A Critique of Genetic Research on Schizophrenia – Expensive Castles in the Air

Joanna Moncrieff, MD
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In the light of the much trumpeted claims that recent research has identified genes for schizophrenia, it is important to review the track record of this type of endeavor.1 Despite thousands of studies costing millions of dollars, and endless predictions that the genetics of schizophrenia would shortly be revealed, the field has so far failed to identify any genes that substantially increase the risk of developing schizophrenia.

Following the advent of molecular genetics, some studies started to find weak associations between this or that gene and being diagnosed with schizophrenia, but attempts to replicate the findings generally failed.  A large genome-wide association study published in 2008, for example, analysed the distribution of 833 single nuclear polymorphisms (SNPs) in 14 genes that were thought to be the most likely ‘candidates’ for being associated with schizophrenia in a sample of 1,870 people with schizophrenia and 2002 controls. The study found no statistically significant effects for any of the genes examined and the authors concluded that ‘it is unlikely that common SNPs in these genes account for a substantial proportion of the genetic risk for schizophrenia, although small effects cannot be ruled out.’2, p 497

Since substantial effects were not showing up, larger samples were constructed by merging different genetic databases. These larger samples allow smaller effects to be detected. Moreover the search was broadened to include the whole genome, since early studies failed to confirm a role for ‘candidate’ genes3.

The recent headlines were generated by a paper which reports a Genome Wide Association study in a combined sample consisting of tens of thousands of people diagnosed with schizophrenia and controls.4 Nine and a half million SNPs were examined. Out of these millions of SNPs, 128 were statistically significantly more common in people diagnosed with schizophrenia, using a ‘p’ value of 0.00001 to correct for the large number of tests conducted. These 128 SNPs were then mapped to 108 chromosomal regions or ‘loci,’ most of which had never previously been thought to have anything to do with schizophrenia. The paper provides no odds ratios or other measure of the strength of the associations between the SNPs and having a schizophrenia diagnosis, but the lead researcher confirmed that each genetic loci was associated with an increase in the risk of schizophrenia of approximately 0.1%.5  Using a method dependent on multiple assumptions (Risk Profile Scores), the maximum amount of variation explained by a combination of the genes identified was 3.4%.4

The genetics of schizophrenia parallels findings in most common physical diseases. A small number of genes with substantial effects have been identified for a small number of conditions (breast cancer, Alzheimers and AMD). Other than this, the hugely expensive human genome project and all the research that has followed from it has failed to reveal that particular genes increase the risk of developing common and important diseases to any relevant degree.6

As in the latest schizophrenia studies, some genes appear to be slightly more common in people with conditions like Type 2 diabetes compared to those without, but having one of these genes will increase the risk of developing the disease only marginally. But the fact that people’s genetic risk varies around the average is simply tantamount to saying that everyone is different.6 We knew that anyway.

These results have lead some commentators to conclude that ‘genetic predispositions as significant factors in the prevalence of common diseases are refuted.’6 Yet researchers and the media continue to report genetic studies as if they represented evidence that bodily diseases and behavioural or mental disorders are genetic conditions- that is conditions that are determined in an important way by detectable genetic variation. The recent schizophrenia study was reported in just such a way. ‘They’ve really managed to show that genetics plays a role’ said one schizophrenia researcher.7 The study authors claim their findings will help unravel the aetiology of the condition and lead to the development of effective and targeted drug treatments.1

It is difficult to see that these findings will have any clinical implications for our understanding of schizophrenia or its treatment, however. Leaving aside the difficulty of defining mental abnormality or ‘schizophrenia,’ if the genes identified predict only about 0.1% of the risk, then whether you have one or two, or even a few or a lot of the genes concerned tells you very little about your particular vulnerability for developing the condition.

Some commentators have concluded that the lack of evidence for a genetic contribution to common diseases shows they are fundamentally environmental conditions. Certainly we know that, in contrast to the effects of particular genes, environmental risks contribute substantially to the risk of many diseases, as well as to mental disorders, albeit in different ways. Work by biologists such as Richard Lewinton, however, shows us that many features of living beings are the result of random variation, and not predictable from either genes or environment.7

To me, the fact that genetics contributes little to our risk of disease, or our likelihood of developing behavioural and mental disturbance, seems a matter of celebration. The idea that we are doomed by our genetic make-up to develop life-threating or disabling conditions is surely a profoundly depressing one.

