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, HapB_T2D, 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.

1. deCODE genetics, 101 Reykjavik, Iceland.
2. University of Iceland, 101 Reykjavik, Iceland.
3. National Human Genome Center, Department of Community and Family Medicine, Howard University, Washington DC 20060, USA.
4. Icelandic Heart Association, 201 Kopavogur, Iceland.
5. National University Hospital, 101 Reykjavik, Iceland.
6. Department of Child and Adolescent Psychiatry, Rheinische Kliniken Essen, University of Duisburg-Essen, 45147 Essen, Germany.
7. Steno Diabetes Center, 2820 Gentofte, Denmark.
8. University of Aarhus, 8000 Aarhus, Denmark.
9. Research Centre for Prevention and Health, University Hospital Glostrup, 2600 Glostrup, Denmark.
10. Institute of Medical Biometry and Epidemiology, Philipps-University of Marburg, 35037 Marburg, Germany.
11. University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 USA.
12. Center for Clinical and Basic Research A/S, 2750 Ballerup, Denmark.
13. Current address: Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, 3516 Civic Center Blvd, Philadelphia, Pennsylvania 19104, USA.

Correspondence to: Agnar Helgason¹ e-mail: agnar@decode.is

Correspondence to: Kári Stefánsson¹ e-mail: kstefans@decode.is

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