Monday, April 22, 2013

Common variants vs mutational load

I recommend this blog post (The Differentialist) by Timothy Bates of the University of Edinburgh. (I met Tim there at last year's Behavior Genetics meeting.) He discusses the implications of GCTA results showing high heritability of IQ as measured using common SNPs (see related post Eric, why so gloomy?). One unresolved issue (see comments there) is to what extent mutational load (deleterious effects due to very rare variants) can account for population variation in IQ. The standard argument is that very rare variants will not be well tagged by common SNPs and hence the heritability results (e.g., of about 0.5) found by GCTA suggest that a good chunk of variation is accounted for by common variants (e.g., MAF > 0.05). The counter argument (which I have not yet seen investigated fully) is that relatedness defined over a set of common SNPs is correlated to the similarity in mutational load of a pair of individuals, due to the complex family history of human populations. IIRC, "unrelated" individuals selected at random from a common ethnic group and region are, on average, roughly as related as third cousins (say, r ~ 1E-02?).

Is the heritability detected using common SNPs due to specific common variants tagged by SNPs, or due to a general correlation between SNP relatedness and overall similarity of genomes?

My guess is that we'll find that both common variants and mutational load are responsible for variation in cognitive ability. Does existing data provide any limit on the relative ratio? This requires a calculation, but my intuition is that mutational load cannot account for everything. Fortunately, with whole genome data you can look both for common variants and at mutational load at the same time.

In the case of height it's now clear that common variants account for a significant fraction of heritability, but there is also evidence for a mutational load component. Note that we don't expect to discover any common variants for IQ until past a threshold in sample size, which for height turned out to be about 10k.

Hmm, now that I think about it ... there does seem to be a relevant calculation :-)

In the original GCTA paper (Yang et al. Nature Genetics 2010), it was found that relatedness computed on a set of common genotyped SNPs is a poor predictor of relatedness on rare SNPs (e.g., MAF < 0.1). The rare SNPs are in poor linkage disequilibrium (LD) with the genotyped SNPs, due to the difference in MAF. This was proposed as a plausible mechanism for the still-missing heritability (e.g., 0.4 vs 0.8 expected from classical twin/sib studies; Yang et al. specifically looked at height): if the actual causal variants tend to be rarer than the common genotyped SNPs, the genotypic similarity of two individuals where it counts -- on the causal variants -- would be incorrectly estimated, leading to an underestimate of heritability.

If these simulations are any guide, rare mutations are unlikely to account for the GCTA heritability, but rather may account for (some of) the gap between it and the total additive heritability. See, for example, the following discussion:
A commentary on “Common SNPs explain a large proportion of the heritability for human height” by Yang et al. (2010)

(p.6) ... We cannot measure the LD between causal variants and genotyped SNPs directly because we do not know the causal variants. However, we can estimate the LD between SNPs. If the causal variants have similar characteristics to the SNPs, the LD between causal variants and SNPs should be similar to that between the SNPs themselves. One causal variant can be in LD with multiple SNPs and so the SNPs collectively could trace the causal variant even though no one SNP was in perfect LD with it. Therefore we divided the SNPs randomly into two groups and treated the first group as if they were causal variants and asked how well the second group of SNPs tracked these simulated causal variants. This can be judged by the extent to which the relationship matrices calculated from the SNPs agree with the relationship matrix calculated from the ‘causal variants’. The covariance between the estimated relationships for the two sets of SNPs equals the true variance of relatedness whereas the variance of the estimates of relatedness for each set of SNPs equals true variation in relatedness plus estimation error. Therefore, from the regression of pairwise relatedness estimated from one of the set of SNPs onto the estimated pairwise relatedness from the other set of SNPs we can quantify the amount of error and ‘regress back’ or ‘shrink’ the estimate of relatedness towards the mean to take account of the prediction error.

... If causal variants have a lower MAF than common SNPs the LD between SNPs and causal variants is likely to be lower than the LD between random SNPs. To investigate the effect of this possibility we used SNPs with low MAF to mimic causal variants. We found that the relationship estimated by random SNPs (with MAF typical of the genotyped SNPs on the array) was a poorer predictor of the relationship at these ‘causal variants’ than it was of the relationship at other random SNPs. When the relationship matrix at the SNPs is shrunk to provide an unbiased estimate of the relationship at these ‘causal variants’, we find that the ‘causal variants’ would explain 80% of the phenotypic variance ...


