The Missing Diversity in Human Genetic Studies

Abstract

The majority of studies of genetic association with disease have been performed in Europeans. This European bias has important implications for risk prediction of diseases across global populations. In this commentary, we justify the need to study more diverse populations using both empirical examples and theoretical reasoning.

Figure 1.. Factors Affecting Ability to Replicate Genotype-Phenotype Associations across Populations (Transferability)

(A) The role of effect size on transferability—monogenic (Mendelian) diseases with large effect sizes will cause disease wherever they occur. In contrast, genetic associations with complex traits affected by a few genes with moderate effect sizes (oligogenic) are less likely to transfer across populations. Lastly, for conditions affected by many genes (polygenic) with small effect sizes, transferability may be limited. For all cases, if risk is assessed by tagSNPs, the degree of LD will affect transferability. (B) The role of differential linkage disequilibrium (LD) on transferability. (Top) A single common causative variant may be tagged by different SNPs in different populations; (bottom) causative variants differ by population (allelic heterogeneity) that are tagged by different SNPs (solid lines) or tagged by the same SNP but with weaker LD (dotted line). In either case, tagSNPs derived from a single population (e.g., European) may be inadequate to allow replication of associations across study populations.

Figure 2.. Summary of GWAS Studies by Ancestry for Studies in the GWAS Catalog through January 2019

We show the distribution of ancestry categories in percentages included in GWAS (https://www.ebi.ac.uk/gwas/home) based on the study (left) and based on the total number of individuals (right).