The genomic landscape of African populations in health and disease

Abstract

A deeper appreciation of the complex architecture of African genomes is critical to the global effort to understand human history, biology and differential distribution of disease by geography and ancestry. Here, we report on how the growing engagement of African populations in genome science is providing new insights into the forces that shaped human genomes before and after the Out-of-Africa migrations. As a result of this human evolutionary history, African ancestry populations have the greatest genomic diversity in the world, and this diversity has important ramifications for genomic research. In the case of pharmacogenomics, for instance, variants of consequence are not limited to those identified in other populations, and diversity within African ancestry populations precludes summarizing risk across different African ethnic groups. Exposure of Africans to fatal pathogens, such as Plasmodium falciparum, Lassa Virus and Trypanosoma brucei rhodesiense, has resulted in elevated frequencies of alleles conferring survival advantages for infectious diseases, but that are maladaptive in modern-day environments. Illustrating with cardiometabolic traits, we show that while genomic research in African ancestry populations is still in early stages, there are already many examples of novel and African ancestry-specific disease loci that have been discovered. Furthermore, the shorter haplotypes in African genomes have facilitated fine-mapping of loci discovered in other human ancestry populations. Given the insights already gained from the interrogation of African genomes, it is imperative to continue and increase our efforts to describe genomic risk in and across African ancestry populations.

Figure 1.

 Haplotype diversity in the 1000 Genomes Project. Haplotypes were counted over windows of six consecutive diallelic SNPs, with a slide of one SNP. For each sample, all counted haplotypes have a frequency ≥1%. See Supplementary Material, Table S1 in (8) for the sample descriptors.

Figure 2.

Fine-mapping of TCF7L2. (A) Regional plot of the TCF7L2 rs7903146 association among West Africans (55). (B) LD plot of the region in 1000 Genomes CEU. (C) LD plot of the region in 1000 Genomes YRI. Consistent with the original report based on genotyping a few SNPS around the locus (54), both sequence and genotype data showed a much smaller haplotype around the lead SNP in the African samples. Note the fine-grained haplotype structure across the whole region in the African ancestry compared with the EA sample.

Figure 3.

Fine-mapping examples. Examples from studies of C-reactive protein (104), serum uric acid (129), serum lipids (116), and T2D (53) showing how smaller haplotype blocks in African ancestry populations helped refine genome-wide significant loci. Data are shown for fine-mapping analyses conducted in sub-Saharan Africans from Nigeria, Ghana and Kenya (AADM) and in AA from the Washington DC region in the United States (HUFS).

Figure 4.

Inclusion of African ancestry individuals in GWAS. (A) Percentage of studies including individuals with African ancestry versus non-African ancestry individuals in the discovery sample. (B) Percentage of studies including individuals with African ancestry versus non-African ancestry individuals in the replication sample. (C). Average sample size of individuals with African ancestry versus non-African ancestry individuals in the discovery sample. (D) Average sample size of individuals with African ancestry versus non-African ancestry individuals in the replication sample. Whiskers indicate 95% CIs. Data compiled from the NHGRI-EBI GWAS Catalog (https://www.ebi.ac.uk/gwas; date last accessed May 17, 2017) from 2015 to 2017.