Objective: Subclinical thyroid disease and even variation in normal range thyroid function have been associated with various adverse health outcomes. While most of the variation in thyroid function is determined by genetic factors, single nucleotide polymorphisms (SNPs) identified via genome-wide association analyses have only explained ~4-8% of this variance. Most SNPs found were in or nearby genes with no known role in thyroid hormone (TH) regulation. Therefore, we investigated the effects of common genetic variants in selected genes with a known role in thyroid hormone regulation on serum TSH and FT4 concentrations.

Methods: SNPs in or within 10kb of ninety-seven TH regulating genes were included (30,168 TSH SNPs, and 30,093 FT4 SNPs). Associations were studied in 72,167 individuals from the ThyroidOmics Consortium. Multiple-testing correction was applied using a false-discovery rate of 1%. Linkage disequilibrium-based clumping was used to identify independently associated SNPs. SNP-based explained variances were calculated using SumHer software.

Results: In addition to the 10 known TSH associated SNPs and 10 FT4 associated SNPs in these regions, we identified 29 novel SNPs associations for both TSH and FT4 in predominantly hypothalamic-pituitary-thyroid axis genes for TSH and in peripheral metabolism and transport genes for FT4. Genome-wide SNP variation explained 21% (SD 1.7) of the total variation in both TSH and FT4 levels, whereas SNPs in the 97 TH regulation genes explained 2.0-2.2% (SD 0.3-0.4) for TSH and FT4 respectively. 

Conclusion: We identified a large number of novel variants associated with TSH and FT4 in genes important in thyroid hormone regulation. However, our analyses show that only a minor part of the variation in TSH and FT4 levels is determined by SNPs in TH regulating genes, which substantiates the need for larger genetic studies to unravel novel, yet unknown, pathways in thyroid hormone biology.