Another Schizophrenia Twin Study That Only Looks Good When You Skim The Results

 In medical school, my Psychiatry Residency, and even the Psychiatry Board Exams, the concordance rate noted for Schizophrenia was 50%. The assumption here is that if one identical twin was diagnosed with schizophrenia, then the other one had a 50% chance of also being diagnosed with schizophrenia (I am told this is still the conventional wisdom). This is an impressive number, even if it doesn't explain why the other 50%, also genetically identical to their schizophrenic sibling is not also diagnosed with schizophrenia. Well, it appears this is far from accurate, as I've discovered when looking at the actual studies, which we admittedly rarely did in our training, as we filled our heads with the "facts" we needed to pass our training and board certification. It appears to be a bit of statistical sleight of hand. [Hat tip to Jay Joseph (blog linked in my blog roll) for looking at this study a bit past the abstract]:

Heritability of Schizophrenia and Schizophrenia Spectrum Based on the Nationwide Danish Twin Register

If one peruses the abstract of this study, you are met with this:

The probandwise concordance rate of SZ is 33% in monozygotic twins and 7% in dizygotic twins. We estimated the heritability of SZ to be 79%. 

Does that mean that if your identical twin has schizophrenia, you have a 33% chance of having schizophrenia? No, I don't think it does. Does it mean that you have a 79% chance with that stated heritability? No, it doesn't, either.

In fact, based on this study, if one identical twin is diagnosed with schizophrenia, the other was diagnosed with schizophrenia only 14.8% of the time. While that's higher than you would expect at random, it is a far cry from what you might think if you skim the study and feels a bit deceptive, really. So let's see where they come up with their figures.

Old Schizophrenia Twin Study That Tells a Different Story

 This study of Finnish Twins is originally from 1984:

Psychiatric Hospitalization in Twins

I think it makes some interesting points and I'm surprised I hadn't seen it before (Hat tip to Jay Joseph). Throughout my residency, I was told that there was a 50% concordance rate for schizophrenia among identical twins. I don't recall this study ever being referenced. It used hospitalization records and seems to have found a much lower concordance rate:

Pairwise concordance rates for schizophrenia (11.0% for MZ and 1.8% for DZ) seem to indicate great environmental influence (high proportion of discordant pairs) with apparent genetic liability (6.1-fold ratio in concordance between MZ and DZ pairs).

That's a surprisingly low figure. Perhaps because they used hospitalization records rather than interviews there was less bias or perhaps one twin wasn't hospitalized when the other was. 

Of course, one might jump on the fact that at least the concordance rate is significantly higher for MZ than DZ, even if not impressive. It's worth pointing out, though, that since doctors are regularly trained to take a family history and are more likely to diagnose someone with schizophrenia if they have a close relative with that diagnosis, that there is potential for inflation. 

I think such inflation would favor MZ twins in particular and this is an impressive point in the article:

Of the MZ pairs concordant for psychiatric hospitalization, 47% had lived together for their whole life time; of those discordant, 16% lived together. The corresponding figures for DZ pairs were 18% and 15%.

It is interesting that the MZ twins who lived together were more frequently diagnosed concordantly with schizophrenia, while not true of DZ twins. I am extrapolating, here, but it also appears that MZ twins are more likely to live together than DZ twins, which suggests some bonding that again brings into question the idea that MZ twins and DZ twins can be compared in this way (for more, see Jay Joseph's work on the EEA). 

If You Can't Make it Happen for Schizophrenia

 This is an expansion of a previous Schizophrenia GWAS:

Mapping genomic loci prioritises genes and implicates synaptic biology in schizophrenia

This is the PGC schizophrenia study. We hadn't really had an update since 2014. It appears they buried the lead with the usual false optimism. They went from 36,000 cases in the previous study to 69,000 in this one. We have been promised that polygenic risk scores (PRS) would explain more and more of the "missing heritablity" as the study sizes increased. Well, in this case, the PRS variance explained went from 3.4% to ... 2.6%. Of course, that 3.4% was apparently an error anyway.They also admit that their previous calculation of 3.4%, often cited in other papers, was calculated in error and was probably lower. Is that to make it look like the 2.6% is not that bad?

