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). 

Interesting Study Related to Cognitive Decline from Schizophrenia

 This study assessed whether cognitive decline from Schizophrenia has a genetic component. 

Schizophrenia polygenic risk predicts general cognitive deficit, but not cognitive decline in healthy older adults

In the early years of psychiatry, Schizophrenia was called "Dementia Praecox," a term coined by Emil Kraepelin, that described the deterioration of cognition associated with schizophrenia more so than the symptoms we normally associate with the disorder. From Wiki:

Dementia praecox (a "premature dementia" or "precocious madness") is a disused psychiatric diagnosis that originally designated a chronic, deteriorating psychotic disorder characterized by rapid cognitive disintegration, usually beginning in the late teens or early adulthood.

This term is no longer used, but the concept behind it is still accepted, that there is a progressive dementia among schizophrenic patients. The idea behind this study is that, assuming the polygenic model of schizophrenia holds true, if someone is not schizophrenic, but has a high polygenic score for schizophrenia (has a lot of the identified variants), then one might expect them to have some cognitive decline. That was not the case, as the study points out:

These results do not support the neo-Kraepelinian notion of schizophrenia as a genetically determined progressively deteriorating brain disease.

I think what this suggests is that schizophrenia, itself, is the cause of the cognitive deterioration, rather than the other way around.  Moreover, it challenges the polygenic model of schizophrenia and the idea of a "continuum" related to the number of susceptibility genetic variants, as Robert Plomin suggested in the book, "Blueprint.

Wake Up Call for Insomnia GWAS

Here is another GWAS, this time for insomnia, that I think buries the lead:

Genome-wide meta-analysis of insomnia in over 2.3 million individuals implicates involvement of specific biological pathways through gene-prioritization

Here's an alternate title:

Based on 1.3 million GWAS, the maximum variance explained was 2.6% and based on 2.3 million individuals the maximum variance explained seems to be only 2% !

- (Hat tip to Veera M. Rajagopal, twitter handle: @doctorveera, who might not really appreciate the hat tip)

Obviously, there is a problem here, when, even when finding novel loci by expanding your dataset, you are getting getting worse "variance explained" from your PRS. I think this suggests that they have already reached their peak, which seems to run in the 2 to 3% range for most behavioral traits. I will once again point out that even this number is suspect, since it is not compared to any null trait. They try to rationalize it by suggesting that that the added data (from 23andMe) was less stringently phenotyped, but you can't have it both ways. Expanding datasets does not appear to give us any more real insight. It just bumps up the number of loci meeting significance, which arguably just a collection of false positives.

As the datasets expands beyond just white Europeans, I suspect this will onlly further water down the success of these studies, since they will not be able to rely as much on pop strat to get correlations.

Bipolar Genetics Makes No Progress

Nice critique by Peter Simons of a genetic study for bipolar disorder among Han Chinese with the diagnosis  of Bipolar Disorder (original study here). A couple of excerpts:

The researchers analyzed thousands of Han Chinese people and found that genetics explained just 2.3% of whether they received a diagnosis of bipolar disorder (BD) or not...

However, it is unclear how tiny correlations like this—which affect but a tiny sample of the population studied and explain less than 3% of the risk for a diagnosis—could help researchers understand the supposed “biological etiology” of bipolar disorder. In fact, they rather show that more than 97% of the reason that someone gets a diagnosis is explained by factors other than biology. 

As I like to point out, even the 3% is quite suspect and is arguably noise and should be tested against a null trait to establish that the 3% is not the null.

The Unembarrassed Bot

 A shortcutting of the usual GWAS is a bot that simply cranks out a Manhattan plot with no further analysis. While, those who do traditional GWAS downplay it, there is really little difference between what they are doing and what the bot is doing other than some shoddy speculation and perhaps a bit of data cleaning, but the real issue is that the bot does GWAS that most would be too embarrassed to publish and these get a lot of hits. Take this one, for example, that ironically, without embarrassment, finds genetic variants for "worrying too long after embarrassment":

This should be a clear indication that silly false positives can be produced from anything you can ask on a questionnaire. In addition to the likelihood of some massive pop strat dependent on particular cultural backgrounds, what exactly is meant by "too long"? Is this a subjective opinion of the person or is it a specific amount of time?