NEW YORK (GenomeWeb News) – A Decode Genetics-led team has applied its genome-wide association study approach, which involves imputing some SNPs from Icelanders' genome sequence data, to find genetic variants contributing both to thyroid stimulating hormone levels and to risk of non-medullary thyroid cancer. The findings appeared online in Nature Genetics yesterday.
"To date, the at-risk alleles of all the variants that confer risk of thyroid cancer associate with decreased serum levels of TSH, suggesting that the primary disorder in non-medullary thyroid cancer is an endocrine one, characterized by decreased concentration of TSH," Decode CEO and University of Iceland researcher Kari Stefansson, the study's senior author, said in a statement.
Through a GWAS involving tens of thousands of Icelanders, the group narrowed in on nearly two-dozen variants linked to TSH levels. By genotyping sites suspected of affecting TSH levels or increasing thyroid cancer risk in additional groups of individuals with and without thyroid cancer from Iceland and elsewhere, the team found three previously undetected loci linked to non-medullary thyroid cancer risk.
Non-medullary thyroid makes up the majority of thyroid cancer cases, Stefansson and co-authors explained, with many of these non-medullary thyroid cancers involving tumors with so-called papillary or follicular histology patterns.
Because at least two of the genetic variants associated with papillary and follicular thyroid tumors through past GWAS also correspond to lower-than-usual levels of TSH, the team decided to look for variants that affect blood concentrations of the hormone as part of their search for thyroid cancer-associated sites in the genome.
Using Illumina microarrays, researchers genotyped 27,758 individuals from Iceland with known blood TSH levels. Along with the sites interrogated directly by the chip itself, they also used genomic data for 457 Icelanders whose genomes were sequenced to 10 times coverage to impute SNP genotypes at millions more sites.
The GWAS led to 22 SNPs that were significantly associated with TSH levels, including one on chromosome 9 that was already implicated in thyroid cancer risk in a 2009 Nature Genetics study by researchers at Decode and elsewhere.
Researchers genotyped the remaining 21 SNPs in 561 individuals with thyroid cancer and nearly 3,200 unaffected individuals. They also included genotyping information for almost 40,000 controls already tested using Illumina arrays.
Another SNP suspected of playing a role in thyroid cancer based on chip and imputed data on hundreds of non-medullary thyroid cancer cases and tens of thousands of controls from Iceland was tested in the same manner.
After this analysis — and additional follow-up experiments in thyroid cancer cases and control groups from the US, Netherlands, and Spain — the team was left with three thyroid cancer-associated variants on chromosomes 2, 8, and 14.
Another variant replicated in just one of the three case-control groups tested, researchers noted, and requires further study in the future.
Consistent with past research, the three thyroid cancer-associated variants had also coincided with lower TSH levels in the initial GWAS. Still, the study's authors explained, more work is needed to understand if, and how, TSH levels relate to cancer risk, since not all of the variants that curtail TSH expression were implicated in the team's thyroid cancer analyses.
"The consequence of the low concentration of TSH may be less differentiation of the thyroid epithelium, leading to a predisposition to malignant transformation," they wrote. "There is, however, more to the story of thyroid cancer because not all sequence variants associating with low TSH levels associate with the risk of the disease."
When they sifted through available gene expression data for almost 1,000 healthy individuals from the Icelandic population, meanwhile, they found that a new thyroid cancer-associated variant called rs2439302 on chromosome 8 appears to influence the expression of at least one gene: the neuregulin 1 coding gene NRG1.
"The strong association results seen for rs2439302 and thyroid cancer on one hand, and the expression of NRG1 on the other hand, strongly suggest that NRG1 plays a role in the etiology of non-medullary thyroid cancer," the study authors noted.