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

Abstract

To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS) including 26,488 cases and 83,964 controls of European, East Asian, South Asian, and Mexican and Mexican American ancestry. We observed significant excess in directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven novel T2D susceptibility loci. Furthermore, we observed considerable improvements in fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterisation of complex trait loci, and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.

Diabetes in Population Isolates: Lessons from Greenland

“…Furthermore, the causal genetic variant and gene have not been identified for most of the detected loci. Previous studies have shown that variants associated with T2D in Europeans are largely transferable to other large populations such as the East and South Asian [17]. However, it is unknown whether the same alleles are associated with metabolic phenotypes in the Greenlandic population.…”

“…In the past decade, GWAS in large, open populations such as Europeans and Asians have proven highly successful in identifying common variants associated with complex diseases and traits, among them T2D and related metabolic traits [15][16][17][18][19][20]. Developments in genotyping and sequencing technologies have further enabled the study of lowfrequency and rare genetic variation [18,21,22].…”

Investigating shared aetiology between type 2 diabetes and major depressive disorder in a population based cohort

“…Single nucleotide polymorphisms (SNPs) found to be associated ( P  ≤ 5 × 10 −8 ) with T2D in two GWAS (comprising 38,840 cases and 114,981 controls [Morris et al, 2012] and 47,979 cases and 139,611 controls comprising a trans‐ancestry GWAS [Mahajan et al, 2014]) were used to perform MR by testing for their association with MDD and current psychological distress. The list consisted of 10 independently associated SNPs from DIAGRAM GWAS that were significant at a genome‐wide level [Morris et al, 2012], and seven further independent loci identified in the DIAGRAM trans‐ancestry T2D GWAS [Mahajan et al, 2014]. 11/17 SNPs were directly genotyped in GS:SFHS and these were the SNPs used in this study (Table II).…”

Genetic architecture of type 2 diabetes

“…While this hypothesis has been debated 26,27 and assessed indirectly 3,28 , we used the near-complete ascertainment of genetic variation in 2,657 genome-sequenced individuals to directly test the importance of 'synthetic' associations 29 . We focused on the ten T2D GWAS loci at which our sample provided the strongest statistical evidence for association (p<0.001), implementing a conditional analysis procedure to assess whether combinations of SNVs within a 5Mb window could explain the common-variant signal (Extended Data Table 8; Methods).…”