Friday, July 03, 2015

Directional dominance on stature and cognition

Interesting results in this recent Nature article. The dominance effect is quite strong: the equivalent of first cousin inbreeding (homozygosity ~ 1/8) results in a decrease in height or cognitive ability of about 1/6 or 1/3 of an SD. That means the effect from alleles which depress the trait increases by significantly more than 2x in the homozygous (AA) as opposed to heterozygous (aA) case.
Directional dominance on stature and cognition in diverse human populations
(Nature July 2015; doi:10.1038/nature14618)

Homozygosity has long been associated with rare, often devastating, Mendelian disorders1, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3, 4. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10−300, 2.1 × 10−6, 2.5 × 10−10 and 1.8 × 10−10, respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months’ less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5, 6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
From the paper:
... After exclusion of outliers, these effect sizes translate into a reduction of 1.2 cm in height and 137 ml in FEV1 for the offspring of first cousins, and into a decrease of 0.3 s.d. in g and 10 months’ less educational attainment.
These results support the claim that height and cognitive ability have been under positive selection in humans / hominids, so that causal variants tend to be rare and deleterious. For related discussion, see, e.g., section 3.1 in my article On the genetic architecture of intelligence and other quantitative traits and earlier post Deleterious variants affecting traits that have been under selection are rare and of small effect.


Emil Kirkegaard said...

I haven't seen a study ruling out the alternative hypothesis: people who are shorter, less bright, have worse education etc. are more likely to mate with closer family members, and thus produce the results.

If one could find phenotypic data for the parents as well as the children, one could test this alternative hypothesis.

steve hsu said...

They discuss this a little bit in the paper, but you're right that it's not completely excluded as a confound.

Furthermore, humans also mate assortatively on the basis of body mass index, for
which we see no effect. A more complex possibility, a form of reverse
causality, could arise when subjects from one trait extreme (for
example, people with high educational attainment) are on average
more geographically mobile, and thus have less homozygous offspring,
with those offspring in turn inheriting the trait extreme concerned15.
We do not think that this mechanism can account for our results, since
it does not readily explain the constancy of our results under different
models, especially the similarity in bFROH for either more or less homozygous
populations. Moreover, we observe similar effects in multiple
single-village cohorts, and the Amish and Hutterites, where there is no
geographic structure and/or no sampling of immigrants, hence such
confounding by differential migration cannot occur. ...

jeffhsu3 said...

In the paper they state that the intergenerational growth in height is not significantly due to changes in FROH. They present no evidence of this and only cite Galton. Let's use Asia (Japan) as an example where first cousin marriages were extremely prevalent in the recent past even up to 22% in 1900s and probably much larger pre-meji reforms. I can't tell which dot in figure 1 represents the biobank Japanese (BBJ) sample and for the love of me I can't find the supplementary table that has FROH calculations between the study groups. But we should be able to extrapolate into the past a bit and determine the average FROH changes since the clam down on first-cousin marriages. I'm willing the bet that this explains some non-trivial portion of the intergenerational change. Selection could represent the rest. I'm willing to bet that these two genetic effects play a larger role than any environmental and nutritional effects.

5371 said...

That's completely nuts. There are plenty of societies of similar economic level at the same time, among some of which consanguinity is common while it is rare in others. People in the former are not on average 15 cm shorter than in the latter.

jeffhsu3 said...

Did I say that this explains the majority or that it explains differences between populations? The majority is narrow sense heritability. What I'm talking about is narrow sense.

I should be clear that FROH probably only explains << 5% of intergenerational differences in these societies. The estimates for bFROH that they've given suggests that for this to have any appreciable effect the relation between FROH and time since cessation of cousin mating must be non-linear (ie FROH grow much faster). I'm too stupid to figure how this relationship grows analytically (does anyone know?), but simulations should be able to tell us the answer.

Bobw said...

So this effect is a non-linear one. Am I thinking about this right? You've previously suggested that most quantitative traits seem governed by linear effects. Is there a conflict? (Probably not. Please be gentle with me.)

steve hsu said...

Yes, this is evidence for dominance, which is a nonlinear effect. For typical traits we expect most of the genetic variance to be linear, with a smaller nonlinear part.

Eddie Morra said...

Do you think that inbreeding could be the cause of the average IQ of 90 in non White Caucasoid populations since they are genetically closer to Europeans than they are to Africans and their genetic IQ is halfway between both ?

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