We will likely never be able to fully account for why some people experience extreme mental states, but we know that poverty, unemployment, insecure attachments, familial disruption, low self-esteem, abuse etc. play a role for many. We would be better concentrating on how to eliminate these from our society if we really want to reduce  the impact of mental disorder, rather than pouring more money into the bottomless pit of genetic research.

* * * * *

This article has been reposted, with permission,
from Joanna Moncrieff’s website

 

References:

1) Wang, S; Study Sheds New Light on Genes’ Role in Schizophrenia, Wall Street Journal, July 21, 2014

2) Sanders AR, Duan J, Levinson DF, Shi J, He D, Hou C, et al. No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics. Am J Psychiatry 2008 Apr;165(4):497-506.

3) Collins AL, Kim Y, Sklar P, O’Donovan MC, Sullivan PF. Hypothesis-driven candidate genes for schizophrenia compared to genome-wide association results. Psychol Med 2012 Mar;42(3):607-16.

4) Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014 Jul 24;511(7510):421-7.

5) O’Donovan, M; Hundreds of genes and link to immune system found in largest genetic schizophrenia study. The Conversation. July 22, 2014
>6) Latham, J.,  Wilson, A.; The Great DNA Data Deficit: Are Genes for Disease a Mirage? Independent Science News. December 8, 2010

7) Lewinton, R.C. The Doctrine of DNA: Biology as Ideology, Penguin Books, London, 1991

39 COMMENTS

  1. Thank you for this article. As someone who was forcibly incarcerated in Norwich State Hospital in Ct, with the diagnosis of Schizophrenia, and tied down and injected with drugs like Prolixin and Thorazine that were to “help” with my “diagnosis”, I pretty much was thrown into hell for the crime of being dysfunctional.
    Years later, I was asked to speak to a local University of Oregon class (https://www.youtube.com/watch?v=iScTrOUIQxc&list=UUt1Cu-VlPNy9wZy7eZCK12A) on my perspective on the origins of what is called “mental illness”, and that forced me to figure it out. One can be an adult child of an alcoholic suicidal mother, Vietnam Veteran, etc, and be perfectly normal, though unable to function in a job.

    But those of us who are or were classified as “mentally ill” are usually ignored by the medical community as we never attended medical school and so “cannot understand” the medical science of the genetic basis of “mental illness”. Thanks to people like you and Bob Whitaker, we have allies who can speak directly to those professionals making billions off the deliberate ignoring of the traumas and needs of the battered and lost.
    Hugh Massengill, Eugene

  2. Dear Dr Moncrieff
    I don’t think they can sucessfully find the genes that cause ‘schizophrenia’ because ‘schizophrenia’ is more a medically invented illness – I say this because its the medical treatment that causes the chronicity. But with the right kind of non drug help most people can make full recovery (this is the way I made recovery myself).

  3. Dr. Moncrieff, I, too, do not believe in the label of schizophrenia — symptoms for that label do exist but actually those various symptoms could be labelled anything else, as far as I am concerned. I know people that had been labelled schizophrenia and once they changed their diet, i.e., cut out grains, gluten, etc., fixed their leaky gut, (which so many of us have) took an excellent source of enzymes and probiotics, they no longer had what is labelled schizophrenia. Two, in particular, also used a very knowledgeable homeopathic/holistic doctor as well as do all the above …. coffee had to be cut out as it antidotes the homeopathic remedy. Perhaps you would like to check out info on the gut/brain connection.

  4. Dr Moncrieff, I too celebrate the failure to identify a genetic contributing factor to this ‘disease’. I truly fear the consequences of such a discovery. What actions would be taken to ensure the purity of the gene pool?

    Anyway, your a psychiatrist so I’ll keep my paranoid delusions to myself lol.

    I watched your lecture at the UNE, myth of the chemical cure last night. Thank you it was wonderful. I was struck by the comment made during the Q & A at about 1:05. A psychiatrist stating that he could predict with almost perfect accuracy what diagnoses the overnight admissions would have based on the doctor they had been examined by. The comment got a laugh from the audience, but at a deeper level it shows what a lottery seeking mental health care can be.

    Do you know of any credible studies that have been done into this type of diagnostic bias?

