The global spectrum of protein-coding pharmacogenomic diversity

Abstract

Differences in response to medications have a strong genetic component. By leveraging publically available data, the spectrum of such genomic variation can be investigated extensively. Pharmacogenomic variation was extracted from the 1000 Genomes Project Phase 3 data (2504 individuals, 26 global populations). A total of 12 084 genetic variants were found in 120 pharmacogenes, with the majority (90.0%) classified as rare variants (global minor allele frequency <0.5%), with 52.9% being singletons. Common variation clustered individuals into continental super-populations and 23 pharmacogenes contained highly differentiated variants (F_ST>0.5) for one or more super-population comparison. A median of three clinical variants (PharmGKB level 1A/B) was found per individual, and 55.4% of individuals carried loss-of-function variants, varying by super-population (East Asian 60.9%>African 60.1%>South Asian 60.3%>European 49.3%>Admixed 39.2%). Genome sequencing can therefore identify clinical pharmacogenomic variation, and future studies need to consider rare variation to understand the spectrum of genetic diversity contributing to drug response.

Figure 1

Summary of the functional annotation of the pharmacogenomic variants in the 1000 Genomes Project individuals. (a) Counts of the different variant classes according to consequence type. (b) Relative proportion of variants across consequence type stratified by global minor allele frequency (MAF) bins. Consequence types that differ significantly in frequency according to global MAF are annotated with Bonferroni corrected P-values. Missense variants displayed the most significant differences in relative frequencies (P=9.68 × 10⁻⁴⁰).

Figure 2

Pharmacogenomic variants with a high level of clinical annotation (that is, PharmGKB Level 1A/B). (a) Scatterplot of allele frequencies of clinically relevant variants in the different population groups. Variants in certain genes, such as CY2C19 and CYP4F2, displayed differences in allele frequencies between super-populations. (b) Violin plot of the number of clinically relevant pharmacogenomic variants carried per individual, grouped by population, and coloured by super-population. Ninety-seven percent of the individuals in the 1000 Genomes Project carried at least one such variant (median of 3).

Figure 3

Pharmacogenes that carried high-confidence loss-of-function (LOF) variants as designated by LOFTEE. (a) The size of the points is proportional to the number of unique LOF variants in the gene, with the cumulative allele count per gene indicated. (b) Combined allele frequencies of LOF variants per gene in each of the global super-populations. Common LOF variants were frequently driven by one super-population.