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Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution

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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Figure 1: Median-joining (MJ) network30 describing the evolutionary relationships between 78 distinct haplotypes, inferred from the genotypes of 63 SNPs and one microsatellite (DG10S478) from the TCF7L2 exon 4 LD block.
Figure 2: The LRH selection test at increasing physical distance from the core haplotype region.

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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).

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Correspondence to Agnar Helgason or Kári Stefánsson.

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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.

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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