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The great majority of thyroid cancers are of the non-medullary type. Here we report findings from a genome-wide association study of non-medullary thyroid cancer, including in total 3,001 patients and 287,550 controls from five study groups of European descent. Our results yield five novel loci (all with P combined <3 × 10 −8 ): 1q42.2 (rs12129938 in PCNXL2 ), 3q26.2 (rs6793295 a missense mutation in LRCC34 near TERC ), 5q22.1 (rs73227498 between NREP and EPB41L4A ), 10q24.33 (rs7902587 near OBFC1 ), and two independently associated variants at 15q22.33 (rs2289261 and rs56062135; both in SMAD3 ). We also confirm recently published association results from a Chinese study of a variant on 5p15.33 (rs2736100 near the TERT gene) and present a stronger association result for a moderately correlated variant (rs10069690; OR=1.20, P=3.2 × 10 −7 ) based on our study of individuals of European ancestry. In combination, these results raise several opportunities for future studies of the pathogenesis of thyroid cancer. Non-medullary thyroid cancers include papillary and follicular subtypes, and are the most common type of thyroid cancer. Here, the authors extend previous work by performing a large genome-wide association study and find five novel loci associated with this disease.

Julius Gudmundsson and colleagues report a genome-wide association study for circulating levels of thyroid-stimulating hormone in 27,758 individuals not known to have thyroid cancer. They follow with thyroid cancer association analyses and identify common variants at three loci newly associated with susceptibility to thyroid cancer. 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; P combined = 1.3 × 10 −9 ), rs2439302 on 8p12 (OR = 1.36; P combined = 2.0 × 10 −9 ) and rs116909374 on 14q13.3 (OR = 2.09; P combined = 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.

Julius Gudmundsson and colleagues report the association of two SNPs on chromosomes 9 and 14 with thyroid cancer in European populations. The variants are near FOXE1 and NKX2-1 , both good biological candidates, and individuals who are homozygous for both risk variants have a 5.7-fold greater risk of thyroid cancer. 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 (T 4 ) and high concentration of triiodothyronine (T 3 ).