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Genetic research into ‘schizophrenia’ – how much can it actually tell us?

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Genetic research into ‘schizophrenia’ – how much can it actually tell us?

Lucy Johnstone and Richard Bentall talk about the role of genes in mental health

 

What causes mental health problems? Following the publication of Oliver James’s book Not in Your Genes last week, the In the Mind BBC series, and the announcement of two recent ‘breakthroughs’ about genes for ‘schizophrenia’ (in Nature, and in Nature Neuroscience), there has been plenty of recent debate about nature vs nurture mental health. From Radio 4 to the Guardian (see here and here) and well beyond, there is robust disagreement about the role that different factors play in our mental well being.

In the attempt to shed some light on the matters, we asked two psychologists to discuss the issue of genetics and their role. Previous DOTW contributor Professor Richard Bentall (of the University of Liverpool) researches social and psychological factors in mental health, but he is also interested in possible polygenetic risk factors for ‘psychosis.’ Dr Lucy Johnstone is a clinical psychologist. Her most recent book, A Straight Talking Introduction to Psychiatric Diagnosis, aims to promote choice by summarising debates about psychiatric diagnosis accessibly.

 

Hi Richard,

You know infinitely more than I do about genetics and research methodology, but I’m interested in unpicking the logic of research into genes for ‘schizophrenia.’

No sensible person dismisses the possibility of genetic contributions – presumably genes are distantly related to every form of human thought, feeling and behaviour, including the fact that I am writing this blog post (partly as a result of having genes for the development of hands, eyes and a brain.) And I don’t think any of us would be surprised if a tiny minority of people with a diagnosis of ‘schizophrenia’ (as claimed in the recent Sanger Institute study) turned out to have some kind of genetically-based learning difficulty. Although then of course we wouldn’t call it ‘schizophrenia.’ We’d call it ‘Sanger Syndrome’ or something like that – and there would be no reason to suppose that it necessarily told us anything at all about the much larger group with a ‘schizophrenia’ diagnosis.

But surely the question is – what kind of explanation is likely to result from research into the genetics of ‘schizophrenia’ anyway?

I’m not a geneticist, but I cannot see, logically, how a non-valid construct like ‘schizophrenia’ or ‘psychosis’ can have genetic causes, any more than I can envisage a group of genes that predispose for ‘hysteria’ or a ‘wandering womb’ or any other redundant psychiatric concept. Moreover, the experiences that are grouped together as ‘schizophrenia’ are thoughts, feelings and behaviours, not biological dysfunctions. How can you have genes that increase the ‘risk’ (the wrong word, I think) of certain thoughts, feelings and behaviours, except in an impossibly distant and indirect sense? For example, it’s likely that genes coding for strong legs increase the ‘risk’ that you will later play football. But that really isn’t an explanation for why people run up and down a field kicking a ball, and nor does it imply pathology. (Although perhaps that point is debatable…) And even if it did, what would you do about it? It seems to me that any such findings would relate to such general traits – e.g. temperamental sensitivity – that it would be neither possible nor desirable to eliminate them.

I really think we need to let go of the idea that there is such a thing as ‘schizophrenia’, or indeed ‘psychosis’, and then see what exactly needs explaining that isn’t already adequately accounted for by the numerous relational and social factors we know about. The emerging trauma-informed approach already incorporates the mediating role of biology via the neurodevelopmental impacts of attachment relationships and evolved threat responses. Obviously, these capabilities are genetically transmitted at some level. But what else are gene studies likely to tell us, apart from confirming the fact that humans have evolved to be sensitive to abuse, trauma, neglect and social exclusion?

Anyway, Richard, you know I have a great many genes that predispose me to being argumentative, so I hope you’ll forgive these comments! But I would be genuinely interested in your take on it.

Lucy

 

Hi Lucy,

It seems to me that there are several issues that need disentangling here.

 

1. A strategy issue: I’m anxious not be open to the accusation of genetic denialism. The point is that we need to restore balance to the nature vs nurture (actually nature x nurture) debate and, to many people, we look silly if we deny that genes play any role (which I know is not your position). It seems to me that the quantitative genetic evidence (from family, twin and adoption studies) all show an association between genes and mental health, and this is supported to some extent by molecular genetic evidence, so we should acknowledge this. The question, as you say, is what does this mean?

 

2. The science issue: But as you say, from a scientific point of view, it’s important to establish how genes are involved.

Of course you don’t need to tell me that schizophrenia is not a useful scientific construct to work with when attempting this and, indeed, the genetic data is often used to make precisely that point these days (the Cardiff group, for example, do not believe in ‘schizophrenia’ as an entity any more than you or I do; they argue – correctly, in my view – that the genetic data is incompatible with the idea that psychiatric disorders segregate into discrete categories like schizophrenia.)

A frequently neglected issue is that genetic research is entirely correlational, and therefore every bit as vulnerable to confounding as any other kinds of correlational research. Hence, just showing an association between genes and mental health does not imply that genes are causal in any simple sense. The recently reported association between SETD1A and schizophrenia, announced as a fundamental breakthrough by researchers at the Sanger Institute, illustrates this perfectly (and raises important ethical issues about the way that genetic researchers report their findings to the public). The gene was found in 10 of about 8000 psychotic patients, but 7 also had learning disabilities, so only 3/8000 non-cognitively disabled psychotic patients had the gene. A separate sample found 4/4000 people with neurodevelopmental problems had the gene. So the gene has a tiny effect in terms of risk of psychosis and is almost certainly really a gene which affects cognitive development. Of course impaired cognitive development is already known to be a small risk factor for psychosis for reasons unknown (maybe lack of cognitive resources impairs the ability to cope with stress, maybe it is a risk factor for experiences of powerlessness and victimization). So it seems very unlikely that SETD1A is causal in psychosis in any simple sense, but this did not stop Sanger Institute Researchers claiming it is ‘conclusively implicated in schizophrenia’, and that its discovery could lead to major therapeutic benefits. To my mind, these kinds of claims are blatantly dishonest and would not be tolerated in other areas of science.

What is really interesting to me is that, properly interpreted, the genetic data does not point to anything like the ‘genes for schizophrenia’. The data is entirely consistent with a more nuanced understanding of psychosis as the end point of a continuum of human variation (the polygenic load concept, for example, is consistent with the continuum model but would be very hard to square with a categorical approach to diagnosis). It is also entirely consistent with the idea that the social environment plays an important role although, egregiously, this has often been denied by some biological psychologists and psychiatrists who don’t seem to understand their own data (the claim that ‘schizophrenia is 80% heritable’ is still often used to promote the idea that psychosis is largely determined by genes whereas, even if this figure can be believed, heritability means nothing of the sort – for a discussion of this issue, see my book Doctoring the Mind).

 

3. The philosophy of science issue: Filippo Varese and I recently penned an editorial about the different standards by which biological and environmental studies are evaluated. Having thought about this issue over the last few days, I’ve come to the conclusion that this problem is much deeper than we then realised. It’s clear to me that biological papers routinely get away with stuff which would consign papers to the dustbin if they were about environmental determinants. For example, in the SETD1A paper referred to above, the researchers pooled data from studies using different methods and, when they realised that they lacked statistical power, added some data that had previously been published by another research group. But it’s not just genetics that’s the problem – a couple of years ago John Ioannidis (who is a bit of a hero of mine) published a meta-analysis of the statistical power of neuroimaging studies, finding that they averaged out at 7% (for those who have not had the benefit of a statistical education, this calculation concerns whether a study sample size is sufficient to detect a true effect, and is normally expected to be above 70%).

Why does this happen? Part of the problem seems to be a cultural (maybe even universal) human propensity for accepting essentialist ideas (there’s some interesting work by developmental psychologists on this) but it seems to me that this is no excuse: the idea of the journal refereeing system is that it is supposed to eliminate natural biases in the evaluation of research, and it plainly fails in this regard. And the problem is wider than psychiatry – there is a real crisis about replication in social psychology at the moment as well.

Science is above all a social process, and a whole host of social pressures affect what scientists do. These days it is routine, for example, for senior academics to be threatened by severe sanctions (redundancy) if we fail to deliver highly cited papers and large grants. And then there’s the power issue. Who gets appointed to grant awarding panels and journal editorships? And what kind of research do they select for further advancement (funding or publication in a high impact journal)? As the philosopher of science Philp Kitcher noted in his 2003 book Science, Truth and Democracy, science has been captured by an undemocratic elite which routinely and without even thinking about what they’re doing hands out large rewards to their mates or people who look like their mates. And, of course, their mates in return hand out prizes back to them.

 

Finally, there is the public understanding of science issue: Given all of the above, it seems to me that the public is up against it when it comes to understanding the nature x nurture issue. Which is where we come in, pushing back the tides…

 

Hi Richard,

We are pretty much in accord about the conceptual issues. What you are saying – and I heartily agree with you – is that these are fundamentally issues not (just) of science, but of power – who has it, in whose interests it operates, and how it is maintained by marginalising accounts that might challenge the dominant ones. Any remotely objective scientific perspective would take a 3% genetic risk – which seems to be what the studies are showing – as strong evidence that the thoughts, feelings and behaviours we call ‘schizophrenia’ are almost entirely a response to the environment – and as we know, those environments typically consist of multiple relational and social adversities.

