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

DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, , , , , Anubha Mahajan, Min Jin Go, Weihua Zhang, Jennifer E. Below, Kyle J. Gaulton, Teresa Ferreira, Momoko Horikoshi, Andrew D. Johnson, Maggie C.Y. Ng, Inga Prokopenko, Danish Saleheen, Xu Wang, Eleftheria Zeggini, Goncalo R. Abecasis, Linda S. AdairPeter Almgren, Mustafa Atalay, Tin Aung, Damiano Baldassarre, Beverley Balkau, Yuqian Bao, Anthony H. Barnett, Ines Barroso, Abdul Basit, Latonya F. Been, John Beilby, Graeme I. Bell, Rafn Benediktsson, Richard N. Bergman, Bernhard OBoehm, Eric Boerwinkle, Lori L. Bonnycastle, Noël Burtt, Qiuyin Cai, Harry Campbell, Jason Carey, Stephane Cauchi, Mark Caulfield, Alex S. F. Doney, Peter J. Donnelly, Alan James, David R. Matthews, Andrew D. Morris, Colin N. A. Palmer, James Scott, Laura J. Scott, Nabi Shah, Andrew R. Wood, Fan Zhang

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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 a significant excess in the 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 new T2D susceptibility loci. Furthermore, we observed considerable improvements in the 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 characterization 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.

Original languageEnglish
Pages (from-to)234-244
Number of pages11
JournalNature Genetics
Volume46
Issue number3
DOIs
Publication statusPublished - 9 Feb 2014

Keywords

  • Alleles
  • Asian Continental Ancestry Group
  • Case-Control Studies
  • Diabetes Mellitus, Type 2
  • European Continental Ancestry Group
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Hispanic Americans
  • Humans
  • Polymorphism, Single Nucleotide
  • Risk Factors

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    DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Mahajan, A., Go, M. J., Zhang, W., Below, J. E., Gaulton, K. J., Ferreira, T., Horikoshi, M., Johnson, A. D., Ng, M. C. Y., Prokopenko, I., Saleheen, D., Wang, X., Zeggini, E., Abecasis, G. R., ... Zhang, F. (2014). Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility. Nature Genetics, 46(3), 234-244. https://doi.org/10.1038/ng.2897