Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility

The majority of GWAS of T2D susceptibility have been undertaken in populations of European ancestry1–5, predominantly because of existing infrastructure, sample availability and relatively poor coverage by many of the earliest genome-wide genotyping arrays of common genetic variation in other major ethnic groups6. However, populations of European ancestry constitute only a subset of human genetic variation and are thus insufficient to fully characterize T2D risk variants in other ethnic groups. Furthermore, the latest genome-wide genotyping arrays are less biased toward Europeans, and more recent T2D GWAS have been performed with great success in populations from other ancestry groups, including east Asians7–12, south Asians13,14, Mexicans and Mexican Americans15 and African Americans16. These studies have provided initial evidence of overlap in T2D susceptibility loci between ancestry groups, as well as for coincident risk alleles at lead SNPs across diverse populations17,18. These observations are consistent with a model in which the underlying causal variants at many of these loci are shared across ancestry groups and thus arose before migration of the human population out of Africa. Under such a model, we would expect to improve the power to detect new susceptibility loci for the disease and enhance the fine-mapping resolution of causal variants by combining GWAS across ancestry groups through trans-ethnic meta-analysis because of increased sample size and differences in the structure of linkage disequilibrium (LD) between such diverse populations6,19–21. In this study, we aggregated published meta-analyses of GWAS in a total of 26,488 cases and 83,964 controls from populations of European, east Asian, south Asian and Mexican and Mexican American ancestry5,11,13,15. T2D GWAS from populations of African ancestry, which would be expected to provide the greatest potential for fine mapping of common causal variants because of less extensive LD than other ethnic groups6, were not accessible for inclusion in our analyses. With these data, we aimed to (i) assess the evidence for excess concordance in the direction of effect of T2D risk alleles across ancestry groups; (ii) identify new T2D susceptibility loci through transethnic meta-analysis and subsequent validation in an additional 21,491 cases and 55,647 controls of European ancestry; and (iii) evaluate the improvements in the fine-mapping resolution of common variant association signals in established T2D susceptibility loci through trans-ethnic meta-analysis despite the lack of GWAS from populations of African ancestry.