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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

    • Struan F A Grant

    Current address: Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, 3516 Civic Center Blvd, Philadelphia, Pennsylvania 19104, USA.

Affiliations

  1. deCODE genetics, 101 Reykjavik, 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, 101 Reykjavik, Iceland.

    • Snæbjörn Pálsson
  3. National Human Genome Center, Department of Community and Family Medicine, Howard University, Washington DC 20060, USA.

    • Adebowale Adeyemo
    • , Yuanxiu Chen
    • , Guanjie Chen
    • , Mezbah Faruque
    • , Ayo Doumatey
    • , Jie Zhou
    •  & Charles Rotimi
  4. Icelandic Heart Association, 201 Kopavogur, Iceland.

    • Rafn Benediktsson
    •  & Gunnar Sigurdsson
  5. National University Hospital, 101 Reykjavik, Iceland.

    • Rafn Benediktsson
    •  & Gunnar Sigurdsson
  6. Department of Child and Adolescent Psychiatry, Rheinische Kliniken Essen, University of Duisburg-Essen, 45147 Essen, Germany.

    • Anke Hinney
    •  & Johannes Hebebrand
  7. Steno Diabetes Center, 2820 Gentofte, Denmark.

    • Torben Hansen
    • , Gitte Andersen
    • , Knut Borch-Johnsen
    •  & Oluf Pedersen
  8. University of Aarhus, 8000 Aarhus, Denmark.

    • Knut Borch-Johnsen
    •  & Oluf Pedersen
  9. Research Centre for Prevention and Health, University Hospital Glostrup, 2600 Glostrup, Denmark.

    • Torben Jorgensen
  10. Institute of Medical Biometry and Epidemiology, Philipps-University of Marburg, 35037 Marburg, Germany.

    • Helmut Schäfer
  11. University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 USA.

    • Robert L Wilensky
    • , Muredach P Reilly
    •  & Daniel J Rader
  12. Center for Clinical and Basic Research A/S, 2750 Ballerup, Denmark.

    • Yu Bagger
    •  & Claus Christiansen

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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.

Corresponding authors

Correspondence to Agnar Helgason or Kári Stefánsson.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    The structure of LD across a 545-kb region containing the TCF7L2 gene.

  2. 2.

    Supplementary Fig. 2

    Comparing the risk of different rs7903146 and DG10S478 and rs7903146 and rs12255372 haplotypes.

  3. 3.

    Supplementary Fig. 3

    Observed and expected rEHH values for HapMap population samples based on three demographic scenarios.

  4. 4.

    Supplementary Table 1

    Association of type 2 diabetes risk with the markers DG10S478, rs12255372 and rs7903146 in West African subgroups.

  5. 5.

    Supplementary Table 2

    Association of HapBT2D with 14 phenotypic traits linked to energy metabolism in Icelandic controls.

  6. 6.

    Supplementary Table 3

    Ancestral states and frequencies of 42 SNPs used in FST selection analyses.

  7. 7.

    Supplementary Table 4

    Demographic settings used in coalescent simulations.

  8. 8.

    Supplementary Table 5

    Interpolated recombination map positions and minor allele frequencies.

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DOI

https://doi.org/10.1038/ng1960

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