Population Structure of UK Biobank and Ancient Eurasians Reveals Adaptation at Genes Influencing Blood Pressure

Abstract

Analyzing genetic differences between closely related populations can be a powerful way to detect recent adaptation. The very large sample size of the UK Biobank is ideal for using population differentiation to detect selection and enables an analysis of the UK population structure at fine resolution. In this study, analyses of 113,851 UK Biobank samples showed that population structure in the UK is dominated by five principal components (PCs) spanning six clusters: Northern Ireland, Scotland, northern England, southern England, and two Welsh clusters. Analyses of ancient Eurasians revealed that populations in the northern UK have higher levels of Steppe ancestry and that UK population structure cannot be explained as a simple mixture of Celts and Saxons. A scan for unusual population differentiation along the top PCs identified a genome-wide-significant signal of selection at the coding variant rs601338 in FUT2 (p = 9.16 × 10^-9). In addition, by combining evidence of unusual differentiation within the UK with evidence from ancient Eurasians, we identified genome-wide-significant (p = 5 × 10^-8) signals of recent selection at two additional loci: CYP1A2-CSK and F12. We detected strong associations between diastolic blood pressure in the UK Biobank and both the variants with selection signals at CYP1A2-CSK (p = 1.10 × 10^-19) and the variants with ancient Eurasian selection signals at the ATXN2-SH2B3 locus (p = 8.00 × 10^-33), implicating recent adaptation related to blood pressure.

Figure 1

Results of PCA with k-Means Clustering The top five PCs in UK Biobank data are displayed. Samples were clustered with these PCs into six clusters by k-means clustering (see Table 1). PC5 is plotted against PC2 because PC5 primarily separated the orange and red clusters, which were separated from the other clusters by PC2.

Figure 2

Results of PCA with Projection of PoBI Samples The top five PCs in UK Biobank data are displayed with PoBI samples projected onto them. PoBI populations that visually best matched the clusters from k-means clustering were used for assigning names to the six clusters (Table 1).

Figure 3

Results of PCA with Projection of Ancient Samples The top five PCs in UK Biobank data are displayed with ancient samples projected onto them.

Figure 4

Selection Statistics for UK Biobank along PC1 A Manhattan plot with −log₁₀(p) values is displayed. Values above the significance threshold (dotted line, p = 1.96 × 10⁻⁸, α = 0.05 after correction for 5 PCs and 510,665 SNPs) are displayed as larger points and are labeled with the locus they correspond to (see Table 3). −log₁₀(p) values larger than 10 are truncated at 10 for easier visualization and are displayed as even larger points.