But given all this, why are we still pursuing the genetic route? We wouldn’t, I hope, search for genetic reasons to explain why people are distressed by homelessness or debt. As you know, I have recently been working in the Valleys of South Wales, one of the most deprived areas in the UK. Just down the road in Cardiff, millions of pounds are being poured into yet more genetic studies – even though their own research fails to support the validity of the concepts they are investigating. Each glowing account of the latest ‘breakthrough’ starts with a statement to the effect that: ‘For the first time, we have evidence that……’ Somehow I must have missed all the retractions. But I know what would have made most difference to the lives of my clients, and it wasn’t genetic research. Should it still have a role?

 

Hi Lucy,

This may be a point where we disagree. The 3% you refer to is, I think, the amount of variance accounted for in genome-wide association studies (actually, some estimates are a bit higher but nowhere near as high as the heritability estimates from quantitative genetics, an embarrassing difference that genetic researchers call ‘missing heritability’). But variance is a correlational concept and therefore does not address the confounding issues referred to earlier.

The problem is not genetic research: it’s naive genetic research. Geneticist have failed to realise that they cannot hope to learn anything by studying genes in isolation. For reasons already explained, showing a (typically tiny) association between a gene and mental health is completely uninformative, unless we explore the pathway by which that gene exerts its small effect. This means addressing what geneticists call the phenotype problem (in other words, looking at patients’ experiences in detail and not just lumping them together into meaningless categories like ‘schizophrenia’), which they talk about but do nothing about in practice. But it also means measuring the social environment and the psychological mechanisms that link risk factors to outcomes, which they never talk about at all. Whereas it is very unlikely that genes ‘cause’ psychosis, they may well modulate the pathways between risk factors and outcomes (think of them as dimmer switches attached to the psychological mechanisms that determine how we react to adverse environments). Research of this kind may well lead to a truly bio-psycho-social understanding of mental health, point the way to personalised psychological and medical therapies, and also help inform public mental health policy.

I have been trying to interest geneticists in this kind of research for a while, and some have been at least willing to talk about it, but my applications for funding for these kinds of projects have all been unsuccessful despite consistently very positive reviews. There is an ideological resistance to this kind of research amongst the senior biologists and doctors who hold power within organizations like the Medical Research Council, who would rather stick to their test-tubes and their machines that go ‘ping’ than support the kinds of studies that might actually help people.

 

Hi Richard,

We agree about the need for a sophisticated approach to genetic research, and it’s a disgrace that it seems so much harder to get it funded. But I return to my earlier point. We’re not funding genetic research into genes that may modulate the pathways between the ‘risk factor’ of bereavement, and the ‘outcome’ of weeping and despair. Why then do we feel the need for an extra genetic layer of explanation for responses to bullying, sexual abuse, racial discrimination, and all the other adversities implicated in ‘psychosis’? And I think we have to be careful about what we mean by ‘biopsychosocial’ models. Unless very carefully defined, they can be used to privilege biological causal factors that have never actually been identified. I’ve always thought this was highly insulting to service users. Breaking down after a horrific series of events isn’t evidence of biological ‘vulnerability’ – with the implicit message that others without this genetic make-up would have coped just fine. It’s a sign of being human.

Using pseudo-medical terms like ‘psychosis’ – a mysterious entity that apparently exists somewhere between the adversities and the response to the adversities, and then becomes an object of investigation in its own right – distracts us from seeing what is in front of our noses. A mountain of research tells us that reducing social inequalities, implementing preventative public health measures, and asking what has happened to you instead of what is wrong with you, is what is urgently needed. Gene studies are not a priority, and may even be a distraction.

We’ve laid out our cases. What do others think?

 

 

 

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9 comments on “Genetic research into ‘schizophrenia’ – how much can it actually tell us?

  1. Hi Lucy & Richard, the thing that unites all humans and gives them power to adherently make changes is a danger to thee shadow-government. So they issued the order to research if it’s possible to alter genes & dna so humans will be born without those “inner senses” that bring us together even while living worlds apart. For them is easier to control a flock of humans without capabilities beyond the 5 senses than it is today (all humans have hereditary ‘inner senses’). I see this venue as one of the main reasons this “genetic-research-on-psychoses” is done.
    Another reason is that all humans are deaf, dumb & blind when it comes to ‘inner senses’ in which case this research is not done to prevent future illnesses but rather to enhance the workings of psychoses in order to make real mindreaders of those who suffer from psychoses. That way I know of at least 90% of warmongering generals that have a genuine interest in this research being done.
    Now all the time humanity is procrastinating with the issue of having ‘inner senses’ people die, murder and enslave (sex-)workers. I’m sure there are people surrounding you supporting your choice whatever that may be and that way you still feel good about yourself no matter if you chose right or not.
    I somehow stand alone in this but have an unshaken believe in my inner senses , something that can not be easily whisked away, even if a lot of people try very hard.
    So, you know bladibla wasup Lucy ? , Rich ? but eh, above all : “Don’t forget to be willfully blind otherwise you cannot be comfortably unaware….”.

