Saturday, September 14, 2013

Pleiotropy, g, and specific learning abilities

This came out earlier in the year but I just noticed it. See also Myths, Sisyphus and g.

Summary for those wishing to follow science but who can't do math: consider many pairs of individuals and ask to what extent similarity in genotype is related to similarity in phenotype (g score, specific ability score, height, weight, etc.). From this analysis one can estimate the extent to which genes influence phenotype (heritability), and to what extent the same genes are influencing two different traits (e.g., height and weight, or reading ability and general cognitive ability g). The bivariate method is described here in more detail.

"These results indicate that genes related to diverse neurocognitive processes have general rather than specific effects."
DNA Evidence for Strong Genome-Wide Pleiotropy of Cognitive and Learning Abilities  (DOI 10.1007/s10519-013-9594-x Behavior Genetics)

Abstract: Very different neurocognitive processes appear to be involved in cognitive abilities such as verbal and non-verbal ability as compared to learning abilities taught in schools such as reading and mathematics. However, twin studies that compare similarity for monozygotic and dizygotic twins suggest that the same genes are largely responsible for genetic influence on these diverse aspects of cognitive function. It is now possible to test this evidence for strong pleiotropy using DNA alone from samples of unrelated individuals. Here we used this new method with 1.7 million DNA markers for a sample of 2,500 unrelated children at age 12 to investigate for the first time the extent of pleiotropy between general cognitive ability (aka intelligence) and learning abilities (reading, mathematics and language skills). We also compared these DNA results to results from twin analyses using the same sample and measures. The DNA-based method revealed strong genome-wide pleiotropy: Genetic correlations were greater than 0.70 between general cognitive ability and language, reading, and mathematics, results that were highly similar to twin study estimates of genetic correlations. These results indicate that genes related to diverse neurocognitive processes have general rather than specific effects. 

[GCTA] ... The bivariate method extends the univariate model by relating the pairwise genetic similarity matrix to a phenotypic covariance matrix between traits 1 and 2 (Lee et al. 2012). The eight principal components described earlier were used as covariates in our bivariate GCTA analyses; as mentioned in the previous section, all phenotypes were age- and sex-regressed prior to analysis.

Twin modelling. The twin design and model-fitting is discussed elsewhere (Plomin et al. 2013a). We fit a bivariate Cholesky decomposition using OpenMx (Boker et al. 2011), which provided a direct comparison with the bivariate GCTA. The correlated factor solution is the least restricted model allowing variables to correlate with one another via genetic, shared environment, and non-shared environment.

... Table 1 shows GCTA-estimated genetic correlations (and standard errors, SE) between ‘g’ and learning abilities for more than 2,238 12-year-old UK twins (randomly selecting only one member of each twin pair to control for potential confounds, such as birth order) based on 1.7 million SNPs measured from the Affymetrix 6.0 GeneChip or imputed from HapMap 2,3 and WTCCC controls (Trzaskowski et al. 2013). Genetic correlations are significant and substantial for all three comparisons—between ‘g’ and language (0.81), mathematics (0.74), and reading (0.89). The GCTA-estimated genetic correlations between ‘g’ and learning abilities are similar in magnitude to the GCTA-estimated genetic correlation between height and weight (0.76). In addition, Table 1 includes bivariate results for ‘g’ versus height and ‘g’ versus weight as ‘negative controls’; their phenotypic correlations are both 0.07. As expected, these comparisons yielded negligible and nonsignificant genetic correlations (−0.03 and −0.06, respectively).

... A more novel question, and central to the present paper, is why, as we have shown here, bivariate genetic correlations estimated by GCTA are as great as twin study estimates. The likely reason is that attenuation of the estimated additive genetic variance due to imperfect linkage disequilibrium between causal variants and genotyped SNPs applies to both the additive genetic variance of the two traits and to their additive genetic covariance by the same proportion. Thus, the GCTA estimate of the genetic correlation is unbiased because it is derived from the ratio between genetic covariance and the genetic variances of the two traits.

Are generalist genes all in the mind (cognition) or are they in the brain as well? That is, genetic correlations between cognitive and learning abilities might be epiphenomenal in the sense that multiple genetically independent brain mechanisms could affect each ability, creating genetic correlations among abilities. However, the genetic principles of pleiotropy (each gene affects many traits) and polygenicity (many genes affect each trait) lead us to predict that generalist genes have their effects further upstream, creating genetic correlations among brain structures and functions, a prediction that supports a network view of brain structure and function.


Richard Seiter said...

Steve, any thoughts on what proportion of genetic correlation you would expect to see for SNPs only vs. including non-SNP differences? Some of those correlations seem very large for SNPs only. Does this affect your rare variants hypothesis? (the paper discusses this a bit: "The common SNPs used on all available commercial arrays only capture what is in LD with them. Rare variants, which have lower minor allele frequency, will thus not be ‘tagged’ and their influence will be missed.")

I'm curious why they chose to do this: "For each cognitive measure, outliers above or below 3 SD from the mean were excluded." and "Similar to the cognitive measures, outliers (± 3SD) were removed" for height and weight. Does anyone know the rationale?

pnin1957 said...

I would guess that they excluded outliers because the genetic architecture of extreme phenotypes may be different from that of normal phenotypes. For example, mental retardation is often due to one large-effect mutation rather than lots of deleterious small effect alleles. Another reason may be that the fit indices used in SEM modeling are very sensitive to extreme values. And some extreme values are just clerical errors.

StevenS123 said...

Hello Steve.

Could you tell me what is the difference between yours and this study? In summary, they did found the alleles that are responsible for high IQs, right? Is this the final nail in the coffin for people who deny genetic contribution to intelligence and possible group differences in intelligence?

steve hsu said...

This study did not find specific genes and does not connect directly to group differences. It does suggest some things about the genetic architecture of cognitive ability.

steve hsu said...

This study just says that there is substantial overlap in the SNPs which account for, e.g., heritability of about 0.5 for height or g, and those responsible for the heritability *due to SNPs* of, respectively, bodyweight or narrow cognitive measures (reading, math ability). In other words, there is pleiotropy among common causal variants. But note the overlap between genes affecting height or IQ is much less (perhaps even close to zero) than for two cognitive traits.

Unaccounted-for heritability (i.e., the gap between 0.5 and some larger value like 0.6 or 0.7 additive heritability) could be due to much rarer variants. "Common" SNP MAFs extend down to 0.1 or 0.05 so it's a matter of terminology whether you want to call them rare or not.

StevenS123 said...


Douglas Knight said...

I didn't read the article carefully, but it seemed to include height as an easy to measure control, uncorrelated with g ("as expected"). Do they just not know the phenotypes are correlated? Or do they have a sophisticated reason for expecting no correlation in this experiment? Has anyone written down a sophisticated expectation for this experiment?

One hypothesis is that the correlation is environmental, say, nutrition, in which case zero genetic correlation is what you should see. But another hypothesis is that both traits are driven by mutational load: the more numerous the genes affecting the traits, the more likely that the same gene will affect both. What does a mutational load hypothesis predict about this paper? Does this result force the rare genes to be smaller and more numerous?

DK said...

Wow, it is deeply reassuring that science proves that intelligence is highly correlated with verbal and math abilities. Who would have thought? I should design a project that explores "pleiotropy" between reading science fiction and reading philosophy of science books.

steve hsu said...

It's not just that g is correlated with math ability. It's that the *genes* which are correlated with g have a lot of overlap with those that are correlated with math ability. This is not surprising to most people, but it does say something about whether there is a real "general factor" of intelligence as opposed to a bundle of separate abilities that just happen to be correlated (e.g., due to environmental effects).

steve hsu said...

They find only limited genetic correlation between g and height. So if you think that genetic load affects both through pleiotropic effects you'd have to restrict it to the part of heritability yet unaccounted for by SNPs -- i.e., variants with MAF below about 0.05 or so.

Diogenes said...

I doubt anyone denies "genetic contribution to intelligence". The huge BUT is:

The effect of genes is mediated by environment. Intelligence as a an absolute trait has still to be defined. (Why are high achieving Asian Americans so underrep'ed in the Forbes 400?)

"DNA markers for a sample of 2,500 unrelated children at age 12 to
investigate for the first time the extent of pleiotropy between general
cognitive ability (aka intelligence) and learning abilities (reading,
mathematics and language skills)"

But how unrelated were they? Guess: they were not gathered from the four corners of the earth and their scores normalized for their respective populations.

Regarding the BGI set of volunteers, it would be nice to see all subsets of order some n where for each subset there is a measure of its geographic diversity along with a measure of the extent to which the subset's population shares certain SNPs.

oregonlocal said...

"Why are high achieving Asian Americans so underrep'ed in the Forbes 400?"

Being a medical doctor has very little to do with becoming a billionaire.

StevenS123 said...

Mainstream media denies heredity of intelligence all the time, at least they do so indirectly.

As for IQ, while I agree that it doesn't tell the whole story, it can be measured and it does correlate with other things that can be measured (wealth, academic success... ), that's what makes it a good place to start, as it really does measure something in the brain, and that something is genetic in origin. Finding the alleles responsible can have huge implications on everyday lives and policies.

Diogenes said...

You're agreeing with something I didn't mean to communicate.

"intelligence is not an absolute trait" means that IQ tests given to peoples living in poverty in the developing world or in the Amazon or New Guinea are meaningless.

when tests are developed for these people then intelligence will be an absolute trait.

Diogenes said...

it disproves genes as a source of shalizi's many factors explanation of g.

Diogenes said...

"Mainstream media denies heredity of intelligence all the time"

This is false. As far as I can remember journalists are liberals, but they aren't morons. Mainstream media will tend to take the position less extreme than that of intelligence researchers though, who are crypto-nazis however insistent their protestations to the contrary..

Diogenes said...

and one needn't look at the genome to see this. lopsided factor scores increase in frequency going up the iq scale. that is, stupid people are stupid in every way, but smart people are often very smart in one way and not so very smart in other ways.

Diogenes said...

the typical ideological rot on this issue is that asians aren't ambitious, creative, aggressive, "salesy" etc. anything to save the most cherished lie that the us is a meritocracy. the us is the LEAST meritocratic country in the developed world.

Diogenes said...

hey hire me i can do all your fortran. not even close to enough detail. i took woodshop, let me build your house.

Diogenes said...

"If you knew the first thing about anything then you would know that the
overwhelming number of jobs are acquired via some sort of personal

That was the point. And the quality of those connections varies enormously.

Diogenes said...

brave new world that has such social capital in it.

you're a typical 'mer'can moron.

Diogenes said...

I wonder if Steve has seen this. Meanwhile intergenerational income elasticity varies enormously from one country to another. So the child's iq is just as correlated to the father's in Denmark, but father's and son's income are barely correlated at all? Greater equality makes for a restriction of range effect?

One might argue that this contradicts previous studies. But were these done in Sweden? Why should results not vary from place to place?

Diogenes said...

I wonder if Steve has seen this. Meanwhile intergenerational income elasticity varies enormously from one country to another.
So the child's iq is just as correlated to the father's in Denmark, but father's and son's income are barely correlated at all? Greater
equality makes for a significant restriction of range effect? Or is it all just a matter of race again?

oregonlocal said...

"pussy whipped", "ugly wives", "boss", "bevins", surfing. etc. disgusting.


Richard Seiter said...

I knew a woman who retired at 41 on a lot more than you'll ever have after selling her business in mortgage securitization. She said, "I never went to college, but I met someone who took me under his wing and showed me the business. It's who you know not what you know."

Interesting. Any idea what happened to her business in 2008? I think calling out people who participated in that financial debacle as role models is an interesting choice. (though I would need to know more details to apply a negative word rather than just saying 'interesting choice') Especially interesting from someone who so consistently criticizes many aspects of pushy, striving American culture.

Diogenes said...

She was 41 in 1998 when I knew her. She wasn't a role model. She was an example. And why would you think she was pushy or striving?

Assistant Village idiot said...

Tangentially related: It has been 17 months since, at your urging in specific, I sent my sample to BGI for the high-IQ research. I just sent Chris Chang a fifth message - which isn't that much spread over 17 months, is it? It's bad enough that I will have to figure out how to read the results on my own, but to not even have any results to read is ridiculous.

Yes, this is a message to your readers not to get sucked into research at your request.

steve hsu said...

Sorry it has taken so long to get results back. Unfortunately, I'm not at liberty to explain all the reasons for the delay.

Perhaps we should have offered a saliva-back guarantee?

Diogenes said...

I'm sure you'll be promoted soon;)

Free complete genome sequencing, and you've been harassing Chang?

That's not just looking a gift horse in the mouth, that's complaining he isn't Secretariat.

Richard Seiter said...

My guess about pushy and striving had to do with succeeding (very much so apparently) at a business like mortgage securitization (in America ;-) and espousing "It's not what you know but who you know." Not a sure thing by any means, but seems like a reasonable speculation which you are free to debunk if appropriate. (note that I am not opposing pushy and striving with "nice" or other attributes)

The line between role model and example can be fine. "on a lot more than you'll ever have" pointed me towards role model.

Fairly long post given that you failed to answer my question about what happened to her business after she sold. One of the American "things" which bothers me is the building up of businesses, selling them for a great profit (or just taking an immense salary over a period of years), and watching them implode at someone else's expense. Not sure if that is what happened here--that's why I'm curious.

About your examples. I agree those illustrate some tendencies which are all too prevalent in America, but do you really think they only occur here? A disturbing thought is that your professor example would be lauded by many and used as an example of the worthlessness of tests (I suppose the important question is whether she was actually good at her jobs, of course that gets us into the morass of job performance and evaluation).

Diogenes said...

at the time she was just a much older woman trying to shtup me. i would have obliged, but there was a "contretemps". so i don't know.

but yes. americans are uniquely class un-conscious. only america's upper and upper-middle classes have any class consciousness at all.

yet the us has the most pronounced and rigid class structure of any developed country. but when race is "backed out" this is not true, i assume.

so there is an american ideology which denies innate differences yet simultaneously uses these as justification for inequality. it's like 1984.

steve himself has spoken of the limited correlation of iq (sat scores) with gpa (with the exception of math and physics) as "hopeful".

just that one instance exemplifies the american ideology as well as any.

btw, my connection with the u of o and steve's is pure coincidence. i had no idea who he was before finding this blog. if i decide for a credential in distilling i'll have to follow him to msu;)

if i write too much, i should say, i'm writing for myself. if no one reads my comments i still get practice writing, trying to make sense.

Assistant Village idiot said...

A fair criticism, except that the original description strongly implied a much quicker response..It is rather easier to accept that something will take two years when you are told it will take two years. Chris has since explained, and his reasons are good ones.

pnin1957 said...

Diogenes is right. In mentally retarded samples, the g factor often explains pretty much all the reliable IQ variance, while in smart samples non-g variance is very prominent. Stupidity is general, while high intelligence is specialized.

Ilya1981 said...

Curious: If the Nazis were right, why would they kill members of an ethnos with average IQ of about one standard deviation above theirs?

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