    Kind regards
    Boans

  5. Thank you for speaking the truth, Dr. Moncrieff. And I agree, it is very disheartening for patients to be told they have “life long incurable genetic” brain defects / “chemical imbalances.” Because, especially for young children who have yet to develop a sense of self, that can take away all a person’s hope, and even cause suicides. It’s wonderful the psychiatrists can now stop claiming schizophrenia and bipolar and all the other DSM disorders are proven genetic illnesses with no hope of recovery.

    Just a side note, I suffered from some of the “schizoaffective symptoms,” but the only time in my life I ever suffered from them was either when first being put on an antipsychotic, or when massively drugged, or relatively shortly after being weaned off of antipsychotics (super sensitivity withdrawal induced manic psychosis). Therefore I have a theory that it is actually the psychotropic drugs themselves that cause the “chemical imbalances” and psychotic symptoms, based upon my experience.

    Do you think the psychiatrists will ever look into the idea that it may in fact be the ADRs and withdrawal effects of their meds that are actually causing the serious mental illnesses? Because, at least in my case that was the reality. And it’d be wonderful if all it took to rid the world of at least most the bipolar and schizophrenia, is to stop putting people on drugs that cause the bipolar and schizophrenia symptoms.

  6. Sincerest thanks yet again, Dr Moncrieff!
    The chemical imbalance and genetic theories cruelly and inhumanely lead people into the hopelessness and helplessness of being labelled DEFECTIVE at the most fundamental level by mainstream biological psychiatry.

    Your articles and the myth-busting fact sheets on CEPUK have been enormously helpful for me in combating the deeply personal effects of the misinformation that was forced down my throat, along with psychoactive drugs, by that psychiatry. I had never experienced the pure torture of falling through the pits of hell (my one and only psychosis in a life of almost 60 years) or the devastating consequences of being forced to accept that I was, according to them, fundamentally defective and required drugging because of an underlying flaw.

    The misinformation out there now on genetics has even greater potential for absolutely horrifying consequences for any person who might not fit with some mainstream view of “normality” or who might fall into biological psychiatry’s clutches.

    It is taking me a long time to reconstruct some semblance of being an acceptable human and to be able to walk again among other humans without the great fear and shame visited on me by my experiences with biological psychiatry. I still have quite a way to go – the trauma and the shattering of a psyche are not easy to heal.

    Your accurate and scientific dismantling of the the weapons used against me is proving to be extremely helpful in that process.

    Again….thanks

    • The patients are subordinated by a dominating alpha group despite such corruption. These disorders are merely lead poisoning and other heavy metals. Heavy metal chelation uses supplements which doctors do not allow. Drs say “no disease is curable.” And, to “never take vitamins and supplements because they are dangerous.”

  7. Following the advent of molecular genetics, some studies started to find weak associations between this or that gene and being diagnosed with schizophrenia

    “Being diagnosed with schizophrenia” is something done to you by someone else. How can there possibly be a connection between someone’s genetic makeup and their likelihood of having someone else call them names, however “scientific” sounding?

    Any study involving “schizophrenia” is inherently flawed because it presupposes the existence of such a disease.

  8. Lloyd I. Sederer, MD, Medical director, New York State Office of Mental Health has written a complimentary testimonial for Dr. Thomas Szasz after a service by him and colleagues to honor this great man. Although most of the article is positive, at times very mainstream Sederer damns Szasz with faint praise or tries to make his theories/ideas of making freedom the ultimate guide untenable while citing absurd examples like dealing with a mental case 250 pound gorilla of a man alone.

    But, what I found most offensive is typical of Dr. Sederer’s posts and books; he spouts typical, decades old LIES like this gem:

    “What’s more, we now have indisputable evidence of major mental illnesses having neurological (as well as genetic and molecular) pathologies — unlike 50 years ago. And with that proof, neurologists still aren’t rushing to fill the shoes of psychiatrists!”

    I find such fraudulent claims from somebody in Dr. Sederer’s position despicable and outrageously dishonest/corrupt. Perhaps he is referring to the recent misrepresentation of the latest very expensive gene research results, which Dr. Moncrieff exposes above:

    “In the light of the much trumpeted claims that recent research has identified genes for schizophrenia, it is important to review the track record of this type of endeavor.1 Despite thousands of studies costing millions of dollars, and endless predictions that the genetics of schizophrenia would shortly be revealed, the field has so far failed to identify any genes that substantially increase the risk of developing schizophrenia.”