  2. Very good read, couldn’t agree more. Both genetics and neuroimaging are popular but on their own hardly informative – psychological basis are needed. Both areas can be complementary to psychology however cannot over-ride it. It is a great shame they indeed scoop most of research resources nowadays. As pointed out their stats are relatively weak and claimed effects small. We probably should treat them with much more distance than do generally do right now. It would be more productive to focus on what we know, as indicated by Lucy, that is chiefly addressing social adversity.

  3. I agree with Lucy, great points made in her last response, about the mediating genes between bereavement and grief – this nails it for me. in so many areas, scientists search for explanations of extremes in human variance, which in psychology have been referred to pejoratively as “abnormal psychology” when all it is just human variance. When people have been through the worst life can offer, to then label people with medicalised terms like “schizophrenia”, “bipolar disorder”, “PTSD”, and so on, seems to me to add insult to injury. I’d agree with Lucy that the useful question is “what have you been through?”.

  4. The remarkable thing about DNA is that it can reproduce a human without flaws – crippled ppl do not give birth to another cripple, blind do not give birth to a blind baby etc etc…
    I’ve been diagnosed with incurable schizophrenia (paranoid type) which I survived by believing in my path – I label myself now as Christian, Buddhist, Sufi-Muslim who became Shaman of sanity…
    Genetics in its early discovery mentions no correlation of parents & birth-defects. Somehow, the humans mis-interpreted this (even scientists) and yelled to the world that certain deceases (illnesses) are hereditary (which is nothing but a dogma (=a repeated lie that became a common truth).
    However, PTSS (post traumatic stress syndrome) is the inability of social surroundings to acknowledge the existing problem of multiple and repeating stress situations) Drugs (and/or medicines) can be used to help live better lives. But drugs are illegal and therefore not of consistent quality and medicines often only dampens the emotional state and doesn’t repair anything.
    As you may have guessed I have that double diagnose and live well using a daily capsule of amfetamines. This diagnoses is indeed a certain kind of insult but also a social stigma that I have to carry and accept in order not to clash with society… I often remind myself that after this life , I’ll be returning home (Leonard Cohen – Old Ideas (2012)) – Sorry if I sound gibberish and incoherent but I’m still suffering from utter sadness and grieve that makes me cry for unknown reasons every day… The speed is the drug that keeps my emotions on a elevated base-line from which I am presentable, amicable and thus acceptable for others….

  5. A few thoughts.
    – Science is about curiosity. Discouraging genetic (or any other) research means encouraging dogmatism.

    – Finding causal relationships between genes and “la condition humaine” starts with finding correlations. There simply is no other way.

    – Genetic research can perfectly well go together with other kinds of research, like psychological research. One doesn’t preclude the other.

    – No doubt about it: genetic research and brain research are awfully abused by mediocre minds putting psychiatric labels on patients. However, the ones to blame are aforementioned mediocre minds, not the researchers investigating brains and genes.

  6. Correlational psychiatric research is valuable, not always spurious as the authors seem to sugest. Bradford-Hill criteria are still valid to get an aproximated idea of whether a relationship between variables may be causal, at least when a direct experimental approach is not possible, as in this case. That said, psychiatric GWAS studies describe correlations that meet several of these criteria, such as temporality, coherence, replicability, biological gradient (polygenic scores) and biological plausibility, since genetic findings are fundamentally involved in brain developement. However, these genetic data doesn´t relate to mental illness itself but to risk of developing psychological problems in a given biographical context.

  7. Thanks for this enlightening exchange. I am pleased to have confirmation – if it were needed – of the social biases within the field of science and research funding.

    So much effort given over to avoiding the personal! So much energy going into resisting basic compassion! So much down-playing of emotion as the driver of our humanity…. I’m a psychotherapist (thrilled to a different kind of ‘science’ – a ‘science of qualities’, Brian Goodwin’s concept). A science that enhances our understanding of what it means to be whatever it is we are – biological, animal, part of nature – and yet, a miracle, a wonder, a mystery that we deny at every turn.

    A problem with replication, indeed, because our variety is infinite.

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