Yet Another Study Showing that Polygenic Scores are Confounded by Population Stratification

 Another study related to height PGS:

Polygenic adaptation on height is overestimated due to uncorrected stratification in genome-wide association studies

It should at some point become clear that GWAS and their cousin, the "polygenic score" are little more than measures of population stratification and other such issues in the population being studied (or the database being used). In this case, here is the money shot:

More generally, our results imply that typical constructions of polygenic scores are sensitive to population stratification and that population-level differences should be interpreted with caution.

I would be grateful if someone could tell me what interpreting with caution would look like? How about stop making these interpretations, instead? 

Parental Wealth is Pop Strat

 This paper discusses how parental wealth is a strongly prone to assortative mating. 

...parental wealth homogamy is high at the very top of the parental wealth distribution, and individuals from wealthy families are relatively unlikely to partner with individuals from families with low wealth. Parental wealth correlations among partners are higher when only parental assets rather than net wealth are examined, implying that the former might be a better measure for studying many social stratification processes. Most specifications indicate that homogamy increased in the 2000s relative to the 1990s, but trends can vary depending on methodological choices. The increasing levels of parental wealth homogamy raise concerns that over time, partnering behavior has become more consequential for wealth inequality between couples.

The reason this is important in terms of genetic studies, is that it creates population stratification that will no doubt present itself as genetic correlations, giving the impression that genes exist for income (yes such studies have been done), as well as other things like educational attainment, when all that is really happening is that the rich are keeping it in the family, so to speak.  They noted that it was less common, but still an issue in Denmark, where the study was done, but worse in other countries (US and UK, for example). Thus these GWAS that purport to show such genetic correlations are likely really demonstrating that certain social/ethnic groups have an unfair proportion of wealth. By this token, if you were going to use "polygenic scores" for educational attainment to decide who should get into an elite school, it would more fair for those with the lowest scores to be given preference...

Yet More UK BioBank Pop Strat Issues Noted.

 There are so many studies coming out noting population stratification issues that it is hard to keep track. This is an interesting preprint looking at CAD and BMI:

Fine-scale population structure confounds genetic risk scores in the ascertainment population

From the Abstract:

we investigated the accuracy of two different GRS across population strata of the UK Biobank, separated along principal component (PC) axes, considering different approaches to account for social and environmental confounders. We found that these scores did not predict the real differences in phenotypes observed along the first principal component, with evidence of discrepancies on axes as high as PC45. These results demonstrate that the measures currently taken for correcting for population structure are not sufficient, and the need for social and environmental confounders to be factored into the creation of GRS. 

One interesting aspect of this study, I think, is that it highlights how it can be necessary to have a good working knowledge of the population you are studying.  This plot is striking in that respect:

This was confined only to white European descent, but still had this kind of stratification. A larger point here is that more and more pop/strat issues arise, many of which were not accounted for in earlier studies and perhaps should lead to corrections. Moreover, for those doing GWAS in the future, particularly in the UK BioBank, it is worth having a bit of skepticism that at least some of what you are seeing is pop/strat that has yet to be recognized.

 

Another Paper Related to Pop Strat issues for GWAS

Another study discussing pop strat issues:

Demographic history impacts stratification in polygenic scores

Points out more issues with population stratification:

We show that when population structure is recent, it cannot be fully corrected using principal components based on common variants—the standard approach—because common variants are uninformative about recent demographic history.

They further note some limitations with sibling based studies:

While sibling-based association tests are immune to stratification, the hybrid approach of ascertaining variants in a standard GWAS and then re-estimating effect sizes in siblings reduces but does not eliminate bias. 

As I've argued previously, the "immune to stratification" point is not necessarily true secondary to factors like varying ages of the siblings and selections biases of the databases. Nonetheless, if using sibling studies  "reduces but does not eliminate bias," and they are bringing the variance explained down to 2 or 3 %, then arguably they are scraping along near the null. So, far from showing that some of the variance explained is retained in sibling studies, it might suggest that there is no real genetic component found.

Finally, it's worth pointing out that despite the growing number of studies showing pop/strat issues in the UK Biobank and other such databases, no one has taken it upon themselves to reevaluate their previous, published GWAS results in light of this. It's as if they are grandfathered in.

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.

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: