Genetic Models of ‘Schizophrenia’ Explain Very Little, Researchers Find

All genetic models combined still explain less than 3% of whether someone gets a schizophrenia diagnosis.

Peter Simons
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In the past few years, the search for a genetic cause for schizophrenia appeared to have stalled. No single gene—or distinct group of genes—could be found to explain the diagnosis. However, researchers soon came up with an alternative hypothesis: the “polygenic model.” Large groups of genes, responsible for all sorts of functions within the human body, were grouped together based on studies that analyzed large portions of the human genome. Although results were mixed, some studies found statistically significant effects, indicating that these gene groupings might have some relationship to schizophrenia.

A new study, just published online in the journal Neuropsychopharmacology, analyzed the explanatory power of these polygenetic models. The research was led by Kristin K. Nicodemus, at the University of Edinburgh, and Kevin J. Mitchell, at Trinity College Dublin.

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Although genome-wide association studies (GWAS) have found statistically significant associations between large gene sets and the schizophrenia diagnosis, the researchers write that existing studies do not clarify how much the statistically significant findings matter. “These analyses do not estimate the contribution of these gene sets to the amount of variance explained,” according to Nicodemus and Mitchell.

Nicodemus and Mitchell wanted to correct this oversight. Working with the Schizophrenia Working Group of the Psychiatric Genomics Consortium, they gained access to the datasets for 39 studies, including 29,125 people diagnosed with schizophrenia and 34,836 people without a diagnosis (all of European ancestry).

The researchers took this data and assessed how much predictive power the genetic associations had. Their research asks, how well could you predict whether someone has a diagnosis of schizophrenia if you knew their entire genome? Their results suggest that the genetic associations explain very little.

The researchers studied several commonly cited contenders, sets of genes like TCF4, FMRP, MIR137, and CHD8. They also looked at sets of genes that are associated with cancer and cardiac problems, for comparison. All told, the statistically significant genetic associations explained a total of 2.28% of whether a person is diagnosed with schizophrenia. That leaves a solid 97. 72% to be explained by other factors, such as the environment’s impact on biology, emotional trauma, childhood experiences, or family dynamics.

The TCF4 set of genes has been the most studied candidate to explain the heritability of schizophrenia. According to Nicodemus and Mitchell, this set was the most significantly associated with a diagnosis. In 29 of the 37 studies that analyzed it, it was found to be associated with schizophrenia (it was found not to be associated with schizophrenia in the other eight studies). In all, this particular set explained 0.6% of whether someone had a diagnosis of schizophrenia or not.

Other sets of genes explained even smaller percentages of the variance in outcome. For instance, FMRP explained 0.43% of the variance and was associated with schizophrenia in 23 of the 39 studies (not associated in the other 16). MIR137 and CHD8 fared even worse.

The comparison sets for cancer and cardiac problems were also statistically significant in their association with schizophrenia.

The researchers also tested a variety of random genetic combinations, which all generated a statistically significant effect. They explain this by writing that it “could be attributable to an omnigenic or highly polygenic background.” That is, they believe that all human genes may have some effect on whether a person is diagnosed with schizophrenia.

 

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Rammos, A., Gonzalez, L. A. N., Weinberger, D. R., Mitchell, K. J., & Nicodemus, K. K. (2019). The role of polygenic risk score gene-set analysis in the context of the omnigenic model of schizophrenia. Neuropsychopharmacology. doi:10.1038/s41386-019- 0410-z (Link)

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25 COMMENTS

    • The term “schizophrenia” is not useful or valid, according to many authorities. People who suffer from mental problems or life problems are not “sick.” This is the normal course of events given what their life struggles are about. All psychiatric diagnoses are subjective, not science, so just from this standpoint, the science of the genetics of this is also pseudoscience.

      I prefer to hear people’s experiences rather than their label, that boils down the experiences into one or a few words so that insurance can pay shrinks and Big Pharma big bucks.

  2. What kind of genetic model can we talk about when a diagnosis of schizophrenia is made both to sick and healthy people? Moreover it’s like in quantum mechanics – the fact of observation affects the characteristics of the particle, if you get schizophrenia – you will have depression etc.

    • “All genetic models combined still explain less than 3% of whether someone gets a schizophrenia diagnosis”
      In other words – less than 3% of people who are diagnosed with schizophrenia have real schizophrenia (spontaneous psychosis). And I constantly say that there are very few such people.

      • In my Experience the answers lie within the Non Drug Approach.

        My Experience of “High Anxiety” or Neuroleptic Drug Withdrawal Syndrome (anxiety at its “worst”); is that it can be accommodated through careful drug withdrawal and straightforward psychological means.

        Below is a Research Paper produced by my historical Psychiatrist and “Neuroscientist” Dr PA Carney at NUIG on the merits of long term Neuroleptic depot injection drugging of “Schizophrenics” in the community in Ireland.

        https://ps.psychiatryonline.org/doi/10.1176/ps.49.10.1361-b

        I was diagnosed by Dr PA Carney as a hopeless case of “Schizophrenia” (1980 to 1984). But I made Full Recovery as a result of coming off the ABOVE medication (very carefully) with help of Practical Psychology.

        I can Factually Represent what I say to be TRUE with Evidence of 35 Years, of Wellness and Independence (1984 to 2019), of the Psychiatric and Disability System.

  4. The researchers should look at the iatrogenic etiology of “schizophrenia.”

    Given the fact that the “schizophrenia treatments,” the neuroleptics/antipsychotics, can create the negative symptoms of “schizophrenia,” via neuroleptic induced deficit syndrome.

    https://en.wikipedia.org/wiki/Neuroleptic-induced_deficit_syndrome

    And given the fact that the neuroleptics/antipsychotics can create the positive symptoms of “schizophrenia,” via antipsychotic induced anticholinergic toxidrome.

    https://en.wikipedia.org/wiki/Toxidrome

    I’m quite certain the most common etiology of “schizophrenia” is iatrogenic, not “genetic.”

    But I’m wondering, the head of NIMH confessed to the “invalidity” of all the DSM disorders, including “schizophrenia,” in 2013.

    https://www.nimh.nih.gov/about/directors/thomas-insel/blog/2013/transforming-diagnosis.shtml

    And at that time Insel also called for an end of spending for research into the “invalid” DSM disorders. When is this waste of our taxpayer dollars, this endless search for the “genetics” of “schizophrenia,” finally going to end?

    “Schizophrenia” is an iatrogenic illness, created with the treatments.

  5. “All told, the statistically significant genetic associations explained a total of 2.28% of whether a person is diagnosed with schizophrenia.”

    I’m not a geneticist, ha, but how does a statistical analysis explain anything? You have “schizophrenia” because we found, of the people studied after being diagnosed with “schizophrenia”, 2.28% had something genetic in common with you. I’m probably not interpreting it correctly, but then the article needs to be a bit more clear.

      • I’m quite certain you are correct. And now that we do have genetic testing, if “schizophrenia” were a “genetic illness,” as has been fraudulently claimed for decades. There definitely should be “genetic testing” done, prior to a diagnosis being given.

        But the psychiatrists can’t do this, because the psychiatrists’ so called “genetic” DSM disorders, do not have medically proven, diagnosable “genetic” etiologies. That’s why “All genetic models combined still explain less than 3% of whether someone gets a schizophrenia diagnosis.”

        • NON DRUG (NON GENETIC) “SCHIZOPHRENIA” SOLUTION

          From SELFHOOD By Dr Terry Lynch

          “..I could see how Stephen was diagnosed as having paranoid schizophrenia. He saw threat and danger everywhere, when objectively there was none. Stephen’s level of selfhood was at rock bottom, and this was a fundamental underlying reason for his problems. His paranoia was entirely understandable as seen from his perspective, given that one of his main experiences was that he constantly felt unsafe, unprotected and unable to generate any personal security for himself. This was borne out in his second session with me. As I mentioned briefly in the section on self-generated security, ten minutes into the session, Stephen looked terrified, and I asked him why. He replied ‘I’m not sure I can get out of this place alive’….”

