice http://www.intervoiceonline.org/

    And in saying this I'm not saying that medication isn't an important tool for many people to help them recover, but it isn't the only option.

  • http://www.blogger.com/profile/16667141403818883626 Derek

    Hi Neuroskeptic,

    This condition is incredible …is incredible that some people can see and feel a situation created by the brain … If, as you mention in the article is genetic … There is the possibility of passing it?

  • http://www.blogger.com/profile/09777560699581144931 nick spurs

    guys and girls listen up,

    i have done a lot of research with this topic and i have also spoken to profesors,

    schizophrenia is genetic in familial cases about 42% the rest are sporadic some researchers beleive there may be a small genetic risk in these cases however, firtslty they dont even know how many or what genes are involved, secondly a few genes popped up a few times but thats about it, in sporadic cases the ilness is caused by hypoxia which causes brain damage to the same areas that are in scizophrenia so hypoxia either alters the genes in these arears and mekes these gene from non risk genes to risk genes or it damages the tissues in the same area or probably both, child abuse has proven to do the same thing, old paternal age is a risk factor but not because the father has risk genes but because older sperm may sometimes be defective which may cause a problem, also about 10% of sporadic causes are of genetic mutations which again had nothing to do with parents. so i would like these researchers to stop blaming genes all the time because firstly they dont even know which genes are invoolved and secondly sporadic schizophrenia patients have different bran abnormalities that famlial so its common sense to be able to see the difference to what a genetic contribution may have to that of a sporadic environmental factor onle. im not saying genes allone cause it as environmnttal factors have to contribute also in some familial cases but in sporadics it is purely environmental i.e hypoxia, child abuse, genetic mutations, and old paternal age that have nothing to do with parents genetic make up.

    so therefore before these researchrs start saying there is always a combination of genes and environment then they should emphasisze that for familial cases only.

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No brain. No gain.

About Neuroskeptic

Neuroskeptic is a British neuroscientist who takes a skeptical look at his own field, and beyond. His blog offers a look at the latest developments in neuroscience, psychiatry and psychology through a critical lens.

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