Another ADHD "Meta-Analysis" Makes Genetic Claims for the Disorder, But Shows the Opposite.

 The latest ADHD GWAS is available in pre-print:

Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains

It is now formulaic to perform a GWAS "meta-analysis," rather than independently examining a new dataset. I put meta-analysis in quotes, because this is not really even what we have, since this new data which makes up half the data in the study has not been in a previous study. As I have noted repeatedly, this is problematic and I will touch on why in this critique. Let's get to the claims. 

 The meta-analysis identified 32 lead variants (r2 < 0.1) located in 27 genome-wide significant loci (Figure 1; Table 1, locus plots in Supplementary Data 1), including 21 novel loci. No statistically significant heterogeneity was observed between cohorts 

The first question you might ask is why these 21 novel loci were not noted in the previous GWAS for ADHD? The argument is that when you increase the number of cases, working with a higher N, you are more likely to pick up smaller correlations. The problem with that argument can be seen by the fact that there were 12 loci found significant previously and now only 6 of them are still significant. If we were talking about two entirely different studies, where the larger one picked up 6 out of 12 loci from the previous study, you might make some claims of a modest success and the authors seem to imply exactly this: 

Six of the previously identified 12 loci in the ADHD2019 study14 were significant in the present study (Table 1), and the remaining six loci demonstrated P-values < 8x10-4 

The problem here is that the data from the ADHD2919 study referenced above WAS INCLUDED IN THE CURRENT STUDY. It makes up about half the data, in fact. Thus we are not talking about independent replication, which apparently was not even attempted (or at least no such results were included). If you make the argument that increasing the case numbers identifies more significant loci, then why wouldn't you expect the previous 12 loci to be confirmed? Without even considering population stratification issues, if you have 12 loci with low p values for correlation, you are bolstering the dataset. The fact that half the loci did not retain significance should sound alarm bells. 

Similarly, it is assumed that increasing case size would increase the identified h2 heritability related to genes. Let's see how that turns out:

The SNP heritability (h2 SNP) was estimated to 0.14 (s.e. = 0.01), which is lower than the previously reported h2 SNP of 0.2214. The h2 SNP for iPSYCH (h2 SNP = 0.23; s.e. = 0.01) was in line with the previous finding, but lower h2 SNP was observed for PGC (h2 SNP = 0.12; s.e. = 0.03) and deCODE (h2 SNP = 0.081; s.e. = 0.014). Between-cohort heterogeneity in h2 SNP is not unusual and has been observed for other disorders like e.g. MDD <Major Depressive Disorder>.

One interpretation of this finding, apparently not occurring to the authors, is that the positive findings they have are little more than population stratification, and even in relatively homogenous (white European) cohorts, such pop strat loses its strength from one study to the next. It is a bit amusing that the counter to this is that it was observed in MDD, circularly assuming that both are valid. In other words, getting contradictory results for other diagnoses validates that it should be expected for ADHD. They, in fact, double down on this dubious argument:

The observation that previously identified loci may not reach genome-wide significance in a subsequent larger GWAS, has also been seen for other psychiatric disorders, e.g. bipolar disorder, where eight out of 19 loci were significant in a subsequent larger study.

It's hard not to laugh, and I'll point out that the "larger" GWAS for other disorders like bipolar disorder also had this contradiction even though they were also using data from the studies that first "discovered" the loci.  

Much of the rest of the study involved "enrichment," statistics, making the argument that cognitive related genes are more common among the significant loci. This is impossible to critique without access to the methods used. However, I would ask the authors to consider whether the 6 loci that did not remain significant were claimed to be enriched in previous studies? Is this an indication for the loci being valid, or is this an indication that these enrichment statistics are misguided?

 

 

 

GWAS Meta-analyis for Bipolar Disorder Gives Glowing Analysis, but is impossible to Interpret (Again)

 A brief review of this GWAS for Bipolar Disorder:

Genome-wide association study of over 40,000 bipolar disorder cases provides novel biological insights (Mullins et al. )

Like almost all the behavioral genetic GWAS studies, this one uses a meta-analysis, despite having new data added to previous data and the new data was never assessed (at least in print) independently. Thus, it is difficult to assess statistically what is success and what is failure, although it is filled with the usual accolades:

This GWAS provides the best-powered BD polygenic scores to date, when applied in both European and diverse ancestry samples. Together, these results advance our understanding of the biological etiology of BD, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

 Well, the best and the only, really. But, of course, I have a lot of questions. The first is related to their significant loci count, and for which I needed partial clarification from one of the authors, as I will discuss after the fold (click "read more" to continue).

