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In order to search for sequence variants conferring risk of thyroid cancer we conducted a genomewide 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 (T 4 ) and high concentration of triiodothyronine (T 3 ).Thyroid carcinoma is the most common endocrine malignancy, and its incidence in industrialized countries has been rising over the past few decades: at present, its incidence is 4.9 and 14.1 per 100,000 in the United States for males and females of European ancestry, respectively (see URLs section in Methods). It has been determined that the risk of thyroid cancer has a greater genetic component than the risk of any other cancer, and the effect has been shown to extend beyond the nuclear family 1-3 . The risk has been reported to be highest for first-degree male relatives of male probands but lowest for first-degree female relatives of female probands 4 . Not much is known about variants in the sequence of the genome that affect the risk of thyroid cancer. However, recently variants at 1p12, 8q24 and in the premiR146a at 5q33 have been implicated in the disease 5-8 .Thyroid cancer is classified histologically into four main groups: papillary (PTC), follicular (FTC), medullary (MTC) and undifferentiated or anaplastic thyroid carcinomas. Most of all thyroid tumors are PTC (80-85%) or FTC (10-15%) 9,10 . Among established risk factors for FTC is deficiency in iodine intake, and for PTC the risk factors include ionizing radiation, nodular disease of the thyroid as well as family history 9 . Medullary thyroid cancer is a part of the multiple endocrine neoplasia type 2 syndrome (MEN2) and accounts for about 1-3% of all thyroid cancer cases. Its pathogenesis can mainly be explained by mutations in the RET oncogene 11 . Anaplastic thyroid cancer accounts for between 1% and 5% of all carcinomas of the thyroid. This subphenotype is one of the most aggressive of all human malignancies, but little is known about its pathogenesis 12 .In Iceland, the annual incidence of thyroid cancer is similar to that in the United States, at 4.6 and 12.1 per 100,000 for males and fe...

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.