Thought Experiment on Genetics and Society

I did something like this on Twitter, but will expand it here:

Let's say we live in a society where all the citizens are genetically identical (1 male and 1 female genetic code) and further that progeny, through laboratory manipulation or the like, retain the same genetic code from one generation to the next:

Will there still be a social hierarchy in such a society? Wouldn't a society require professionals and a working class. If it was along the lines of our current system, some would be doctors and some janitors and some field workers. Would those born to wealthy and well educated families have a leg up in also achieving educational and professional success? Might one also expect some homeless, some people with substance abuse problems, some people who are unhealthy? Some who turn to a life of crime? Some who would be humanitarians? Would there not eventually be wars and some way in which groups would be prejudiced towards other groups? Would people be more alike, or would they go out of their way to differentiate and be even more diverse in personality?

This is all quite obvious, isn't it? Gene hunting is not going to uncover human nature. We are human beings first. For the most part, genes simply display the costume that each of us wears. The exceptions to this fact are simply that: exceptions.  Marking people's personal traits by identifying generally unrelated genetic variations does little more than create meaningless divisions in our society and a perception of humans as genetic automatons.

"Educational Attainment" and the Wobbly Null

New study related to genetic studies of Educational Attainment:

Avoiding dynastic, assortative mating, and population stratification biases in Mendelian randomization through within-family analyses

Like a previous study, it makes the point that within family analysis significantly "attenuates" the educational attainment, in this case related to correcting for height. Here's the rub, though. In the previous study, the fact that EA was significantly diluted by within family results was somehow lauded as a demonstration along these lines: "At least there is still something, so it proves there is some genetic component to EA." This study, however seems to take the opposite approach:

The Mendelian randomization estimate using the sample of unrelated individuals implied that each 10 cm increase in height caused an increase of 0.17 (95%CI: 0.14–0.20, p-value = 8.5 × 10−26) years of education. After allowing for a family fixed effect, the Mendelian randomization estimate was greatly attenuated suggesting little evidence of a causal effect of height on education

In this case, the attenuation was taken as evidence of a null value, to demonstrate that they were able to get the pop strat out of the picture. However, if something like height has even a small effect on EA and the tiny results for genetic variants for EA after within family analysis, then it's worth asking whether there are any actual genetic variants related to someone being better or smarter in a way that allows them to get more education (c'mon, this should be obvious), or whether there are just a few physical confounders giving us the slight variance accounted for. You can't have it both ways.

Genes for Substance Abuse Has Made No Progress, but Unjustified Optimism Continues

Yet another genetic study of substance abuse:

Using polygenic scores for identifying individuals at increased risk of substance use disorders in clinical and population samples

Highlights:

These PRSs explain ~2.5–3.5% of the variance in AUD (across FT12 and COGA) when all PRSs are included in the same model. 

...usefulness for identifying those at increased risk in their current form is modest, at best 

This was from an all white European sample, ftr, with the assumption that pop strat is accounted for. One can assume, as has been the case, that such pop strat will be found and water this down to next to nothing. That said, is the null 0% or is 2 or 3 % about as low as you can get? I'd be happy to see an example in which a PRS does worse than this.

So is the conclusion that perhaps we are barking up the wrong tree? Of course not:

 Improvement in predictive ability will likely be dependent on increasing the size of well-phenotyped discovery samples. 

The shell game continues...

Nice piece on genetic correlation vs causality

This piece:

What Causes Genes?A genetic association doesn't necessarily mean a genetic cause.

Gives a good overview of why genetic correlations don't necessarily live up to their billing. (From Jaime Derringer, Ph.D.).

Addendum: As a reader mentions, this piece was apparently inspired by this study:
Population phenomena inflate genetic associations of complex social traits.

From that paper:

In conclusion, our results demonstrate some of the causal structures that may bias univariate and bivariate genetic estimates such as heritability and genetic correlations, particularly when applied to complex social phenotypes. 

Study Showing Weakness of PGS, even within ancestry

I already put up a blog post on the preprint of this new study last year:

Variable prediction accuracy of polygenic scores within an ancestry group

Here is the Abstract:

Fields as diverse as human genetics and sociology are increasingly using polygenic scores based on genome-wide association studies (GWAS) for phenotypic prediction. However, recent work has shown that polygenic scores have limited portability across groups of different genetic ancestries, restricting the contexts in which they can be used reliably and potentially creating serious inequities in future clinical applications. Using the UK Biobank data, we demonstrate that even within a single ancestry group (i.e., when there are negligible differences in linkage disequilibrium or in causal alleles frequencies), the prediction accuracy of polygenic scores can depend on characteristics such as the socio-economic status, age or sex of the individuals in which the GWAS and the prediction were conducted, as well as on the GWAS design. Our findings highlight both the complexities of interpreting polygenic scores and underappreciated obstacles to their broad use. 

