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 x 10(-27)) and rs944289 on 14q13.3 (OR = 1.37; P = 2.0 x 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)).

Figure 1

A schematic view of the association results and LD structure in a region on chromosome 9q22.33. (a) Single-marker (blue diamonds) association results for SNPs from the Illumina Hap300/370 chip. The results are based on analysis of 192 and 37,217 Icelandic thyroid cancer cases and controls, respectively, and shown are P values corrected for relatedness. (b) Pairwise correlation coefficient (r²) from the CEU HapMap population and the relative location of genes in the region, based on the UCSC Genome Browser, build 36. The locations of rs965513 and rs10759944 are not resolved in this image.