Fig. 4. Illustrations of the need to consider diverse human populations in the genetic analysis of disease.

a | Interactions between the maternal killer cell inhibitory receptor (KIR) genotype and the fetal trophoblasts illustrate evolutionary trade-offs in pregnancy. Birthweight is under stabilizing selection in human populations. The interaction between maternal KIR genotypes (a diversity of which are maintained in the population) and the fetal trophoblasts influence birthweight. African (AFR) populations, relative to European (EUR) populations, maintain larger proportions of the KIR AA haplotype¹⁷⁶, which is associated with improved maternal immune response to some viral challenges; however, it is also associated with low birthweight. Alternatively, the KIR BB haplotype is associated with higher birthweight but increased risk of pre-eclampsia. b | Current strategies for predicting genetic risk are confounded by a lack of inclusion of diverse human populations. Thus, they are more likely to fail in genetic risk prediction in populations that are under-represented in genetic databases. For example, polygenic risk score (PRS) models trained on European populations often perform poorly when applied to African populations. This poor performance stems from the fact that the genetic diversity of African populations, differences in effect sizes between populations and differential evolutionary pressures are not taken into account. The weights for each variant (blue circles) in the PRS derived from genome-wide association studies are signified by w1, w2 and w3. c | Population-specific adaptation and genetic hitch-hiking can produce different disease risk between populations. Haplotypes with protective effects against disease may rise to high frequency in specific populations through genetic hitch-hiking with nearby alleles under selection for a different trait. For example, selection for lighter skin pigmentation caused a haplotype that carried a variant associated with lighter skin (blue circle) to increase in frequency in European populations compared with African populations. This haplotype also carried a variant protective against prostate cancer (blue triangle).