My Four Laws of the Behavioral Genetics Fallacy

 I discussed these in more length, here as a response to Eric Turkheimer's Three Laws of Behavior Genetics. But just wanted to lay them out in one short post (credit Turkheimer for the second, which is his third).

My Four Laws of the Behavioral Genetics Fallacy:

1. Any behavioral trait studied within a society will be correlated genetically to specific subpopulations, regardless of whether these genetic correlations are directly related to the trait.

2. A substantial portion of the variation in complex human behavioral traits is not accounted for by the effects of genes or families.

3. Differences in human behavior, intelligence and personality are not accounted for by structural or functional differences in the brain.

4. Advancements in understanding human behavior and psychology require inner exploration from the scientist, the subject or both.

Some Comments on "The Three Laws of Behavior Genetics" (and the two other laws)

Twenty years ago, Eric Turkheimer wrote an often cited paper titled:

Three Laws of Behavior Genetics and What They Mean

This paper is still often cited today and perhaps has taken on a life of its own, with a more deterministic interpretation than Turkheimer apparently intended and for which he recently clarified in a blog post his original intent. Nonetheless, much of the criticism of his paper comes from those in the genetic determinism camp, with the extremes being the "race scientist" crowd. So, since I sit on the other end of the see saw from the genetic determinists with Turkheimer poised somewhere in the middle, I will weigh in with my own thoughts about his three laws, as well as the two additional non-Turkheimer laws added into the soup. In the process of this, I will posit my own Four Laws of the Behavioral Genetics Fallacy. First, let's lay out the three laws that Turkheimer posits:

First Law. All human behavioral traits are heritable.

Second Law. The effect of being raised in the same family is smaller than the effect of genes.

Third Law. A substantial portion of the variation in complex human behavioral traits is not accounted for by the effects of genes or families.

I agree with perhaps one and a half of these laws. I’ll start with my half agreement with the First Law. For starters, I take issue with the use of the term “heritable,” because the term predates genetics and has had many different meanings and interpretations over the years, as this article points out:

The term ‘heritability,’ as it is used today in human behavioral genetics, is one of the most misleading in the history of science. Contrary to popular belief, the measurable heritability of a trait does not tell us how ‘genetically inheritable’ that trait is. Further, it does not inform us about what causes a trait, the relative influence of genes in the development of a trait, or the relative influence of the environment in the development of a trait.

Is This a Successful Study for Bipolar Genetics? That's how they are billing it.

A "new" GWAS came out for Bipolar Disorder. As yet, I have only seen the abstract, but I wonder whether I need to see more? Let me comment on a few things:

"Eight of the 19 variants that were genome-wide significant (P < 5 × 10−8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity."

Is that really what it's consistent with? If you have variants that were found to be significant in previous studies and you include the data from those studies in your current study, even if the effect size was small (and, the power now increased), you should expect most of them to retain significance, even if they weren't significant in the new data set independently. The fact that half of them have lost significance is a good indication that most or all of them were false positives to begin with. Moreover, once again, why not do an independent GWAS (I'm assuming they did not) of the new data and compare it to the old data?
Now let's look at the very next sentence:

Genes for Ice Cream Flavor preference...

Yes, the bar gets lowered once again as it approaches a Coke vs. Pepsi gene.  This time we have a "study" that purports to find genes for a preference for chocolate vs. vanilla ice cream (and strawberry, of course).  I know, you are thinking I'm making this up, so here it is.  I'm pretty sure, back in the day, I considered using exactly this possibility to mock these studies, but opted on "finding raisins to be tasty."  I'll get a little bit into the study, but first, let me ask anyone reading this to try to catch yourself in that moment between when something absurd was stated and when you convince yourself that it is somehow valid because, you know, it's science and all.  I like to call that the "Emperor has no clothes!" moment.  Maybe that moment has already passed you by, so try, really try, to remember how you felt in those few seconds before you had to tuck it away.  That moment is important.  It's the brief time when one can see, no matter how much they've been inundated with "scientific" pronouncements to the contrary, that this entire field of study might just have a kind of absurdity to it.
Can't go there?  Well, then you have to believe that there are genetic variants for preferring chocolate or strawberry ice cream over vanilla.  Lot's of them, in fact.  Or you have to explain why this study is not valid and other GWAS studies are.  Let's go through this important study:

