Discovery of common variants associated with low TSH levels and thyroid cancer risk

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Abstract

To search for sequence variants conferring risk of nonmedullary thyroid cancer, we focused our analysis on 22 SNPs with a P < 5 × 10−8 in a genome-wide association study on levels of thyroid stimulating hormone (TSH) in 27,758 Icelanders. Of those, rs965513 has previously been shown to associate with thyroid cancer. The remaining 21 SNPs were genotyped in 561 Icelandic individuals with thyroid cancer (cases) and up to 40,013 controls. Variants suggestively associated with thyroid cancer (P < 0.05) were genotyped in an additional 595 non-Icelandic cases and 2,604 controls. After combining the results, three variants were shown to associate with thyroid cancer: rs966423 on 2q35 (OR = 1.34; Pcombined = 1.3 × 10−9), rs2439302 on 8p12 (OR = 1.36; Pcombined = 2.0 × 10−9) and rs116909374 on 14q13.3 (OR = 2.09; Pcombined = 4.6 × 10−11), a region previously reported to contain an uncorrelated variant conferring risk of thyroid cancer. A strong association (P = 9.1 × 10−91) was observed between rs2439302 on 8p12 and expression of NRG1, which encodes the signaling protein neuregulin 1, in blood.

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Figure 1: Study design and results.
Figure 2: Correlation between relative expression of NRG1 in blood (y axis) and genotypes (x axis) of rs2439302 on 8p12.

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Acknowledgements

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

Author information

The study was designed and results were interpreted by J.G., P.S., D.F.G., A.K. and K.S. Statistical analysis was carried out by P.S., D.F.G., G.M., G.T., J.G. and A.K. Subject recruitment and biological material collection and handling was organized and carried out by J.G., J.G.J., S.N.S., H.He, W.L., R.N., M.D.R., R.T.K., M.C.H.de.V., T.S.P., M.d.H., E.A., A.P., E.P., A.G.-C., A.D.J., F.R., G.B.W., H.B., L.T., I.O., G.I.E., U.S.B., H.Holm, K.K., H.K., J.R.G., L.A.L.M.K., R.T.N.-M., T.J., H. Hjartarson, J.I.M., A.de.la.C., J.H., U.T. and T.R. Genotyping was supervised and carried out by J.G., A.J., A.S., H.He, H.J., H.Th.H., O.Th.M., W.L. and U.T. 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), A.d.l.C. (US) and R.T.N.-M. and L.A.L.M.K. (The Netherlands).

Correspondence to Julius Gudmundsson or Kari Stefansson.

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Competing interests

The authors from deCODE are employees of deCODE genetics Inc. M.D.R. has previously been on an advisory board for Veracyte, Inc. and has been on an advisory panel for AstraZeneca.

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