An assessment of the portability of ancestry informative markers between human populations

Abstract

Background: Recent work has shown that population stratification can have confounding effects on genetic association studies and statistical methods have been developed to correct for these effects. Subsets of markers that are highly-differentiated between populations, ancestry-informative markers (AIMs), have been used to correct for population stratification. Often AIMs are discovered in one set of populations and then employed in a different set of populations. The underlying assumption in these cases is that the population under study has the same substructure as the population in which the AIMs were discovered. The present study assesses this assumption and evaluates the portability between worldwide populations of 10 SNPs found to be highly-differentiated within Britain (BritAIMs).

Methods: We genotyped 10 BritAIMs in approximately 1000 individuals from 53 populations worldwide. We assessed the degree to which these 10 BritAIMs capture population stratification in other groups of populations by use of the Fst statistic. We used Fst values from 2750 random markers typed in the same set of individuals as an empirical distribution to which the Fst values of the 10 BritAIMs were compared.

Results: Allele frequency differences between continental groups for the BritAIMs are not unusually high. This is also the case for comparisons within continental groups distantly related to Britain. However, two BritAIMs show high Fst between European populations and two BritAIMs show high Fst between populations from the Middle East. Overall the median Fst across all BritAIMs is not unusually high compared to the empirical distribution.

Conclusion: We find that BritAIMs are generally not useful to distinguish between continental groups or within continental groups distantly related to Britain. Moreover, our analyses suggest that the portability of AIMs across geographical scales (e.g. between Europe and Britain) can be limited and should therefore be taken into consideration in the design and interpretation of genetic association studies.

Figure 1

Global Fst distribution for 2750 random markers. The global Fst values of the 10 BritAIMs are indicated by vertical lines.

Figure 2

Fst values of the 2750 random markers within Europe (A) and within the Middle East (B). The Fst values of the 10 BritAIMs are indicated by vertical lines. BritAIMs that lie within the top 5% of the empirical distribution are highlighted with asterisks.

Figure 3

Levels of population differentiation for 2 BritAIMs with significantly high Fst within Europe (A) and 2 BritAIMs with significantly high Fst within the Middle East (B). Each box in each matrix represents a population pairwise Fst comparison. The shaded boxes in the matrices show which pairwise Fst values are significant compared to the empirical distribution at three P value thresholds (see the P value legend).

Figure 4

Worldwide allele frequencies and population differentiation for rs7696175, the most highly differentiated BritAIM within Europe. The vertical bar chart displays the minor allele frequency in each of the populations represented in the CEPH-HGDP panel with sample sizes (number of individuals) on the left. The shaded boxes in the 53 × 53 and 7 × 7 matrices show which pairwise Fst values are significant compared to the empirical distribution at three P value thresholds (see the boxed-in P value legend) for the population by population comparison and the continent by continent comparison, respectively.