My Strategy For the Short Term

As noted in the subheading above, I have been interested in the lack of solid genetic evidence for mental illness, particularly schizophrenia, for 25 years and I have written several letters to psychiatric journals challenging these studies.  The past few years, I have been busy doing other things, but now I have created this blog to devote an entire website to challenging the studies that claim to show such links.  The question is just how far back and how many studies do I need to challenge?  Hundreds of genetic linkage studies have been performed, all claiming some gene or genetic loci is linked to a disorder.  None of these studies have been replicated and most are eventually, directly or indirectly, refuted by the studies that come after them.  I have already looked at two studies from the past two years. 

There were  three landmark studies from 2009 in Nature, that got the media fairly excited, with the usual “Genes found for Schizophrenia” inaccuracies.  The meager findings of these studies have already been discussed by others.  However, I think it is worth analyzing even the weak claims made by those studies, so my plan is to refute  these studies over the next couple of weeks, to eliminate even the meager claims made.  At that point, I feel we are at close to point ZERO, where I can legitimately claim that there are no valid, replicable studies showing any specific genetic link for schizophrenia to date.  That way, I can then address only the new studies to come out.  I intend to bury this waste of time, money and misinformation under the scrap heap of bad science.  Good riddance!

My Critique of: NATURE GENETICS - Genome-wide association study identifies five new schizophrenia loci, Stephan Ripke et al

If I was even willing to accept this study on its face, this is my “shorter” interpretation of its conclusion:

“We did a mega-analysis of 17 genetic loci genome scan studies for schizophrenia.  We found 7 genetic loci correlating to schizophrenia.  Of those, 5 were NOT FOUND IN ANY OF THE ORIGINAL 17 STUDIES, NOR IN ANY PREVIOUS STUDY.  The remaining 2 were found in SOME of the studies.  Thus, any correlations other than those two found in any of the studies have been effectively negated. “

Thus, even if you accept the study, the conclusion seems to point to the fact that almost all of the findings in the studies it analyzes were, in fact, statistical artifacts.  Interesting.  It's more interesting that the authors did not  seem to be aware of this fact, or didn't think it was pertinent. 
Moreover, like many meta-analyses (or mega-analyses at the case may be) the study itself uses some rather complicated statistical analysis that I think is already questionable, and I discuss that briefly below the fold.  It will cost you $32 to check out the full study for yourself.  I paid it so you don't have to...

My First Critique of a Study for this Blog: Talkowski et al, Cell Magazine, "Sequencing Chromosomal Abnormalities Reveals Neurodevelopmental Loci that Confer Risk across Diagnostic Boundaries"

I wrote a letter criticizing this study from Cell Magazine. Receiving no response, I wrote a follow-up letter to that letter. That was several months ago. To date, I have not received a response. I will therefore present my criticisms here. If you have a scientific or medical background and you would like to respond to my criticism, I will be happy to carry on a dialog through the comment section: This study generated a number of media articles further promoting the misconception that there have been genes or genetic loci that have been definitively linked to various mental disorders. Note a headline related to this study:

  Researchers discover new genes contributing to autism, links to psychiatric disorders 

 Now, is that really what the researchers discovered? Let's take a closer look. Here's what they found:

Screening the genomes of 38 individuals diagnosed with autism or other neurodevelopmental disorders found chromosomal breakpoints and rearrangements in non-protein-coding regions that disrupted 33 genes, only 11 of which previously had been suspected in these disorders. 

 So we have a "screening" study and 22 of the 33 genes were noted for the first time and the other 11 had been "suspected." The idea of a screening study is to find possible genetic links to examine in future confirmational studies. You should do the follow-up study before making specific claims. Yet the author is quoted as follows:

"The theory that schizophrenia is a neurodevelopmental disorder has long been hypothesized, but we are just now beginning to uncover specific portions of the genetic underpinnings that may support that theory," says Talkowski. "We also found that different gene variations -- deletion, duplication or inactivation -- can result in very similar effects, while two similar changes at the same site might have very different neurodevelopmental manifestations. We suspected that the genetic causes of autism and other neurodevelopmental abnormalities are complex and likely to involve many genes, and our data support this."

 Well, your data doesn't really support this, Dr. Talkowski. It only supports it if you were to ignore the possibility of false positives and the genes you found are actually directly related to the diagnoses in question. In this case, the researchers focus on a subgroup of patients with autism and “abnormal chromosomes,” which is not typical or classical autism and already brings the research into question when extrapolating it to those without genetic abnormalities and is additionally compounded by including schizophrenia despite no obvious chromosomal abnormalities in most individuals diagnosed with schizophrenia. There is some question as to whether such cases are even looking at the same thing as classical autism and schizophrenia in individuals without chromosomal abnormalities. Furthermore, no control is used looking at a similar group of individuals with chromosomal abnormalities without autism to see if they also have similar DNA disruptions. Actually, a second and third control should also be used to determine how many individuals with autism and no structural chromosomal abnormalities have such DNA disruptions as well as a group of non-autistic individuals without chromosomal abnormalities (“normals”) with such DNA disruptions. It is not enough to just claim that such disruptions are “known to be significantly more common in autism and autism spectrum disorders.” The fact that such disruptions may or may not be more common might, in fact, be a red herring and have nothing to do with the disorder itself. Such controls should be done in any of these experiments and the lack of such controls make the data impossible to analyze as anything more than random. I would venture to guess that that is, in fact the case. I would also point out to the authors that, to date, there has not been a single consistently replicated study showing a gene, genetic loci or DNA disruption (etc.) for schizophrenia. Thus, for your group to find a “significant number” of such genes is interesting and surprising, to say the least. Let me suggest that a less interesting, but more realistic headline for the results of the study would be this:

Researchers do a genetic screening that may be worthwhile for future confirmational studies.