    Dr. Peter Breggin and Dr. Jay Joseph along with many others and several articles at MIA have debunked psychiatry’s bogus gene claims for what are now declared INVALID voted in stigmas in the junk science DSM even by Dr. Thomas Insel, Head of NIMH. Thus, how can genes be found for unreliable, invalid disorders voted in by consensus to push the latest most lucrative lethal drugs on patent, which are now the horrific neuroleptic drugs that Dr. Moncrieff has called The Bitterest Pill? Dr. Moncrieff has lamented the outrageous bogus explosion of bipolar “diagnoses” for minor problems that results in many more people taking lethal neuroleptic drugs that will cause many huge negative, toxic effects while reducing one’s life span an average 25 years while making them prone to early dementia per Dr. Grace Jackson!

    And to add insult to injury, I just read that most people stigmatized with bipolar end up losing their jobs within about five years by being fired due to the despicable lies and disease mongering perpetrated by main stream psychiatry to make anyone given this bogus stigma appear to be a deranged, dangerous mental case without their toxic drugs with bogus claims they will never recover, etc. Considering rape, abuse trauma victims are stigmatized as bipolar, such “treatment” is malpractice at its worst. Dr. David Healy exposes the sordid reasons why bipolar became the latest fad fraud which had more to do with pushing the neuroleptic and so called mood stabilizer toxic drugs when others were going off patent for prior fads of anxiety and depression in his great book, MANIA.

    Isn’t it time after about 100 years of lies and bogus claims of genetic causes for their invented, unproven “disorders” and especially their “sacred symbols” of bipolar and schizophrenia as their latest garbage can stigmas that these emperors wearing no clothes, wolves in sheep’s clothing and boys who cry wolf should be treated with the contempt they deserve and disciplined for committing fraud as well as the incompetent or dishonest publications that publish these never ending lies to keep the corrupt biopsychiatry/Big Pharma cartel making their billions by destroying countless lives?

    Once again, ideology and neoliberal capitalism/oligarchy trumps citizens’ rights to the truth and protection of their health and even worse the health of their children being destroyed by psychiatry with impunity with the bipolar stigma and neuroleptic drugs.

    http://www.huffingtonpost.com/lloyd-i-sederer-md/thomas-szasz-md-radical-a_b_5744244.html?utm_hp_ref=health-news&ir=Health+News

  9. I was struck by the statement that AT BEST, the genetic markers they discovered could possibly account for 3.8% of the tens of thousands of diagnosed individuals. I read in an article just a few minutes earlier that well over 80% of schizophrenia-diagnosed individuals were traumatized in their youth. Which of these appears to be the better predictor of psychotic symptoms developing? Is it even close? Wouldn’t it make more sense to work on the area that is so well correlated, and over which we also have a much greater degree of control?

    It is amazing how the delusion about genetic causality continues, despite complete and colossal failures all along the road, and despite the much more obvious and clear correlations with environmental conditions. It is very much reminiscent of the eugenics movement – the “science” is driven by the ideology, and any evidence to the contrary is simply ignored as irrelevant.

    —- Steve

    • Steven
      I don’t believe there is any such thing as ‘schizophrenia’ ; I think its a false term and that its dangerous – because it writes a person off.
      When I went to see psychotherapists they told me that they were not interested in diagnosis, but in any problems I might have that were limiting me in the present. They were able to help me with these problems, so that eventually I was able to survive successfully without tranquillizers.

      • Of course, I agree with you 100%. That’s why I used the term “Schizophrenia-diagnosed” rather than “schizophrenic.” I use that term only because that’s what they purport to be studying in their efforts to prove a genetic underpinning to this pseudo-disease. My point is that their efforts are a dismal failure, and that looking at what happened to people and how they are experiencing the world is the best approach, rather than “diagnosing” them with a “disease” that has no physiological reality whatsoever. In other words, your psychotherapists’ view is in accord with my own.

        —- Steve

  10. Fiachra,

    It’s my understanding that schizophrenia has had a fluid definition of symptoms during it’s historical existence as a disorder. For example, it was initially used to describe the symptoms of what is now the disease dementia praecox. It seems that in recent years it was thought to be a real brain disease because atrophy of the brain had been seen in those so diagnosed. However, Nancy Andreasson’s research published in 2011, showing that the brain damage correlated directly to the amount of neuroleptics given, has pretty much disproven that schizophrenia, the supposed disease, causes atrophy of the brain. Schizophrenia is not a proven disease entity.

