A very large genome-wide association study (GWAS) of brain and intracranial size has just been published in Nature Genetics. The study looked at brain scans and genetic information from over 20,000 individuals, and discovered two new genetic variants that affect brain and head morphology, one which affects the volume of the skull, and one of which affects the size of the hippocampus.
The main study is very well carried out, and the two associations look to me to be well established. However, there are a few little things about the paper that, when combined with some biased reporting in the press, that have been bothering me. Firstly, the main result that has been reported in the news is that the study found an “IQ gene”, but this was only a very small follow-on in the study, and the evidence underlying it is relatively weak (certainly not the “Best evidence yet that a single gene can affect IQ”, as reported by New Scientist). Secondly, the authors use a misleading reporting of statistics to hide the fact that one of their association could easily be cause by an (already well known) association to general body size.
Is HMGA2 an “IQ gene”?
The majority of the press around this study has been reporting that it found an “IQ gene”. However, the main part of the study didn’t look at IQ at all, only at various measured of brain size. The authors followed up their findings in a small subset of their data (1642 individuals) to see whether their two identified variants were correlated with IQ. One of them, a variant in the gene HMGA2, was found to show weak evidence of association with IQ, increasing it by an estimated 1.29 points. However, the degree of evidence for IQ association was much weaker than for intracranial volume, and could easily be a false positive (presumably why it wasn’t heavily emphasized in the paper itself).
There is further evidence that this association may not be real. The largest (I believe) genome-wide study of the genetics of IQ, published in Molecular Psychiatry last year, listed about 200 variants that showed even weak evidence of association to IQ. No variants in or near the HMGA2 gene were included on this list. Most common variants that increased IQ by more than about 1 IQ point would included on this list, suggesting that the HMGA2 either isn’t associated with IQ, or the strength of the association has been overestimated.
Combining the data from these two studies would have given over 5000 samples, which would be big enough to be properly test the association to IQ for the HMGA2 variant either way. Perhaps someone will do something like this soon – until then, I would not treat the HMGA2 as an established “IQ gene”.
Is HMGA2 actually a gene for general body size?
The variant in HMGA2 has previously been shown to be associated with height. An obvious question is whether this variant directly affected intercranial volume, or whether it just affects general body size (taller people have bigger heads). The authors state:
Structural equation modeling showed that the effect of rs10784502 [the HMGA2 variant] on intracranial volume could not completely be accounted for by the indirect effects of this SNP on height or by the correlation between height and intracranial volume
It always pays to be somewhat suspicious when a statement like this is made without any indication of how strong the statistical evidence for it is. Digging deeper into the long supplementary appendix, we find that the statistical analysis does not in fact show this at all. While a model that considered the variant to cause changes in both height and intracranial volume fitted slightly better than one where only height is directly affected, both models fit the data about as well as each other, and it is not possible to distinguish between them statistically (the p-value on the difference in models is p = 0.09). In fact, the data we see is entirely compatible with this gene only directly affecting height, and only indirectly affecting intracranial volumea
The statistics and the main text tell a very different story. It is likely that this was a simple mistake, introduced by the repeated edits that these sorts of papers always go through. However, as it stands, the main text gives a very misleading impression of what the statistics show.
New methods, old flaws
The vast majority of this paper follows the laid down protocols for a high-quality genome-wide association study. The sample size is very large, population stratification and other confounders are well controlled for, and tough standards for strength of evidence were used. This is the legacy of GWAS: a study must be well powered, well performed and stringent, or it is worthless.
But beyond the GWAS portion of the study, these standards of evidence are loosened significantly. A third association near the gene gene DDR2 is (rightly) described as “suggestive” in the abstract, because in a GWAS framework the evidence is not considered strong enough (it has p = 5 x 10^-7, whereas we require p < 5 x 10^-8). Contrast that to the way that the IQ association is treated, where much weaker evidence is taken as indicating an association, or in the height vs intracranial volume test, where the p-value isn't even stated in the main text (presumably because the actual evidence is too weak for anyone to believe). GWAS standards are not there because GWAS are somehow more prone to false positives if not handled properly (they are in many ways less prone to them). There is no point in keeping rigorous standards of evidence if you are going to start breaking them during follow-up, and it does the field a disservice if your genome-wide-significant brain size association ends up alongside your nominally-significant IQ association in a news report. The image for this post is, somewhat unusually, a structural MRI of my own brain.
