Type 2 Diabetes Risk Alleles Demonstrate Extreme Directional Differentiation among Human Populations, Compared to Other Diseases

Open Access
Publisher Website
Google Scholar
Abstract
Many disease-susceptible SNPs exhibit significant disparity in ancestral and derived allele frequencies across worldwide populations. While previous studies have examined population differentiation of alleles at specific SNPs, global ethnic patterns of ensembles of disease risk alleles across human diseases are unexamined. To examine these patterns, we manually curated ethnic disease association data from 5,065 papers on human genetic studies representing 1,495 diseases, recording the precise risk alleles and their measured population frequencies and estimated effect sizes. We systematically compared the population frequencies of cross-ethnic risk alleles for each disease across 1,397 individuals from 11 HapMap populations, 1,064 individuals from 53 HGDP populations, and 49 individuals with whole-genome sequences from 10 populations. Type 2 diabetes (T2D) demonstrated extreme directional differentiation of risk allele frequencies across human populations, compared with null distributions of European-frequency matched control genomic alleles and risk alleles for other diseases. Most T2D risk alleles share a consistent pattern of decreasing frequencies along human migration into East Asia. Furthermore, we show that these patterns contribute to disparities in predicted genetic risk across 1,397 HapMap individuals, T2D genetic risk being consistently higher for individuals in the African populations and lower in the Asian populations, irrespective of the ethnicity considered in the initial discovery of risk alleles. We observed a similar pattern in the distribution of T2D Genetic Risk Scores, which are associated with an increased risk of developing diabetes in the Diabetes Prevention Program cohort, for the same individuals. This disparity may be attributable to the promotion of energy storage and usage appropriate to environments and inconsistent energy intake. Our results indicate that the differential frequencies of T2D risk alleles may contribute to the observed disparity in T2D incidence rates across ethnic populations. We identified 12 risk alleles that had been validated to increase the risk of type 2 diabetes (T2D) in five or more different subpopulations. These risk alleles share a consistent pattern of decreasing frequencies in the human genomes from Sub-Saharan Africa and through Europe to East Asia regions. These differential frequencies are statistically significant, compared with European frequency-matched control genomic alleles and risk alleles for other diseases. The differential frequencies of T2D risk alleles further caused the significant differentiation of genetic risks of T2D, with higher risk in the African and lower risk in the Asian populations. The differences might be caused by the promotion of energy storage and usage appropriate to environments and inconsistent energy intake. Future evolutionary and environmental analysis of this unique pattern may provide further insight on the origin of T2D and modern disparities in T2D incidence.