    And I agree with you, Steve, “it’s amazing how the delusion of genetic causality continues.” And I, too, read that 85% of those diagnosed as schizophrenic, had dealt with traumatization in childhood. Historically, and today, the serious mental illness labels are given to people so the mental health professionals can cover up child abuse. The psychiatrists label victims of child abuse with unproven “mental illnesses,” and then create real iatrogenic illnesses with their toxic drugs in their victims, so society does not have to deal with the real and serious societal problem of abuse of children.

    • This is the “dirty little secret of the two original educated professions.” And six stigmatized and drugged children in the neighborhood of those who sexually abused my child, violently killed themselves within a four year period – my ex-pastor’s neighborhood had the highest child suicide rate in the nation. Perhaps, rather than stigmatizing and drugging victims of child abuse, our society should actually be putting the child molesters in jail instead?

    • Btw, severe child abuse and neglect can cause developmental problems in the brain (there was a very controversial study in I believe Romania on kids who were raised in institutions as opposed to kids who had foster parents). So even if brains of people with schizophrenia would be different it does not imply causality of genetics.

  11. An interesting article, Joanna.

    I’d very curious to know your take on genetic research into homosexuality, in what ways it is similar and in what ways different from the search for biomarkers for schizophrenia and other “mental disorders”.

    I disagree however with your last paragraph. If we are unlikely to ever have a complete picture of the etiology of “extreme” mental states it is because we stubbornly keep looking in the wrong places and avoiding the obvious questions about the impact of stress on the developing brain and the many shapes which stress can take, particularly in intra-familial relationships. But many of these questions are uncomfortable, and researchers and not just researchers but also sons and daughters and fathers and mothers.

    • Now I’d be interested in that too. More importantly, how is all the research used?

      Do gay men and lesbians say, “Hay, I can’t help being gay, so stop being horrible to me,” or do we say, “I neither know or care why I am gay, but I’m not putting up with any homophobia from anyone?”

      The first is popular but the second is stronger.

    • johndoe
      Its possible to make complete Recovery, and I think thats the main thing. For me Recovery has been a type of individual thing, with the help of supportive people. The medical approach had nothing to offer, it was an expensive and dangerous obstruction.

    • There is no gene identified for homosexuality and unlikely to be one. It’s most likely the way your brain develops – what is the hormonal environment of the womb and the fetus that determines the sexual orientation (there were studies in rats which show that altering hormonal status in critical developmental periods can change orientation in adulthood). People are simply born that way.
      As for looking in uncomfortable places – researchers actually are doing that, I’ve recently attended the biggest European neuroscience conference and the one of the main topics was influence of trauma and chronic stress on mental illness.

    • johndoe,
      Thank you so much for saying this. I agree 100%.

      “If we are unlikely to ever have a complete picture of the etiology of “extreme” mental states it is because we stubbornly keep looking in the wrong places and avoiding the obvious questions about the impact of stress on the developing brain and the many shapes which stress can take, particularly in intra-familial relationships. But many of these questions are uncomfortable, not just to researchers but also to sons and daughters and fathers and mothers.”

      • 100,000%.

        The impact of stress, especially intra-familial stress, not only on the growing brain but on the body as well as the personality and mind. We just do not see and do not want to see what’s right in front of us. I really like psychologist/author Dr. Faye Snyder on this topic – the reasons why we have a tendency as a culture to “shut the eyes” – to protect those in power (incl./partic. parents) and go on continuing the cycle of injury, scapegoating others, those we see as weaker – often our own children, or other vulnerable/less powerful groups in society – and avoid really looking at and dealing with these tough interpersonal and power dynamics, and rectifying/healing them.

        There are harmful things which many parents do inadvertently to their own children, because similar things were done to them, they haven’t realized, healed and transformed from their own experience yet, and thus they can’t see their own children and their children’s needs clearly, or cannot seem to come up with adequate nurturing or overcome their destructive drives. Then, instead of identifying and sticking up for children’s true needs, we choose to protect what we see as the parents’ egos instead, not “blame” (hold them accountable), and simply “don’t go there.” Many defensive parents refuse to have it any other way, as well, and we as a society give in to their demands.

        Of course this is not the only reason. There’s also the money to be made, and the prestige of a deluded profession to continue propping up. But the parent~child dynamic – and the bias in favor of parents and the powerful at the expense of children and the less powerful – is a central element in play in all of this. This is one of the things that riles me up most about the mental health paradigm, the denial that it’s in, the lack of justice, the way it chooses to collude with the powerful and “shut the eyes” to what by this time should be obvious. That is why this ‘movement’ is very much a social justice movement. Not only is it about flawed science, it is very much about power – a dysfunctional power struggle – and repression/suppression/oppression (?) at its core.

