Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution (original) (raw)

Nature Genetics volume 39, pages 218–225 (2007)Cite this article

Abstract

We recently described an association between risk of type 2diabetes and variants in the transcription factor 7-like 2 gene (TCF7L2; formerly TCF4), with a population attributable risk (PAR) of 17%–28% in three populations of European ancestry1. Here, we refine the definition of the TCF7L2 type 2diabetes risk variant, HapBT2D, to the ancestral T allele of a SNP, rs7903146, through replication in West African and Danish type 2 diabetes case-control studies and an expanded Icelandic study. We also identify another variant of the same gene, HapA, that shows evidence of positive selection in East Asian, European and West African populations. Notably, HapA shows a suggestive association with body mass index and altered concentrations of the hunger-satiety hormones ghrelin and leptin in males, indicating that the selective advantage of HapA may have been mediated through effects on energy metabolism.

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Acknowledgements

We thank all the individuals that provided DNA samples and other information that made this study possible. A.H., H.S. and J.H. were supported by the German National Genome Network. O.P., T.H., G.A., K.B.-J. and T.J. were supported by the Danish Medical Research Council, the Danish Diabetes Association and the European Economic Community (EUGENE 2 LSHM-CT-2004-512013). Support for the Africa America Diabetes Mellitus (AADM) study is provided by NIH grant 3T37TW00041-03S2 from the Office of Research on Minority Health. This project is also supported in part by the National Center for Research Resources (NCRR), the National Human Genome Research Institute (NHGRI) and by the National Institute for Diabetes and Digestive and Kidney Diseases (grant DK-54001). Requests for materials should be addressed to A.H. (agnar@decode.is) or K.S. (kstefans@decode.is).

Author information

Author notes

  1. Struan F A Grant
    Present address: Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, 3516 Civic Center Blvd, Philadelphia, Pennsylvania, 19104, USA

Authors and Affiliations

  1. deCODE genetics, Reykjavik, 101, Iceland
    Agnar Helgason, Snæbjörn Pálsson, Gudmar Thorleifsson, Struan F A Grant, Valur Emilsson, Steinunn Gunnarsdottir, Inga Reynisdottir, Unnur Thorsteinsdottir, Jeffrey R Gulcher, Augustine Kong & Kári Stefánsson
  2. University of Iceland, Reykjavik, 101, Iceland
    Snæbjörn Pálsson
  3. Department of Community and Family Medicine, National Human Genome Center, Howard University, Washington, 20060, DC, USA
    Adebowale Adeyemo, Yuanxiu Chen, Guanjie Chen, Mezbah Faruque, Ayo Doumatey, Jie Zhou & Charles Rotimi
  4. Icelandic Heart Association, Kopavogur, 201, Iceland
    Rafn Benediktsson & Gunnar Sigurdsson
  5. National University Hospital, Reykjavik, 101, Iceland
    Rafn Benediktsson & Gunnar Sigurdsson
  6. Department of Child and Adolescent Psychiatry, Rheinische Kliniken Essen, University of Duisburg-Essen, Essen, 45147, Germany
    Anke Hinney & Johannes Hebebrand
  7. Steno Diabetes Center, Gentofte, 2820, Denmark
    Torben Hansen, Gitte Andersen, Knut Borch-Johnsen & Oluf Pedersen
  8. University of Aarhus, Aarhus, 8000, Denmark
    Knut Borch-Johnsen & Oluf Pedersen
  9. Research Centre for Prevention and Health, University Hospital Glostrup, Glostrup, 2600, Denmark
    Torben Jorgensen
  10. Institute of Medical Biometry and Epidemiology, Philipps-University of Marburg, Marburg, 35037, Germany
    Helmut Schäfer
  11. University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA
    Robert L Wilensky, Muredach P Reilly & Daniel J Rader
  12. Center for Clinical and Basic Research A/S, Ballerup, 2750, Denmark
    Yu Bagger & Claus Christiansen

Authors

  1. Agnar Helgason
  2. Snæbjörn Pálsson
  3. Gudmar Thorleifsson
  4. Struan F A Grant
  5. Valur Emilsson
  6. Steinunn Gunnarsdottir
  7. Adebowale Adeyemo
  8. Yuanxiu Chen
  9. Guanjie Chen
  10. Inga Reynisdottir
  11. Rafn Benediktsson
  12. Anke Hinney
  13. Torben Hansen
  14. Gitte Andersen
  15. Knut Borch-Johnsen
  16. Torben Jorgensen
  17. Helmut Schäfer
  18. Mezbah Faruque
  19. Ayo Doumatey
  20. Jie Zhou
  21. Robert L Wilensky
  22. Muredach P Reilly
  23. Daniel J Rader
  24. Yu Bagger
  25. Claus Christiansen
  26. Gunnar Sigurdsson
  27. Johannes Hebebrand
  28. Oluf Pedersen
  29. Unnur Thorsteinsdottir
  30. Jeffrey R Gulcher
  31. Augustine Kong
  32. Charles Rotimi
  33. Kári Stefánsson

Corresponding authors

Correspondence toAgnar Helgason or Kári Stefánsson.

Ethics declarations

Competing interests

A.H., G.T., V.E., S.G., I.R., U.T., J.R.G., A.K. and K.S. own stock or stock options in deCODE Genetics.

S.F.A.G. owns stock options in deCODE, and as an employee of the Children's Hospital of Philadelphia, he is currently involved in a lawsuit filed by deCODE.

Supplementary information

Supplementary Fig. 1

The structure of LD across a 545-kb region containing the TCF7L2 gene. (PDF 200 kb)

Supplementary Fig. 2

Comparing the risk of different rs7903146 and DG10S478 and rs7903146 and rs12255372 haplotypes. (PDF 93 kb)

Supplementary Fig. 3

Observed and expected rEHH values for HapMap population samples based on three demographic scenarios. (PDF 104 kb)

Supplementary Table 1

Association of type 2 diabetes risk with the markers DG10S478, rs12255372 and rs7903146 in West African subgroups. (PDF 14 kb)

Supplementary Table 2

Association of HapBT2D with 14 phenotypic traits linked to energy metabolism in Icelandic controls. (PDF 24 kb)

Supplementary Table 3

Ancestral states and frequencies of 42 SNPs used in FST selection analyses. (PDF 29 kb)

Supplementary Table 4

Demographic settings used in coalescent simulations. (PDF 17 kb)

Supplementary Table 5

Interpolated recombination map positions and minor allele frequencies. (PDF 201 kb)

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Helgason, A., Pálsson, S., Thorleifsson, G. et al. Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution.Nat Genet 39, 218–225 (2007). https://doi.org/10.1038/ng1960

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