HughLygon said...

"IQ is like height", Steve "thinks". But does Steve think?

From one of his posts, "the fact that cognitive abilities reliably have positive correlation is highly nontrivial".
Those who can do the Rubic's cube without help are likely to have larger vocabularies than those who can't. This is "highly non trivial"? What does an RC know about the Mishnah? What does a Muslim know about Evelyn Waugh? There is a pernicious assumption that non-verbal ability is never acquired. A plumber was conceived a plumber. This is a prejudice of the acadamey.

In general, the biological basis of differences in intelligence cannot be resolved by studying populations within the dominant culture of liberal capitalism. Show me that Finns and traditional Lapps both scoring high on IQ tests have genes in common, and I will be able to say, "Steve, these 'traditional' Lapps scoring so high are much less traditional than the rest", or "Steve, these 'traditional' Lapps scoring so high are less Lapp than the rest."

Steve should read "The Myth of Sisyphus".

misdreavus said...

1) You, like many a mortally confused but well meaning skeptic, make the classic error of conflating learned knowledge with the ability to think and reason. (Raymond Cattell took pains to distinguish between the two through his "fluid" and "crystallized" intelligences, but that is a different matter entirely.) To illustrate the folly of your reasoning via reductio ad absurdum, the average mountain gorilla in the Congo knows the properties of _hundreds_ of medicinal herbs that you and I do not. I suppose this proves that gorillas are just as intelligent as human beings, but only in their own unique way?

2) I hate to break it to you, but there is no alternative to modern industrial civilization. If the Dayak people of Borneo had independently discovered the germ theory, the theory of evolution, or an effective anti-malarial prophylactic independent of Western influence, we would have to take their culture-bound definition of intelligence very seriously. (Whether or not this knowledge is even useful in their traditional cultural milieu is a non sequitur. It matters to everyone living today, and that is all that matters.) If voodoo and magic actually worked, all of us would have to admit that illiterate Bantu tribes know far more than we are willing to give them credit for -- yet they plainly do not. All of their amulets and potions and incantations prove worse than useless under an epidemic of measles or a torrent of bullets.

As it stands currently, modern civilization is an uncontested champion in the battleground of ideas -- and if you have the chutzpah to denounce capitalist excess while typing away on a keyboard, IQ scores do an excellent job measuring your capacity to succeed in your culture.

3) Swedish admixture would surely not account for more than a fraction of the IQ variation among Lapps, and no competent researcher would expect any other outcome.

stevesailer said...

If Cochran's theory that mutational load is associated with paternal age, we should be able to check if younger brothers are shorter or dumber than older brothers using one of those Scandinavian conscript databases.

Richard Seiter said...

This is an interesting take on studies that show birth order is correlated with success. I have always assumed the reasons were a combination of social effects and maternal nutritional status deteriorating over time. Does anyone know of a birth order study that included parental ages as variables and also measured height and IQ?

Iamexpert said...

It's well known that birth order negatively correlates with IQ and fraternal birth order positively correlates with homosexuality and homosexual pedophilia and pedophilia negatively correlates with height

stevesailer said...

One theory is that the more male fetuses a woman gestates, the more likely hormonal reaction problems are to crop up in the next male baby. Ray Blanchard estimated about 15 years ago that this could account for about 1/7th of all cases of male homosexuality.

But, if the Nordics keep records as well as I assume they do, I bet we could tease out birth order effects from paternal age on the height and test-taking ability of conscripts.

HughLygon said...

too dumb to respond to.

misdreavus said...

Are you going to refute anthing I have said, or not?

HughLygon said...

Nothing you said can be refuted, because you said nothing. If it matters, I am not in the Jewish camp of Lewontin and Gould or the Afghani camp of Shalizi. All prominent, public sides in this matter are f---ing retards. I am a very firm believer in eugenics and ZPG.

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