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Nice post. I don’t think it’s quite fair to fault the authors for reporting the IQ association. One could certainly argue that knowing that the SNP has an effect on intracranial volume massively changes the prior probability that it has an effect on IQ. It’s true that the combining with other studies would have been ideal. Assuming they couldn’t do that for some reason, the way the association is reported seems fine to me–it’s definitely worth mentioning, and they don’t oversell it.
To follow up on my previous comment, what the authors do is analogous to finding SNPs robustly associated with cholesterol levels, and then following up to see if they are associated with heart disease (e.g., http://www.nature.com/ng/journal/v40/n2/full/ng.76.html). IMO, this type of analysis is absolutely worth doing and reporting.
Regarding what they *really* found about IQ/gene correlation, the study *report* may have played down the actual connexion. It’s Not_Nice to publish that sort of thing, politically incorrect. It can get you the James Watson treatment, where you lose your job, lose your grants, if enough influential egalitarisns raise hell…
link to “published in Molecular Psychiatry last year” is/was broken.
@cariaso
Er yes random bracket got in there somewhere. Fixed now.
@Joe
Yes the analysis was worth doing, and provides valuable information – the IQ association should definitely be followed up further. However, the main problem I have is that the test was underpowered, and the p-value weak, so it really should be treated with a lot of caveats that just weren’t present in the paper, and definitely weren’t present in the press coverage.
@Big Don
The extensive existing literature, large public support and massive press interest in IQ genetics makes the claim that someone would play down an IQ association frankly absurd.
I have three problems with this post. (1) The English is extremely poor; so the meaning of several statements needs deciphering (two short examples : “The imagine for this post is, somewhat unusually, a structural MRI of my own brain” and “…the authors use what looks me to be a misleading reporting of statistics to hide the fact that one of their associated could easily be caused by an (already well known) association to general body size”. (2) A very large amount of monies alas was spent on GWAS studies; most if not all of them have no value at all. I remember in NIH a GWAS enthusiast reporting on kidney cancer did not find association with VHL a gene responsible for ~85% of kidney carcinomas. (3) The genetic, gene basis of IQ was for a long time a tabu in this country: research was not funded, papers rejected; a friend of mine moved to England to continue his work on intelligence. Luckily this has changed. Michael Lerman, M.D.,Ph.D.
The English is extremely poor; so the meaning of several statements needs deciphering
smart enough to be a double doctor, but not smart enough to shake off trivial typos?
Luke Jostin`s interesting post raised a number of important issues. I just like to highlight here a couple of additional points: HMGA2 knockout mice and human/chicken HMGA2 haploinsufficiency is linked to small (pygmy) body size. Haploisufficiency in humans is also linked to mental retardation. Increased HMGA2 expression, on the other hand, is associated with increased body structure and bone structure defects (plus lipomas) in human and mouse (dogs and cattle as well). Based on these established facts, it is, in my opinion, almost impossible at this level to specifically distinguish between head/intracranial size and overall body size effects. More interesting than looking at IQ would be to investigate an association of HMGA2 with certain brain activities (of course, not feasable at this point) since HMGA2 has been shown to affect juvenile neuronal stem cell renewal. Likewise, since HMGA2 is an established oncofetal protein, a possible link between HMGA2 levels, body size , and occurence of certain types of cancer would be worth exploring.
@michael
The post was copyedited, but a bug in the html caused it to break. I reverted it last night, hence the unusually raw form of the text.
Does this mean Phrenology is legit?
To “razib”: it’s not typos. “Silence is golden”, I rest my case.
To michael lerman, it’s not “tabu”.
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For those interested in the genetics of IQ variation, I wouldn’t so quickly dismiss the significance of a gene related to greater body size. The general increase in body size is one of the means by which hominids evolved greater intelligence. Intra-racially at least, taller people tend to have somewhat higher IQs than shorter people. Intelligence varies on an absolute scale; it doesn’t take into account body size. One might reasonably say, “Pound for pound, Sugar Ray Robinson was the greatest boxer who ever lived.” But no one would ever think to say, “Pound for pound, Tom is the brightest student in the chemistry class!”
Yes well there is a strong correlation between height and IQ too.
Are we going to hear some silly hand waving about brain to body ratios in worms next? That never gets old.
Or that 95% of the brain does nothing? Sorry but I get pretty sick of these selective interpretations, which are often intentionally misleading.