Exploring public genomics data for population pharmacogenomics

Abstract

Racial and ethnic differences in drug responses are now well studied and documented. Pharmacogenomics research seeks to unravel the genetic underpinnings of inter-individual variability with the aim of tailored-made theranostics and therapeutics. Taking into account the differential expression of pharmacogenes coding for key metabolic enzymes and transporters that affect drug pharmacokinetics and pharmacodynamics, we advise that data interpretation and analysis need to occur in light of geographical ancestry, if implications for drug development and global health are to be considered. Herein, we exploit ePGA, a web-based electronic Pharmacogenomics Assistant and publicly available genetic data from the 1000 Genomes Project to explore genotype to phenotype associations among the 1000 Genomes Project populations.

Fig 1. Geographic MAF distribution of 501 PGx variants found in the 1000 Genomes project populations.

Fig 2. Chromosomal location and functional consequence distribution per chromosome of the PGx variants.

The accompanied table shows the PGx variants and genes located in each chromosome.

Fig 3. Distribution of common (MAF≥0.1) possibly damaging (left) and benign (right) PGx variants across 1kG populations.

These are African/AFR (GWD, MSL, ESN, YRI, LWK, ACB, ASW), Ad Mixed America/AMR (MXL, CLM, PEL, PUR), East Asian/EAS (CHS, KHV, CHB, JPT, CDX), European/EUR (TSI, IBS, GBR, CEU, FIN), South Asian/SAS (PJL, STU, ITU, BEB, GIH) ancestral groups.

Fig 4. Minor Allele Frequency heatmap for 79 PGx variants that are common (MAF> = 0.1) and rare (MAF< = 0.005) in at least one 1kG population.

Fig 5. Minor Allele frequency distribution for the ten most differentiated PGx variants among 1kG ancestral groups.

Fig 6. Genomic annotation plot combined with PGx variant MAFs in 1kG populations.

Fig 7. Individual haplotypes that did not match to any known haplotype per gene.

Colours represent the five ancestral groups. Grey fills indicate haplotype matches.

Fig 8. Haplotype Frequency (HAF) heatmap for 53 PGx haplotype that are common (HAF> = 0.1) and rare (HAF< = 0.005) in at least one 1kG population.

Fig 9. Distribution of three phenotypes (WT/WT-green, WT/V-orange, V/V-red) for 5 highly covered genes with high phenotypic difference among 1kG populations.