Learning about the elitist opinions of a study's authors through their dubious study

This preprint of an alleged "study, " "GENETIC CONSEQUENCES OF SOCIAL STRATIFICATION IN GREAT BRITAIN", is the kind of filth that has only been suggested in previous studies, but apparently they are feeling puffed up enough to just go full-on eugenic.  I realize that they believe that what they are saying is backed up by genetic evidence, but that's what the phrenologists thought, as well.  Realistically, I can't fully dispute all of the claims, as I am not familiar enough with the geography of England and the socio-economic aspects of their society.  Nonetheless, it's not hard to see what is happening here, if one really wanted to see it, which is that their beliefs about the genetics of superior sorts (i.e.,  people more like them) are causing them to miss the forest through the trees in terms of stratification of a society.  I am quite confident that I can tell you the authors' politics, socioeconomic and geographic backgrounds and opinions about various mental illnesses, without having met any of them.  It is an elitist view of the world, written by elitists, for the pleasure of other elitists.  They should be ashamed.  So, let's go through this, shall we:

New Depression Study Finding 102 Variants. What is Replication?

A new Depression study claiming 102 genetic variants has just come out (pre-publish).  I don't want to do an extended critique, so I will stick to a few main points:

More Risk-Taking genetics

I will make a quick point related to this study:
Genetics of self-reported risk-taking behaviour, trans-ethnic consistency and relevance to brain gene expression (Strawbridge, et al.).

The study notes 8 novel loci for this so-called "risk-taking behavior" (diagnosed by asking people one question: “Would you describe yourself as someone who takes risks?”), as well as noting "...two replicated previous findings."  My quick point is that the 2 "replicated" SNP's were from a previous study by the same author using the same UK Biobank dataset (which has expanded since the last study from a few months ago).  Obviously, you would expect some "replication" when using overlapping datasets.

In short, no independently replicated SNP's from previous studies of this ilk, and some of the SNP's, even bolstered by using some of the same data, were not replicated.  Moreover, no independent analysis of the new data, which was simply folded into the old study in a meta-analysis type of format.  Again, in an attempt to bolster N, the study did not look at the new data independently.  

I might add to this critique when I've had more time to examine it in detail. 

Genes for loneliness, health club attendance, bar hopping and churchgoing, all in one study!

I am attempting to critique this study:

Elucidating the genetic basis of social interaction and isolation (Day et al.)

There are many directions I can go with such a critique.  The most appealing and easiest, would be to mock it with a couple of quick quotes and be done with it.  Then, I think to myself, are there people out there that take a study like this seriously?  And, of course there are a lot of people who take a study like this seriously.  

I'm hoping, though, that there are a few scientists who have been holding onto these GWAS studies as some sort of proof of all kinds of mental constructs, who might have a bit of a crisis of confidence when reading something like this.  Perhaps they would like to dismiss this as an outlier, or misguided in some way.

Here's where they have a problem.  Because, this study was done by the book.  It has all the elements used to prove that there are genetic associations for these traits, just as studies are done to find associations for IQ, mental disorders, and personality traits.  So if you are touting GWAS studies related to any of these traits, you need to explain why your study is good and this one is ridiculous, or you need to embrace this ridiculous study.  There is no in between.

With that in mind, I will go through how this study follows the same formula as your cherished studies and you can decide which side of the health club attendance gene fence you sit on.

Are you Hangry?...

I hesitate to go after studies that have a ridiculous enough premise to start with, but after critiquing GWAS studies, they are all starting to sound a bit ridiculous and I think we have a bit of a slippery slope, where there is this idea that a gene can be found for just about anything you can conceive of.  Do you like raisins?  Maybe there's a gene for that.  Do you think elephants are simply beautiful?  Perhaps it's a gene that makes you think that...
So here is a real study that was done to determine whether there is a gene for getting "hangry."  What is hangry, you might ask?  Well, of course it is the propensity to get angry when you get hungry.  Get it?  Hangry...   Here is a link to it so that you don't think I'm making it up
In any case, I'll take it on...

Another GWAS meta-analysis that suggests replications when the opposite is the case

"Since the discovery of general cognitive ability (or ‘g’) in 1904..."  (When I read a sentence like this, I am already a bit leery of what will come next.)

This critique is for the following study: 

Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.  Gail Davies, et al.

This study is a meta-analysis of several studies I have already critiqued, here, here and here, as well as some new cohorts.  If I understand correctly, the new ones are the CHARGE and COGENT cohorts, but  in any case, it does not appear that any of the new datasets were ever studied independently related to cognitive ability and were simply added to the N of the meta-analyis.  I have a problem with this, which hopefully will become obvious as you read this critique. 

A Quick Review of a Dyslexia GWAS study claiming two significant loci

I will try to trim this review down to its barebones for an easier read, but welcome any comments or clarifications.  The study in question can be found here.

Genome Wide Association Scan identifies new variants associated with a cognitive predictor of dyslexia 

The study is on a much smaller scale, with only a few thousand cases, so one might expect fewer false positives.  In this case, likely we have two.

Another Genetics and Intelligence GWAS/Meta-Analysis

I have been hoping to look at more studies based on intelligence and genetics, and tried to reach out to scientists and authors touting genetic evidence for intelligence to cite specific studies that they find convincing.  I have received no reply to my request, so for now I will pick and choose as I see fit.  I take, and prefer, requests, however.

This critique is for the following study:

A combined analysis of genetically correlated traits identifies 187 loci and a role for neurogenesis and myelination in intelligence (Hill et al., 2017)

It is another GWAS/meta-analysis study.  Anyone who is following my critiques on this blog will probably assume, correctly, that I am going to harp on the lack of a random control.  I'll get to that, but wanted to make a few comments, first.

Another Depression GWA/Meta-Analysis claims 44 risk variants for Major Depressive Disorder

This is a critique of this study, titled:   

Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depressive disorder

After only a couple of weeks and, now, my 6th critique of a genetic study, I once again have the same issue before I even get started on the study:  There is no randomized control.

Educational Attainment genes or a whole lot of nothing

I took a look at this study, because I was told that there are some really fantastic studies related to genetics and intelligence/educational attainment that have come out since 2015.  This one is from 2016.  I am very unimpressed:

Genome-wide association study identifies 74 loci associated with educational attainment

Each of the studies I've looked at so far involving GWAS have a fundamental problem right up front and this one is not an exception.

Depression GWAS Study, 2018

This will be my first critique of a depression GWAS study (Link Here):

Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathway (Howard, et al.)

Let me start by discussing the first sentence of this study:

"Depression is a polygenic trait that causes extensive periods of disability. Previous genetic studies have identified common risk variants which have progressively increased in number with increasing sample sizes of the respective studies."

Risky Business: Making your own diagnoses, backed by hundreds of false positives.

For the same reasons that I am hesitant to waste time on silly studies, I think it is worthwhile to not let these things go unchecked, and I'm not seeing anyone else trying to debunk this foolishness, so in addition to more traditional studies, I will take what I think is a much needed critical eye to a study  like this one:

Genome-wide study identifies 611 loci associated with risk tolerance and risky behaviors

GWAS/Meta-Analysis 78,308 (Sniekers): A critique of this study claiming numerous genetic correlations to intelligence

Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence

 I had someone cite this study as strong evidence for specific genetic linkages to intelligence.  I'm getting a lot of, "A lot has changed in the field lately," types of comments, which are maybe a bit condescending, but not entirely off base.  To be honest, I'm surprised at how little change there has been since I was critiquing these studies 15 to 20 years ago.  They still jump to the same conclusions.  They still have no sense that their studies are producing false positives.  Some of the terminology has changed and, really, they are a bit overly technical and harder to read (or I'm just getting older).  Despite the fact that I disagree with the conclusions of this study, as I will lay out shortly, there is something to be said for dumbing down your points a bit, unless your goal is a bit of technical obfuscation (not accusing, just saying...).

The "Merit" Genes

This paper, entitled "Genetic influence on social outcomes during and after the Soviet era in Estonia,"  purports to show that, after the fall of communism in Estonia, genetically superior individuals were able to rise to the top, because the new capitalistic society was based more on merit (meritocracy).