          “…I focused on enabling Stephen to progressively raise his level of selfhood…”

          “….Stephen was now aware of his own terror and inability to make himself feel safe, whereas previously he was not aware of this and instead was entirely focused on the dangers that lay waiting relentlessly for him everywhere. …”

          “…I used these experiences to get Stephen thinking about the accuracy of his interpretations of these episodes…”

          “…His level of self-protection and self-generated security began to increase, slowly at first, then gathering pace….”

          “…Because he was doing well, his psychiatrist agreed to reduce his medication slightly, and I subsequently continued the process of gradually reducing Stephen’s medication…”

          “…Stephen has been off all schizophrenia medication for over three years. He lives a full life, goes where he likes, thrives in social situations, and has a level of selfhood higher that at any previous time in his life…”

    • I think it means that of all the people who end up diagnosed with “schizophrenia”, only 2.28 out of every 100 had some gene that supposedly conferred vulnerability to “schizophrenia.” Or to put it another way, the idea that “schizophrenia” is caused by genetic variation is BS.

      • It might make sense if you talked about variations instead of A variation. The nutrient dependencies may have genetic influences, but different ones for each dependency are more likely than single “key” ones that affect all of them. The same probably exists for heavy metal poisonings, another cause for schizophrenias, particularly for metals like copper, which is a necessary nutrient in small quantities, but can bring on depression and/or one of the schizophrenias when found in excess. (notice I like to use the plural instead of the singular “schizophrenia”)

        • Your point is well taken. The biggest problem with the psychiatric/DSM viewpoint is the absurd assumption that all people or even most people who behave or feel or think in a certain way have something wrong with them, or that all such people have the same thing wrong with them.

        • A medical doctor told me she had a client with a schizophrenia diagnosis. Exploring with him, she found he had a gas leak in his apartment. When the leak was fixed, he was ok. I think that these environmental causes, vs sociological ones, are rare.

  6. Schizophrenia Diagnosis

    In my own case my original “schizophrenia diagnosis formulation” was “Peculiar”.

    Relevant Factual information within the formulation pertaining to me, was inaccurate and vague, as if doctors were attempting to deny responsibility; while at the same time claiming “Severe Mental Illness”.

    I was recorded as living in the UK in the previous 6 months to hospitalization when in fact I had been living in Holland. And the Irish Doctor that identified this, kept his name completely off the records.

  7. “Although genome-wide association studies (GWAS) have found statistically significant associations between large gene sets and the schizophrenia diagnosis, the researchers write that existing studies do not clarify how much the statistically significant findings matter. “These analyses do not estimate the contribution of these gene sets to the amount of variance explained,” according to Nicodemus and Mitchell.”

    Excuse me but believing you’ve found “statistically significant associations,” and than still believing that [you’ve found statistically significant associations] after realizing that you can’t clarify that what you’ve found matters at all…well, that certainly is too far along the line of incoherent logic to be seen as simple schizophrenia.

    You see if you keep on going on that it MUST be something physical (biological, genetic), and when you find something, but don’t know what it has to do with anything, BUT it’s “physical” then you’re on the right track.

    And all “schizophrenics” are supposed to admit that they just aren’t brainwashed enough if they don’t believe it, or are they supposed to turn the table and start wasting their time and good will looking for genetic flaws in people looking for genetic flaws!?

  8. Thanks Peter, for continuing the ongoing story on the faulty genetic studies.

    Since you mention many times “statistical significance,” I’d like to chime in on that and its implications.

    I am not saying the papers you cite here are guilty of this, but in general it is good to be aware of the abuses of the use of “statistical significance.”

    Here is an article showing how the popular media twists research data. A doubling of effect, in this case, meant going from 1% to 2%. http://www.slate.com/articles/technology/future_tense/2016/02/schizophrenia_genes_found_not_so_fast.html

    Many scientists are concerned about this type of abuse, as 700 signatures attest in the prestigious publication “Nature:”
    https://www.nature.com/articles/d41586-019-00857-9