My Letter to the UK Biobank

I will update with any reply from them: Update: Reply after the fold - exactly what you would expect ... Double Update: I have deleted the tepid e-mail I received and attached the e-mail that the UK Biobank sent to researchers which appears to lay down the hammer on these shenanigans. Kudos to the UK Biobank and I hope that their actions will match the sentiment of their e-mail.

My Letter:
To Whom it May Concern:

I am writing this letter to express my concern over an apparent misuse of the UK Biobank. I am referring specifically to this study: https://www.nature.com/articles/s41467-019-13585-5

Genome-wide analysis identifies molecular systems and 149 genetic loci associated with income

It is my understanding that the UK Biobank was conceived to identify health issues related to genetics and one would presume that the majority of those who have provided DNA and other information about themselves, did so altruistically, with the understanding that it would be put to such use in order to aid in the discovery of new disease treatments and to improve health care for the citizens of the UK and beyond. Therefore, I find it rather disturbing that a study that purports to find genes related to a person’s income is given the use of the UK Biobank to make such an analysis. Such studies contain more than a hint of eugenics, and promote the harmful impression that a person’s income is somehow related to their genetic endowment which, among other issues, has political implications related to the current economic system, its validity and fairness.

This study appears to be related to other studies that have utilized the UK Biobank, with many of the same authors, that try to identify genes for “intelligence” and “educational attainment.” Clearly, such studies have created a slippery slope for this type of dubious science to seep into general acceptance and I think they cloud the original intent and purpose of the UK Biobank. Such studies have a sordid history, often embraced by those with a racist agenda, and judging from the interest it is garnering on social media sites, this study is no exception. One might wonder whether the Biobank volunteers would reverse their consent if they understood that their DNA information was being accessed for these dubious purposes.

Moreover, while such studies are nicely self-serving for the highly educated, high-income scientists who perform them, it would probably come as no surprise to most in the UK that the genes particular individuals possess have an influence on how much education and income they receive, considering the long history of social class stratification and the likelihood that such genes are nothing more than identifiers of particular social and racial categorizations, wherein their “income” is heavily influenced by which of these categories they are identified with, rather than some sort of magical genes that provide an entrepreneurial advantage for a select few. There is simply no reason that such studies should be given access to the UK Biobank. They create harmful and erroneous perceptions and divisions and turn the UK Biobank into a political entity rather than an aid to human well being.

In addition, and most importantly, it appears that the authors of this study deliberately misrepresented their intent, claiming that their study would be used to determine “The relationship of cognitive function and negative emotions with morbidity and mortality: an aetiological investigation.” This does not appear to be at all representative of the study they performed, as even the title of the study makes clear. They also apparently applied for an extension with the following rationale:

“One outcome we are also interested in exploring in relation to prior cognitive function and other factors is dementia. For instance, we would like to investigate the extent to which prior cognitive function helps predict later onset of vascular dementia independently of other risk factors. We have research experience in the cognitive epidemiology of dementia. This is not an outcome that we specified in our original application so I am writing to ask for approval to expand the scope of our project to include dementias as an outcome.”

Anyone reading this study can see that both of these descriptions have little to do with the true focus of the study and, in reality, are a complete misrepresentation. It seems clear that they were just gratuitously added in order to give the study the kind of authenticity it would need to secure the use of the UK Biobank, with the knowledge that it otherwise did not merit it, or more sinisterly, was part of an attempt to perform a study that would be otherwise viewed as ethically questionable. It is a fraudulent and hubristic maneuver, that shows a disdain for the intent and spirit of the UK Biobank, and is arguably scientific misconduct. Although this and other such studies will pay lip service to health and well-being issues, it appears much more likely that these issues are merely a “Trojan Horse” for their true intent, which is a scientific justification for societal privilege and elitism by way of genetic determinism.

I would like to suggest that the UK Biobank apply more scrutiny to studies of this nature, and ask you to consider preventing the authors responsible for this study from further access to the UK Biobank.