        • Agreed. It’s curious how the developed world gets horrified and rightly so by female genital mutilation (done by loving mothers and aunts on little girls in barbaric rituals) but many are OK with beating kids to achieve discipline because “they did it to me and I’m fine”, “it’s always been that way” etc. The same excuses. Our culture paternalises many people, the elderly, women, children, poor people. I can’t understand why in many custody cases kids’ opinions are given little or no consideration, even if kids are already in their teens.

        • You are so right. Alice Miller has written eloquently on this topic for years. Either we deal with what our parents did to us, or we pass it on. Unfortunately, the 80s and the DSM/biological brain disease movement completely undermined Miller and her ilk in favor of protecting those in power from criticism. It happened in the larger society as well – the rich, corporations, the powerful all became immune to criticism, whereas in the 60s, there was a hell of a lot more accountability. We need a revolution back in that direction. We need to recognize that the person with more power ALWAYS has the primary responsibility for creating safety and a sense of value, especially when children’s fragile egos are involved. Adults need to be held responsible for what they do to kids, or else the kids become adults and continue the cycle. It’s really about that simple.

          —- Steve

  12. Genetic conditions are conditions which are CAUSED by a mutation in a specific genomic or mitochondrial sequence. Everything else is a disease which stems from interaction between somebody’s genetics, development and environment. Blaming schizophrenia on genes is like blaming lung cancer on genes forgetting that the most important risk factors for them are trauma/abuse and smoking respectively. It’s ridiculous. Even if they are some genes with make you slightly (0.1%…) more susceptible to “schizophrenia” or cancer the answer is not to do genetic tests on people but to get rid of or minimise environmental factors that are the main cause.

  13. I cannot believe that they cannot accept that schizophrenia is merely symptoms of heavy metal poisoning such as lead. These mental disorders/personality disorders are almost always caused by heavy metal intoxication. Why don’t they admit it? Heavy metal chelation is the process which removes heavy metals from the body, and science cannot use medicine for this nearly as efficiently as natural substances such as chlorella, cilantro, alfalfa, and many more. Schizophrenics can recover but they would have to use supplements and doctors always say not to use herbs and supplements. Drs also always say that there is no cure for any disease. Why does this continue?

  14. I’m a little concerned that you’re taking the small amount of explained variation from GWAS as proof that genetics plays a small role in the disease. You should really, really read about twin studies. Looking at fraternal vs. identical twins, we can get very good estimates of how much of a disease is caused by genetics. Both fraternal and identical twins grow up in similar environments, so much of the environmental component in the comparison cancels out, but fraternal twins share 50% of their genes and identical twins share 100% of their genes. If identical twins share disease status more than fraternal twins, then at least some of it has to be genetic. The concordance rate in schizophrenia is higher in identical twins (40-60%) than in fraternal twins (10-20%) (Gottesman and Shields, 1982; Gottesman, 1991). This is how we know that roughly 80% of the risk of schizophrenia is genetic (NOT from GWAS, but from twin studies). That said, GWAS has been a disappointment. My guess is that this is because GWAS looks at common genetic variants. Probably most of the genetic variants that cause schizophrenia are super rare (like just in one family or one person even). GWAS studies don’t look for rare variants, so they haven’t found them. I’m not saying we don’t have free will, but messing with genes (deleting them, changing their sequence) WILL have an effect on you, and I don’t think it’s surprising that some genes are important for brain function.

      • Thanks for the link! I thought the article was interesting and well-written, and I think I agree that Twins Reared Apart (TRA) studies aren’t the best for assessing phenotypic heritability, precisely because they rely heavily on the assumption that all similarities between separated twins are due to genetics (isn’t that what we’re trying to measure? :D). The studies I mentioned are not TRA studies, and so this article does not apply to them. When the twins are raised together (not apart), the excess concordance rate in identical twins over fraternal twins is very likely due to genetics, as shared environment should contibute equally to the phenotypic variation in both identical and fraternal twin groups. The only caveat I can think of is if there were major socioeconomic differences between the group of identical twins and the group of fraternal twins (in which case the shared environment might preferentially affect one group over another). This can be controlled for. I’d be interested in seeing a similar critique for studies of twins reared together if you remember seeing one. Thanks!

    • “Probably most of the genetic variants that cause schizophrenia are super rare (like just in one family or one person even).”
      That does not explain it. If you had a simple determination by one or two alleles then you could trace it even within in one family like you do with simple genetic disorders a such as cystic fibrosis. Unless you make a claim that one person has a lot of “schizophrenia genes” and somehow they are all super rare. Sounds unlikely.
      I do believe that there are some alleles to predispose people to react to stress in a certain way (not everyone reacts the same to trauma, abuse etc) and they can probably be identified for GWAS studies. However, the question is – how is that at all relevant to actually helping people to avoid disabling psychosis? None of these genetic variants is of any use as a drug target simply because there is no single molecular dysfunction to be addressed. There’s no chemical imbalance to be drugged.
      Maybe instead of looking for chemical treatments we should offer other interventions, which work: psychotherapy, social support, Open Dialogue. Also there are some people who “hear voices” and seem to be dealing with that just fine – maybe we should just live them alone and let them live their lives the way they know best.

      • I guess I am making the argument that you say sounds unlikely, that one person has a lot of “schizophrenia genes”, many (or most) of which may be rare. I’m definitely not making the claim that schizophrenia is Mendelian, though looking at what I initially said, I can see how it could be construed that way, so I think it’s fair that you brought it up. I think the easiest way to make this more clear is to explain just how many rare variants an individual has. Each person has around 20,000 differences from the reference genome just in their genes, and they have around 2,000,000 differences when looking at the whole genome. If you just look at rare variants [present in <0.5% of the population], there are "130–400 non-synonymous variants per individual[protein coding changes], 10–20 LOF[loss-of-function] variants, and 2–5 damaging mutations"[ref 1]. Again, that's just in the coding sequence of genes and there could be many more functionally important changes in regulatory regions of the genome outside of genes. In fact, each person has 2000-10000 rare–less than 0.5 percent–changes at evolutionarily conserved positions throughout the genome, and GWAS only looks at variants present in 5 percent of the population. Which is missing a lot of rare genetic variation, some of which likely has functional effect. Now combine this with the very likely possibility that many genes contribute to schizophrenia, and you can see how these variants might be present in one person or family (or at least be rare) but still not be amenable to the family studies that are used for Mendialian disorders (like Cystic Fibrosis). Your parents could pass on several of these rare variants, but any given variant won’t necessarily track perfectly with the phenotype as it would for a Mendialian disorder. A related problem with GWAS is that you need a LOT of people to find variants with small effect sizes. We’re good at finding common variants with large effect sizes (with GWAS), and rare variants with huge effect sizes (Family studies for Mendialian traits), but we still have a lot of trouble finding rare variants with medium effect sizes. This is a huge, unexplored part of human genetic variation, so I think it’s premature (especially when taking into account twin studies) to say that these disorders are “fundamentally environmental conditions”. And if you think about it, why would a detrimental variant (one that contributes to schizophrenia) be present in more than 5% of the population? Of course the worst and likely causative variants will be at least somewhat rare. They aren’t great for fitness.

        Maybe there are a lot of schizophrenia genes, but they interact with each other and cluster in the same pathways. These pathways would still potentially be druggable. Current drugs do work much of the time for the positive symptoms of schizophrenia, but they usually don’t work for the negative symptoms and they have pretty bad side effects, so they are far from ideal. Regardless, I agree that pyschotherapy, social support, and open dialogue are very very important. I just don’t think the failures of GWAS should mean we stop looking for the genetic contributions to schizophrenia (as argued in this post).

        1 http://www.nature.com/nature/journal/v491/n7422/full/nature11632.html

        • There’s another problem with this line of thinking. Of course everything we are as biological creatures can be tracked back to our genes but it does not make it “a genetic disorder”. Take obesity – some people can eat whatever they want and never get fat while some gain weight quite easily. It does not make obesity a genetic disorder – the main contributing factor is lifestyle and (with rare exceptions which can be tracked to single mutation or hormonal disorder etc.) given proper environment every person has a chance to keep their weight in check. There is a difference between genes which cause disease, predispose for a disease or are permissive for a disease. While I believe that there are some genetic variants that may predispose to or protect against psychosis (I don’t think schizophrenia exists as some single cause definable entity) I would not go as far as to say it’s genetic. If you do that all diseases become genetic and the phrase loses it’s meaning.