Increased genetic diversity of ADME genes in African Americans compared with their putative ancestral source populations and implications for pharmacogenomics

Abstract

Background: African Americans have been treated as a representative population for African ancestry for many purposes, including pharmacogenomic studies. However, the contribution of European ancestry is expected to result in considerable differences in the genetic architecture of African American individuals compared with an African genome. In particular, the genetic admixture influences the genomic diversity of drug metabolism-related genes, and may cause high heterogeneity of drug responses in admixed populations such as African Americans.

Results: The genomic ancestry information of African-American (ASW) samples was obtained from data of the 1000 Genomes Project, and local ancestral components were also extracted for 32 core genes and 252 extended genes, which are associated with drug absorption, distribution, metabolism, and excretion (ADME) genes. As expected, the global genetic diversity pattern in ASW was determined by the contributions of its putative ancestral source populations, and the whole profiles of ADME genes in ASW are much closer to those in YRI than in CEU. However, we observed much higher diversity in some functionally important ADME genes in ASW than either CEU or YRI, which could be a result of either genetic drift or natural selection, and we identified some signatures of the latter. We analyzed the clinically relevant polymorphic alleles and haplotypes, and found that 28 functional mutations (including 3 missense, 3 splice, and 22 regulator sites) exhibited significantly higher differentiation between the three populations.

Conclusions: Analysis of the genetic diversity of ADME genes showed differentiation between admixed population and its ancestral source populations. In particular, the different genetic diversity between ASW and YRI indicated that the ethnic differences in pharmacogenomic studies are broadly existed despite that African ancestry is dominant in Africans Americans. This study should advance our understanding of the genetic basis of the drug response heterogeneity between populations, especially in the case of population admixture, and have significant implications for evaluating potential inter-population heterogeneity in drug treatment effects.

Figure 1

Ancestral origins of ADME genes in African Americans. The examples of ancestral origins of three ADME core genes in African Americans: (A)ABCB1, (B)CYP3A4, (C)CYP1A2, where each box has 122 rows representing the diploid sequences of 61 individuals. Blue colored fragments mean originating from European, red means originating from Africa, and gray means unknown component. The start and end positions of genes are plotted at corresponding locations using green bars, and the up- and down-stream 100 kb regions are also included in the figures. (D) The percentage of local European genetic components in ASW for 32 ADME genes. The red bar at the bottom of panel represents the average percentage of European genetic components from the whole genome, while the error bars represent the SD of the percentages. Note that for CYP2E1, GSTM1, SULT1A1, UGT1A1, UGT2B15, ABCG2, SLC22A1, and SLCO1B1 the percentages are average values, while for the remaining genes they are consistent values (see Additional file 2: Figure S2).

Figure 2

Allele frequency patterns of 32ADME core genes in African Americans. (A) A scatter plot of observed vs. expected allele frequencies of 32 ADME core genes in African Americans. (B) The allele frequency distribution of 806 highly differential SNPs (a frequency difference larger than 0.37 between at least two populations) among the three populations.

Figure 3

Genetic diversity patterns of 32 ADME core genes and 252 ADME extended genes. (A) Derived allele frequency spectra of core genes, (B) Expect heterozygosity distributions of core genes, (C) Haplotype diversity distributions of core genes, (D) Derived allele frequency spectra of extended genes, (E) Expect heterozygosity distributions of extended genes, (F) Haplotype diversity distributions of extended genes. In these panels, black represents ASW, blue represents CEU, and red represents YRI.

Figure 4

LSBL analysis and natural selection testing of the ADME core genes. Brown represents the genes with significant L_ASW, blue represents genes with significant L_CEU, and green represents significant L_YRI. The diamond symbol represents the genes with significant CLR scores, whereas the cycle symbol represents the genes with significant iHS scores.

Figure 5

Analysis of locus-specific differentiation of 32 ADME core genes. (A) The distribution of the F_ST loci and all sites located in 32 ADME core genes, including regions 10 kb up- and down-stream. In the figure, the dashed line represents the cutoff with an empirical P value of 0.01 (F_ST = 0.221). (B) The variant effect prediction of highly differentiated loci.

Figure 6

The haplotype distribution analysis. The haplotype distribution in three populations: (A)CYP1A2 and (B)NAT2.