The fact of the matter is that this is a very bad result. This is not even a within family calculation, which one might expect to be very close to 0%. I think at this point, getting 2 or 3 percent of the variance explained is essentially a null finding, and I challenge any authors who claim otherwise to compare it to obvious null traits.

I might have more to say about this related to the loci they say reached significance, but can't find the old PGC data to compare it with directly. In any case, the only thing that increasing N does is bolster the number of "significant" loci and I expect none of these loci will independently meet statistical significance in any other study.

What this study really suggests, when you take away the spin, is that the entire model of a polygenic mechanism for schizophrenia is pie in the sky. This points to a larger problem, which is that if any psychiatric trait should be due to a physical (genetic) cause, one would think schizophrenia would be a sure thing. If you can't make it happen for schizophrenia, good luck making it happen for dubious diagnoses like ADHD or really any other psychiatric trait.

Genetic Prediction of Schizophrenia via Polygenic Risk Score Has No Clinical Utility

 A new study from Schizophrenia Bulletin tested various risk factors on a group of individuals in a Netherlands. In addition to other risk factors, they used Polygenic Risk Score (PRS) developed from previous studies. This summarizes the results:

We calculated the relative contribution of each (group of) risk factor(s) to the variance in (change in) mental health. In the combined model, familial and environmental factors explained around 17% of the variance in mental health, of which around 5% was explained by age and sex, 30% by social circumstances, 16% by pain, 22% by environmental risk factors, 24% by family history, and 3% by PRS for schizophrenia (PRS-SZ). Results were similar, but attenuated, for the model of mental health change over time. Childhood trauma and gap between actual and desired social status explained most of the variance.

 This is a weak result all around, but particularly bad was the PRS which had a predictive success of 0.5 % (3% of 17%). Thus, just knowing a person's age and sex was almost twice as predictive as the PRS. If the person had a history of pain or other medical complaints, that alone was 4 times more predictive for schizophrenia. This is simply a dismal failure and the continued hope that this will be good enough to be clinically useful is little more than wishful thinking. Realistically, to be clinically useful, it would have to be 25 to 50 times better than this and I am guessing it has come close to peaking.

Cross Ancestry Study of Schizophrenia puts out its best face (only)

I wanted to make a few quick points about this study:

Comparative genetic architectures of schizophrenia in East Asian and European populations

I tried to ask a few questions to one of the authors promoting it on Twitter, but he did not respond, so if I am incorrect about any fact, leave a comment here and I will update. Let's start with the Abstract, which is below in full:

Schizophrenia is a debilitating psychiatric disorder with approximately 1% lifetime risk globally. Large-scale schizophrenia genetic studies have reported primarily on European ancestry samples, potentially missing important biological insights. Here, we report the largest study to date of East Asian participants (22,778 schizophrenia cases and 35,362 controls), identifying 21 genome-wide-significant associations in 19 genetic loci. Common genetic variants that confer risk for schizophrenia have highly similar effects between East Asian and European ancestries (genetic correlation = 0.98 ± 0.03), indicating that the genetic basis of schizophrenia and its biology are broadly shared across populations. A fixed-effect meta-analysis including individuals from East Asian and European ancestries identified 208 significant associations in 176 genetic loci (53 novel). Trans-ancestry fine-mapping reduced the sets of candidate causal variants in 44 loci. Polygenic risk scores had reduced performance when transferred across ancestries, highlighting the importance of including sufficient samples of major ancestral groups to ensure their generalizability across populations.

The reason I am showing the entire abstract is to point out what it doesn't say: That the study apparently failed to replicate any of the previous significant loci for schizophrenia (as far as I can tell). The authors simply ignore this, almost as if it is expected, yet expend a lot of time trying to make lemonade out of a lemon without telling us it was a lemon, trying to justify why schizophrenia would present in the same way in different cultures, when it is presumably due to entirely different gene sets.
In my view, you would not expect any of the loci to match between the two studies because the loci are generally false positives, probably enhanced by population stratification issues that are going to be different in these two different populations. Let me go over some of the findings and why I believe they are consistent with pop/strat, false positives after the fold: