Copy number variation in schizophrenia

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Nature has published a couple papers reporting (using partially overlapping samples) associations between rare recurrent microdeletions and schizophrenia. The paper from Deocde Genetics hits an evolutionary angle from the first sentences:

Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed.

Rare variants often have much larger phenotypic effects than more common ones; this case is no different:

All three deletions, at 1q21.1, 15q11.2 and 15q13.3, significantly associate with schizophrenia and psychosis in the combined sample with high odds ratio (OR) (p = 2.9x10e-5, OR = 14.83; p = 6.0x10e-4, OR = 2.73; and p = 5.3x10e-4, OR = 11.54, respectively)

Note that despite these massive odds ratios, these deletions explain a tiny fraction of all cases of schizophrenia due the their extremely low frequency. Still, these genomic regions seem like important areas for following up via functional studies or searching for more common polymorphisms.

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9 Comments

  1. Schizophrenia is not a coherent diagnostic entity – this has been an open ‘secret’ in psychiatric circles for decades. ‘Schizophrenia’ is a vaguely defined mish-mash of a large number of clinical and causal entities.  
     
    So this study translates into something like ‘severe psychotic illness can be caused by a variety genetic mutations’ which is not very surprising. 
     
    But the fact that this study got published in Nature shows why the bogus diagnostic category of schizophrenia has been sustained – it sounds much more impressive to imply that you have discovered the cause of a disease than that you have discovered that gene mutations can damage brain function.

  2. So then there’s still room for the New Germ Theory take on it. 
     
    I thought the A.P.A officially got rid of “schizophrenia” in favor of a bunch of smaller syndromes a while back.

  3. TGGP 
     
    In the end, it will probably emerge that all disease is either due to germs or genes…

  4. So this study translates into something like ‘severe psychotic illness can be caused by a variety genetic mutations’ which is not very surprising 
     
    hm. I find this something of an odd objection–the point is not that mutations can cause disease, but the discovery of which mutations cause disease.  
     
    Schizophrenia is not a coherent diagnostic entity – this has been an open ‘secret’ in psychiatric circles for decades. ‘Schizophrenia’ is a vaguely defined mish-mash of a large number of clinical and causal entities 
     
    from the point of view of mapping the genetics of a trait, the consequence of imprecise categories is a loss of power. in this study, the sheer number of individuals studied makes should make up for it to some extent. the authors discuss this a little:Removing cases with psychosis, other than ‘diagnostic and statistical manual of mental disorders’ and ‘research diagnostic criteria’ defined schizophrenia (in total 147 cases: 39 with unspecified functional psychosis, 86 with schizoaffective disorder, 10 with schizophreniform and 12 with persistent delusional disorders; Supplementary Information), gave comparable results for the 1q21.1 deletion (P = 2.31 times 10-5, OR = 15.44), whereas the association for 15q11.2 and 15q13.3 deletions was no longer significant (P = 9.57 times 10-4, OR = 2.66 and P = 1.02 times 10-3, OR = 11.29, respectively (uncorrected for 66 tests)). Historically, classification schemes tend to group diseases by their signs and symptoms. There is, however, no reason why the phenotypes associating with a particular CNV should be confined to the current nosological boundaries of any single psychiatric disorder. Our findings, in this respect, resemble those from the 16p11.2 deletion and the translocation disrupting the DISC1 gene in a large Scottish pedigree, and support the idea that the same mutation can increase the risk of a broad range of clinical psychopathology.

  5. Genetic tests are refining disease categorization. E.g., in breast cancer, pathologists using cell morphology or staining can’t distinguish between two major classes of ductal carcinoma. One class has only a small chance of remission and doesn’t require chemotherapy. The other cancer class is likely to return unless the patient undergoes chemotherapy. A gene expression test, MammaPrint, can reliably determine what type the patient has and whether chemotherapy is appropriate. 
     
    Better genetic testing will lead to refined diagnosis which will lead to improved treatment. This will become very important when patients routinely have their genome scanned. That should begin happening in about five years.

  6. Fly
     
    Schizophrenia (and other psychiatric conditions) are different from breast cancer in that they are not proven to be of pure morphological origin. Neither their prognosis is proven to depend solely on morphological factors. A breast cancer patient in an advanced stage is highly unlikely to be helped by psychotherapy, but to advanced schizophrenia patients it happens rather often. Such improvement in psychiatric conditions, on the other hand, is difficult to predict, and sometimes it depends more on a personality of the physician than that of his patient. 
     
    To study the genetic associations of psychiatric disorders is very academically interesting, I admit. It has questionable practical significance, however, since many psychiatric patients would surely benefit more from the doctor’s understanding of their psychological issues, than his discussing their genetic abnormalities. 
     
    “Better genetic testing will lead to refined diagnosis which will lead to improved treatment.” 
     
    This is a very optimistic statement. Much sooner “better genetic testing” will lead to preventive use of psychiatric drugs, and this will have consequences that are hard to foresee.

  7. sk 
     
    psychotherapy = placebo effect 
     
    Stick needles in people and give it a name (acupuncture) and a lot of folks will experience significant pain relief.

  8. To study the genetic associations of psychiatric disorders is very academically interesting, I admit. It has questionable practical significance, however, since many psychiatric patients would surely benefit more from the doctor’s understanding of their psychological issues, than his discussing their genetic abnormalities. 
     
    Maybe that’s true today; I wouldn’t know. But anyway, ja, und? Pick a timescale that’s short enough, and the very same evaluation applies to anything under the sun. Eg, penicillin in 1928. Fifteen long years later it wasn’t nearly so academic anymore. Frankly, I do doubt that the widespread use of dense genome scans will lead to a big change in schiz outcomes over the subsequent decade… but IMO no one’s prediction about that could really be all that confident.

  9. Eric J. Johnson 
     
    If I understand your thought correctly, it has to do with the general desirability (or, indeed, “unstoppability”) of scientific progress. Because we are narrow-minded by definition, we can never know what future brings, and which of today’s academic topics will suddenly become real-life issues. I agree with this general notion. 
     
    Its specific applicability to the field of practical psychiatry, however, raises my concerns. I am not quite sure there has been any scientific achievement in psychiatry in the last 50 or so years that significantly improved the lives of psychiatric patients in the long-term perspective. The antibiotics did that. 
     
    It probably is not because the whole psychiatric science is bad, but because (1) so much of it is for profit, and (2) its achievements get bent significantly on their way to practical implementation. 
     
    Extrapolating from the past, I am terribly worried about how hospital administrators, drug manufacturers, insurance companies and other interested parties may “interpret” the scientific data, and how it will affect the patients.

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