Damning on its face, but the authors appear to not want to give up the ship, and give only a few passing mentions of pop/strat and other confounding issues with these large genetic databases. At what point do you reject the model if the studies aren't giving you the expected results? Time will tell...

More Bias in DNA databanks.

This study:
Genetic analyses identify widespread sex differential participation bias
is yet another example of the bias problems in these large consumer and other databases. This one looked at several, including 23andMe and the UK Biobank.
With 23andMe, a GWAS just for "male vs. female" had 150 "signficant" loci and many of these loci were previously correlated to complex traits from other GWAS that used the database. This is a problem, because it suggests that many of the previously discovered loci for particular traits might actually just be an indication of bias in the databank and have no causal relationship to the trait as the authors point out:

Finally, we demonstrate how these biases can potentially lead to incorrect inferences in downstream analyses and propose a conceptual framework for addressing such biases. Our findings highlight a new challenge that genetic studies may face as sample sizes continue to grow.

A broader problem related to this is... Every GWAS performed to date using the biased databank, since this form of bias was not recognized when those studies were performed. I don't expect it to happen, of course, but this should lead to a reevaluation of any GWAS previously performed using the database with a correction that will further dwindle the results. Sex differences is an easy to recognize bias to test for, but there are no doubt many more that remain unrecognized and the fact of the matter is, that you will never  be completely sure you have eliminated them all, so you can never say for sure whether you are finding anything but noise in these studies (I think that is the case, for the record, with behavioral genetic phenotypes). So in addition to population stratification issues in these studies, which also never seem to be fully recognized, the databases themselves have their own stratification issues.

Interesting Update: Another study just came out that incidentally looked at the same thing in the UK BioBank. This one found NO hits. I think this is likely a good demonstration of how participation bias created a very large number of false positives (23andMe) vs. the UK BioBank, which perhaps didn't have the same participation bias and shows that a large number of "significant" hits can be produced simply with noise. Again, we are left with the question of whether anything from these studies are true genetic correlations.

The Trickle down of GWAS to Race Science

I like to point out that many of the genetic studies related to "IQ," "g" and "Educational Attainment," whether or not their intentions were good, tend to attract racists of varying degree, from the smooth-talking race scientists down to white nationalists and overt racists trying read the study as a whites are smarter than blacks because of their genes misinterpretation (leaving aside the fact that most of the studies are unreplicatable). This study which examines which people tend to pick up particular studies on social media sites like Twitter quantifies this and notes:

Our study provides conclusive quantitative evidence that white nationalists and adjacent communities are engaging with the scientific literature on Twitter. Not only are these communities a ubiquitous presence in the social media audience for certain research topics, but they can dominate the discourse around a particular preprint and inflate altmetric indicators.

Often, once this process begins, the scientists involved in the study and other experts in the field attempt to debunk this misappropriation of the science. Unfortunately, this does little more, in my view, than amplify the debate in a "both sides" dichotomy, effectively giving credence, or at least attention, to the racist views. While scientists will try to defend or find a use for such studies to justify their existence, these are often a reach and fall flat, leaving one to ask what purpose they serve other than to energize racists? 

Genes for Getting Beaten Up or Mistreated as a Child (Yes, this is a real study)

This is an actual genetic study to which some people are proud to have their attached:

Genomic influences on self-reported childhood maltreatment

The study failed to replicate (big surprise), and is entirely bogus and I could go through it and pick it apart but, instead, I am just going to say that the implication here is that there are genes for getting beaten up as a kid. I guess, that's what they are trying to say, anyway. I am just going to say that I find this disgusting and refuse to even engage with it further. The authors should be ashamed of themselves for printing it. I'll also point out that this is another example of a UK Biobank study where the application for the use of the database was deliberately vague. If you need to use subterfuge to get your study printed, then you are being doubly unethical.  Hopefully, as noted in my previous post, this type of drivel will be prevented from further use of the UK Biobank.

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. 

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?

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:

IQ and longevity claim takes a hit

This paper  calls the lie on this paper:

Arden et al.  The association between intelligence and lifespan is mostly genetic Int J Epidemiology

The claim was not only that IQ was associated with a longer lifespan, but that "genes for IQ" (a fantasy of the IQ people) were directly correlated with longevity.  Great read.  It's all starting to collapse.

Blueprint?