As noted, I removed the intitial response to my e-mail and have provided the e-mail sent out to UK Biobank researchers after the fold:

Perhaps We Have a Use for These GWAS, Afterall

In my last post, I briefly critiqued this study absurdly correlating genetics to income and offered a challenge to the authors. My opinion of GWAS is obvious to anyone who skims through this blog, but it occurs to me that perhaps we might have a use for GWAS, afterall, as I recently tweeted:

Here’s a different take: The extent to which you can correlate genes to income in a society, is a direct measure of the unfairness and class stratification of that society. 

If we assume, as I do, that most genetic correlations in the behavioral genetics realm are due to population stratification, then we know that any genetic correlations would demonstrate ways in which the society is stratified. This could be in obvious ways such as racial delineations, but might also include more subtle classist issues (He/She is not from the right family...) and would be an even better way to measure more covert discrimination. By the way, I think this is provable in the sense that other societies will have entirely different loci correlated to income, a fact that will cause a lot of mental gymnastics to explain away.
If we can't prove the causality of the genes flagged in such studies, shouldn't we assume that they are an indication, of an unfair stratification of the society? If we could rid ourselves of all such genetic commonalities, wouldn't that lead us to a true meritocracy? Therefore, wouldn't it make sense and be more fair to give job and college admission preferences to those with the LOWEST polygenic scores for income? As the very "not racist" individuals who embraced this study and took me to task on Twitter pointed out, shouldn't we pursue the truth wherever it happens to lead?

A Challenge to the "Income" Genes Clan

I was going to do a longer critique of this study:

Genome-wide analysis identifies molecular systems and 149 genetic loci associated with income

However, I do a lot of these and it seems like I  go after each head of a hydra, only to be met with one more absurd than the last.  Instead I am going to say a couple of things and offer a challenge to the authors. This study claimed to have found 30 loci associated with income (29 novel). They then went digging around the UK BioBank, for which many of the authors in this study are all too familiar, and used MTAG for other dubious phenotypes, like "Educational Attainment", and "intelligence" to crank up another 120 associations. Imagine the assumptions of the authors regarding income, our economic system, the illusion of meritocracy, IQ, the primacy of income, and the fantasy that you can add up a bunch of genetic variants and determine the likelihood of a high or low income for a person.

A couple of points about the 30 loci noted above. First, there were only 2 previous loci correlated with this trait in the past. So one of the two was not significant. You might think, well, at least they replicated one loci. However, the previous 2 loci come from a smaller version of the same damn UK BioBank dataset. Thus, even though they were using some of the same data as their last study (yes, same authors, same database), one of the loci didn't reach significance with additional data. So what we really have are 30 "novel" loci, that have never been replicated. This, in my opinion, is what one might view as a "screening study." So, good, go and do a GWAS of an INDEPENDENT dataset that you haven't been turning upside down for the past 5 years and see if any of these same loci meet significance instead of trying every kind of gymnastic exercise to correlate these likely false positives into something meaningful.

In fact, I challenge the authors of this study to do a GWAS for "income" on an independent dataset other than the UK BioBank, which at this point is like playing poker when you can see what's in everyone else's hand, and see if you can even replicate a single one of these loci. I'll even handicap you and say you can use all white people again, but somewhere other than the UK. 

If you can't replicate any of these loci, then admit you are playing a shell game, pack up your shit and go find a real, honest job, instead of fueling the prejudices of Charles Murray and Quillette.

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:

The Intelligence Gene Shell Game

A literature review looking at GWAS for "intelligence" brings home the point I try to make regularly on this blog:

Data on 17 published intelligence GWASs (3 of which reported no associations whatsoever) were downloaded from the GWAS Catalog and analyzed in the current study. Results show a generally low rate of replication: over 87% of the 2,335 included SNPs were reported only once, and only 4 of the 17 studies included follow-up testing in a replication sample. Of these 4, none found any replicable genome-wide significant hits. 

When You Don't Realize You Are a Eugenicist

This study related to geographic stratification of genetic variants had a lot of promise and is actually quite a good source of information, in my view, on the inherent problem with the UK BioBank and population stratification issues that confound GWAS. Unfortunately, the authors take it in a very different direction, exemplified by this quote in a promotion piece written by the lead author:

With this paper, we ended up showing how social stratification in a modern meritocracy makes it increasingly less likely that someone close by shares recent ancestors with you and more likely that they share a genetic talent for socio-economic success. 

This is, to put it bluntly, eugenics. The paper in question shows nothing of the kind. In my view, in fact, it shows the opposite; that this is not a "modern meritocracy," and I think that holding such a belief is a sure tip-off of the biases of the authors in their rather misguided and disturbing conclusions.
Let's take a look at the study with a starting point of assuming that all of the genetic variation seen in "Educational Attainment" is related to population stratification and assortative mating that confounds GWAS (particularly in the UK BioBank).

PTSD and the GWAS Hype Machine

A new PTSD GWAS makes a few bold claims.  I think it's a good example of the kind of hype that these studies, which show next to nothing, crank out to hype their results. In this puff piece related to the study, they start with:

Large study reveals PTSD has strong genetic component like other psychiatric disorders

Which 1. It does not and 2. Is not really shown to be true of other psychiatric disorders, either, except in the same hyped fashion as this study. Now let's look at this from the same puff piece:

The study team also reports that, like other psychiatric disorders and many other human traits, PTSD is highly polygenic, meaning it is associated with thousands of genetic variants throughout the genome, each making a small contribution to the disorder. Six genomic regions called loci harbor variants that were strongly associated with disease risk, providing some clues about the biological pathways involved in PTSD.

 If it is highly polygenic, on what basis are they saying this if only 6 loci were strongly associated with disease risk (this is not even accurate, as I'll discuss in moment)? "Genome-wide, a substantial number of variants had some level of association with PTSD, showing the disorder to be highly polygenic," What this is saying is that there are other loci (presumed genetic variants) that did not reach significance, but they include through the subterfuge of "polygenic scores." There is no basis, other than the hopefulness of those doing these studies, that these below significant findings are anything more than non-significant findings. I'll  also note that none of these 6 loci were found in previous studies. Thus, this is an entirely unreplicated study. Now, let's take a look at the loci they did claim to find:

Depression and Bipolar: Looking at the Positive While Inadvertantly Demonstrating the Negative

I wanted to critique this study which I admittedly struggled to get my head around, so I needed to get help from one of the authors on Twitter. In short, it takes data from two previous studies of depression and bipolar disorder and recombines them. Here is his given explanation:

The combination of the MDD and the bipolar data (which have not been combined in this way before). That is, we are seeing some loci have statistical evidence for "MDD or bipolar" versus control individuals that we haven't seen when looking at either individually so far.

I'm not really sure if that is what they established even on its face since, as I understand it, they simply combine the data from the two studies and perform new GWAS's for both Bipolar Disorder and Depression, creating a new case vs. control for both (I welcome the authors giving a better explanation than I'm putting forth, lest I be accused of creating a straw man. I really just don't fully understand the underlying premise). In doing so, they came up with 15 new loci related to these disorders without using any new data. I believe the point here is to show that bipolar disorder and depression have some genetic commonalities that were demonstrated. They go on to assess these further, but I suggest maybe the lede was buried here and that the study demonstrated another, perhaps more plausible, conclusion: That the original significant loci were false positives, as are these. Let me explain below the fold:

Here Come the Gay Genes

This is a new GWAS related to homosexuality or "same-sex, sexual behavior" as they describe it. Before I even begin this critique, I'll point out the obvious-to-ask question from any such claim, as noted in the study:

We observed in the UK Biobank that individuals who reported same-sex sexual behavior had on average fewer offspring than those of individuals who engaged exclusively in heterosexual behavior... This reproductive deficit raises questions about the evolutionary maintenance of the trait, but we do not address these here.

Yes, it certainly does raise that question. I understand that a thousand explanations have been thrown out for this, none of which has any evidence to back it, and suggest the possibility that we are working with an absurd premise.
Now let's go back to the description of "same-sex, sexual behavior." By what  criteria do we group some kid who, say, had one same-sex sexual experience at summer camp with someone who identifies as homosexual. You would group such and individual as "non-heterosexual"? That seems a stretch and ignores their self-identification. Is there some causal relationship between these two things, genetic or not? I don't think anyone could realistically group these individuals together for a study of this nature. I question even doing a study of this nature, but I think that one would want to first identify individuals that are clearly homosexual rather than confound the study with what might largely be a culturally related experimentation phase.
Once again, I might add, the UK BioBank has been noted in a few recent studies to be replete with population stratification issues, notably related to age and it is noted that young people who participate have higher rates of a same-sex experience. I won't get into too much detail along these lines other than to suggest that such population stratification could easily account for the few significant loci that were found. Now, let's look at some of the numbers and the dubious claims of replication behind the fold:

PTSD GWAS: Another fast and loose with the term "Replication"

This study, a GWAS for PTSD (or symptoms related to PTSD, might be more accurate), like most found a few loci with significant p values. They found 8 in a sample of 120,000 "European Americans" and zero in a sample of 20,000 African Americans. I'd say this is what you might expect for the false positive rates of such studies. They go on to claim that it was "replicated in the UK Biobank." I'll make a quick point after the fold:

Another Unreplicated, hyped study of Anorexia Nervosa

This post takes a quick look at this GWAS study for Anorexia Nervosa. Let me start this off by saying that Anorexia Nervosa is quite clearly a disorder created by our society and compounded by particular childhood trauma issues that I won't get into here. Moreover, looking at this disorder as some kind of metabolic disease and trying to pass it off as a genetically based disorder is very unfortunate and I think shows some real lack of understanding of clinical disorders, and bizarrely reduces it to chemical mechanisms.  In the long list of authors for this paper, I would hope at least a few have some actual clinical experience with this disorder, but you wouldn't get a sense of it from the paper.
Now that I got that out of the way, let me briefly discuss the paper itself, which follows the usual formula for GWAS these days:

Question:
Does a dog or a bumblebee have a higher IQ?

Conjuring some within-family pop strat

Are you ready to hear something? I want you to see if this sounds familiar: any time you try a decent crime, you got fifty ways you're gonna f**k up. If you think of twenty-five of them, then you're a genius... and you ain't no genius. 

-Mickey Rourke to William Hurt in Body Heat

In a recent Twitter discussion, wherein I suggested that "Educational Attainment" GWAS/PGS are largely bogus, bolstered by population stratification and assortative mating, someone noted:  "Sooo, you'll bet against EA3 explaining even 1% in any new European sample within families?" The implication here is that, despite the many studies coming out lately suggesting the extent to which polygenic scores are subject to stratification issues, if even 1% is explained in a "within family" PGS, then at least something is genetic. This is quite a lowering of the bar from the supposed 13% from EA3 (the third large educational attainment GWAS study), which I assume from some of the recent studies (here and here), they see dwindling away. Anyway, something is better than nothing, so this is a way to suggest "something" is there. Certainly, when looking at "in family" GWAS/PGS, you are going to expect significantly less population stratification, since you are looking at individuals that share the same parents, upbringing and DNA.  For example, a recent study showed significant attenuation when looking at "in family" (which surprisingly, considering the authors, they attributed to socioeconomic confounders). Nevertheless,  even a smaller percentage is still something and now they might claim, at the cost of a predictive dilution, that they eliminated all stratification issues by using "within-family" analysis. Well, I'm not so sure about that, as I will discuss below the fold.

Another study questions polygenic scores

This new study:

Variable prediction accuracy of polygenic scores within an ancestry group

is yet another in the long line of studies showing that polygenic scores are replete with problems like population stratification and assortative mating. It buries the lede a bit, in that it takes another swing at the so-called "educational attainment" genetics, probably because I sense the authors don't want to completely give up the ship, but let me make a few points about the study.

The Depression Gene that Wouldn't die

This is a good piece about a gene variant that was presumed for a couple of decades to be related to depression, with hundreds of studies surrounding it, leading to more and more theories of how it effects depression. The gene was 5-HTTLPR which is presumably related to serotonin and gave everyone the feels, because it validated the use of Prozac and similar serotonin based drugs. Then it turned out to be bogus. I believe I was asked specifically about this gene in my psychiatry board exam. Another take home message from this is that if you are jumping on some new study purporting to find a gene or genetic variants for a mental disorder, put it in a drawer for a few years and see if it holds up. They never do, but they are never wrong.

Hoping for a House of Cards

I've already done a review of Robert Plomin's "Blueprint," but I take it a step further in this piece in Logos, pondering whether this is really all they've got and, if so, where that leaves the field of psychiatry,  were the whole GWAS/Polygenic Score research behemoth, which has hogged so much of the mental and material resources for furthering the field, finally hits its dead end? You might call it a fantasy piece.

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:

More pop/strat discussion related to polygenic scores

This article in Quanta magazine highlights a couple of recent studies in which population stratification issues are giving artificially inflated polygenic score results that don't subsequently have validity when looking at even a relatively similar population, much less diverse populations.  These were for height, which seems like the most obvious candidate for a genetic trait for which one could get a valid polygenic score, but they had to walk back previous claims.  If they can't get if for height, one should immediately ask why anyone would take such a score seriously for say, depression, or "educational attainment." They are putting a lot of time and effort into these studies and the best they can say to date is that maybe some of the correlations are valid, but pop/strat has not been ruled out as the exclusive cause of all their SNP correlations and subsequent polygenic scores.

Alzheimer's "Genes". Another Faux Replication

I will make the same point for this GWAS for Alzheimer's Disease. Again, we have an example of meta-analysis, with new data that has never been studied independently folded into previous studies with a claim of more loci "discovered" and, as one person noted, "the gold standard in field," for replication.  It's amazing how they have watered down replication and now try to call this a gold standard.

Genetics and the Need for Certainty: Looking at the World Through a Genetic Lens

Wrote this piece for "Ordinary Times" related to my quixotic battles with genetic studies and the overgeneticization of our society (at least that's where it took me).  I was writing for a presumed non-scientist audience, so maybe it will be a little more understandable and less dry for someone who is interested in the basic debate I'm trying to put out there.  Or not...

The UK BioBank: The Beast of Pop/Strat

Here is yet another study looking at population stratification issues related to GWAS studies and polygenic score results: Apparent latent structure within the UK Biobank sample has implications for epidemiological analysis.
They looked at geographic structure and found that the UK Biobank is subject to a lot of stratification in that regard. They looked at BMI (body mass index), household income, and educational attainment and found all of them to be subject to geographic population stratification, even with principle component analysis.  First they looked at a smaller subset of genetic data from a previous study (ALSPAC)

...we anticipate that the educational attainment of people who migrate for economic reasons differs from people who do not. Educational attainment is therefore aligned to subtle genetic differences even in this apparently geographically and ethnically homogenous population and this is co-incident with axes of ancestry.

They move on to the beast, the UK Biobank:

Britain's Private Schools Makes a Point About Population Stratification

This article about the British private school system is not directly related to genetics, but goes to a point I've made earlier about genetic studies of "Educational Attainment" and how they will inevitably be filled with false positives related to population stratification.  Let me start with a quote from the article:

What particularly defines British private education is its extreme social exclusivity. Only about 6% of the UK’s school population attend such schools, and the families accessing private education are highly concentrated among the affluent. 

So we have a closed off group that has better access to higher educational opportunities, and of course there is a big payoff for them as we can see here:

Copy of my Review of Robert Plomin's "Blueprint"

 I'm told that my review of Robert Plomin's "Blueprint" in Free Associations is sometimes difficult to download on tablets and phone, so I will add a copy of it here:

Biogenetic Overreach by Steve Pittelli 

Blueprint: How DNA Makes Us What We Are (MIT Press, 2018) is the latest book by genetics researcher and author, Robert Plomin. It begins with discussions about twin and adoption studies, an area where Dr. Plomin has extensive experience as a researcher. This serves as a springboard for Plomin to discuss DNA research, particularly “polygenic scores,” for which he possesses an almost evangelical zeal. Mixing this with his own research anecdotes and theories about a self-described “DNA Revolution,” Plomin’s meandering narrative is, at times, difficult to follow and has a utopian feel. 

As Plomin acknowledges, much of the early DNA research related to psychological traits (and most traits in general) failed to find specific genes related to the trait in question. When such genes were found, the experiments were never replicated, creating a “replication crisis” in the field. In Dr. Plomin’s view, this crisis was solved by the larger datasets now available and the polygenic score, which “predicts” the likelihood of particular traits by tallying up the number of genetic variants a person has that have been shown to correspond in some way to particular traits. I would suggest that this is a significant lowering of the bar for replication and does not eliminate the crisis. 

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: