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Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations

Abstract

In order to search for sequence variants conferring risk of thyroid cancer we conducted a genome-wide association study in 192 and 37,196 Icelandic cases and controls, respectively, followed by a replication study in individuals of European descent. Here we show that two common variants, located on 9q22.33 and 14q13.3, are associated with the disease. Overall, the strongest association signals were observed for rs965513 on 9q22.33 (OR = 1.75; P = 1.7 × 10−27) and rs944289 on 14q13.3 (OR = 1.37; P = 2.0 × 10−9). The gene nearest to the 9q22.33 locus is FOXE1 (TTF2) and NKX2-1 (TTF1) is among the genes located at the 14q13.3 locus. Both variants contribute to an increased risk of both papillary and follicular thyroid cancer. Approximately 3.7% of individuals are homozygous for both variants, and their estimated risk of thyroid cancer is 5.7-fold greater than that of noncarriers. In a study on a large sample set from the general population, both risk alleles are associated with low concentrations of thyroid stimulating hormone (TSH), and the 9q22.33 allele is associated with low concentration of thyroxin (T4) and high concentration of triiodothyronine (T3).

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Figure 1: A schematic view of the association results and LD structure in a region on chromosome 9q22.33.

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Acknowledgements

We thank the study participants whose contribution made this work possible. This project was funded in part by the following contract numbers: US National Institutes of Health CA16058 and CA124570.

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Contributions

The study was designed and results were interpreted by J.G., P.S., D.F.G., J.T.B., A.K. and K.S. Statistical analysis was carried out by P.S., D.F.G., F.G., J.G., J.T.B., M.L.F. and A.K. Subject recruitment, biological material collection and handling was organized and carried out by J.G., J.G.J., J.T.B., S.N.S., H.He, R.N., E.A., E.F., E.P., B.S., M.M., G.I.E., U.S.B., H.Holm, K.K., H.K., J.R.G., T.J., T.R., H.Hjartarsson, J.I.M., A.d.l.C., J.H. and U.T. Genotyping was supervised and carried out by J.G, J.T.B., A.S., H.He, M.J., D.N.M., S.M., O.B.S., H.Helgadottir, W.L., T.B., A.d.l.C., T.R. and U.T. Authors J.G., P.S., D.F.G. and K.S. drafted the manuscript. All authors contributed to the final version of the paper. Principal collaborators for the replication case-control samples were J.I.M. (Spain) and A.d.l.C. (US).

Corresponding authors

Correspondence to Julius Gudmundsson or Kari Stefansson.

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Competing interests

The authors from deCODE are shareholders in deCODE genetics Inc.

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Supplementary Methods, Supplementary Figures 1 and 2, Supplementary Tables 1–5 (PDF 1061 kb)

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Gudmundsson, J., Sulem, P., Gudbjartsson, D. et al. Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations. Nat Genet 41, 460–464 (2009). https://doi.org/10.1038/ng.339

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