My review of Robert Plomin's, "Blueprint:  How DNA Makes Us What We Are".
(If you are on a tablet or phone, it's easier to read the PDF format)

Yet More Evidence that PRS is Largely a Measure of Population Stratification

Here is another study pointing to the lack of validity of polygenic risk scores.  This one was for height:

We find that the signals of selection using UKB effect-size estimates for height are strongly attenuated or absent. We also provide evidence that previous analyses were confounded by population stratification Therefore, the conclusion of strong polygenic adaptation now lacks support. 

If you aren't able to control for population stratification for something as straight-forward and quantifiable as height, then certainly you won't be able to do better with "Educational Attainment" or really any more complex psychiatric trait or mental construct.  The null here, is that polygenic scores largely measure population stratification and I would be interested in what could be demonstrated that would lead one to reject the null.  Moreover, the failure of PRS also brings into question the polygenic (and, presumably omnigenic) models for phenotypes. 

Stratification and PRS Difficulties

It is becoming clear that population stratification is  a big issue in when assessing polygenic scores.  This study demonstrates:

 Our results emphasize that we have limited understanding of the interplay between our current PS and genetic population structure even within one of the most thoroughly studied populations in human genetics. Therefore, we recommend refraining from using the current PS to argue for significant polygenic basis for geographic phenotype differences until we understand better the source and extent of the geographic bias in the current PS.

Much of the work on this study involved height, so drawing conclusions about more complex mental traits would be even more confounding.  (Would be useful to have a better understanding of the differences in population between Eastern and Western Finland). 

McCRISPR and the Collective Sanctimony of the Scientists Who Made it Happen

I don't want to add too much to the obvious ethical lapse of the recent CRISPR human guinea pig experiment by Chinese genetic scientist, He Jiankui, as there is an endless stream of outraged scientists, exemplified by this article in Nature: CRISPR-baby scientist fails to satisfy critics. I would, however, like to make a point about the collective scientific outrage, exemplified by a few quotes in the article linked above:

“I’m happy he came, but I was really horrified and stunned when he described the process he used,” says Jennifer Doudna, a biochemist at the University of California, Berkeley, and a pioneer of the CRISPR–Cas-9 gene-editing technique that He used. “It was so inappropriate on so many levels.”

So, it was "the process he used" rather than what he did.  If only he had used a more appropriate process.  Let's look at another quote:

Longevity "genetics" appears to be strongly inflated due to assortative mating

This study just came out which used the Ancestry database to assess the genetic heritability of longevity, which has been previously formulated as upwards of 15 to 30%.  They found that, in fact, taking away assortative mating it is below 10%.  They used pedigrees and compared the in-law siblings.
A GWAS in such a scenario, then, would pick up a lot of extraneous, noncausal genetic associations that were really just related to commonalities from assortative mating, leading one to believe that these genes had some specific role for longevity and possibly wasting a researcher's time.
I would be interested in seeing a similar study on educational attainment, as I think it might very well show the same thing.  I have, in fact, postulated just this in previous posts on here.

A Recent Critique of PRS

This preprint (updated) does some mathematical modeling and shows that PRS, even with h2 = 1, is not as useful as previously thought.  I'll spare you the math (which I'm still trying to wrap my head around) and leave you with their conclusion:

"In summary, our investigation clears up some misconceptions on PRS and demonstrates that PRS is not as useful as its name suggests, and as powerful as the genetics community expects neither for predicting polygenic traits. We hope this research will serve as a wake up call to the genetics community in appreciating more about the challenges in studying complex polygenic traits. As such, more resources and efforts can be devoted in performing better experiments and developing better statistical methods." 

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:

"Minimal Phenotyping" to crank up your GWAS hits creates more problems

This study points out that minimal phenotyping (dumping anyone into your GWAS with a 1 or 2 question screening rather than meeting full diagnostic criteria) for major depression is getting hits that are then tied to CNS enrichment (genes found more commonly in the central nervous system, implying some brain mechanism), but the ones that were "enriched" were actually the extra ones picked up by minimal phenotyping.  This is a problem, because CNS enrichment would be expected to be more prominent for those who met the full criteria for MDD, rather than just answering a couple of questions about depression.  This implies that there are likely false positives, or at the very least, non-specific positives, unrelated to major depression.  Thus, when you try to isolate functional neurological aspects of the disorder, either to understand cause or pursue pharmaceutical options, etc., you are likely barking up the wrong tree.  CNS enrichment is also used as a backdoor method to imply the validity of the genetic variants found in particular GWAS studies related to mental disorders.
So, adding to the fact that there have been no independently replicated, significant genetic variants found for depression, to date, even with minimal phenotyping, we also cannot confirm that these genes have any relation to depression by assessing CNS enrichment.

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: