Researchers have identified 23 newly associated variants for thyrotropin (thyroid-stimulating hormone) and 25 variants for free thyroxine 4 (FT4), resulting in a substantial increase in the number of variants known to determine interindividual variation in thyroid function, according to the results of a study published in the Journal of Clinical Endocrinology & Metabolism.
The candidate gene study investigated the effect of single nucleotide polymorphisms (SNPs) in 96 established thyroid hormone-regulating genes on serum thyroxine and FT4 concentrations in individuals from 22 countries in Europe.
The researchers assessed 54,288 individuals for thyrotropin and 49,269 individuals for FT4. The mean age of study participants was 55.1 (SD 11.8) years, and 52.0% were women. The study authors searched PubMed from inception to February 2021 to create a complete list of genes involved in thyroid hormone regulation.
The investigators obtained association statistics for all SNPs within the 96 candidate genes from the ThyroidOmics Consortium dataset. Linkage disequilibrium-based clumping was used to select independently associated SNPs for each trait.
A total of 39 SNPs in or close to 13 candidate genes were independently associated with thyrotropin concentrations, of which 23 SNPs in 13 genes were novel. The novel genes included those that have a role in thyrotropin signaling (CGA, GNAS, TBL1X), regulation of thyroid differentiation and expression or transcription of thyroid-specific genes (FOXE1, NKX2-1), transportation of iodide into the thyroid and iodination of tyrosine residues (SLC26A7, TPO), and thyroid hormone conjugation (SULT1B1).
A total of 39 independent genetic variants in or nearby 25 candidate genes were associated with FT4, of which 25 variants in 18 candidate genes were novel. The novel associated candidate genes have a role in thyroid hormone metabolism (DIO3OS, SULT1A1, SULT1B1, UGT1A7), thyroid hormone transport (ABCB1, SLC16A2, SLCO1B1), regulation of peripheral thyroid hormone action (NCOR1), encoding or influencing the expression of factors in the hypothalamic-pituitary-thyroid axis (TRH, TRHR, IGSF-1, CGA, PDE8B), or pituitary development and differentiation (LHX3, FGFR1).
The GLIS3, CGA, FOXE1, PDE8B, SULT1B1, and TPO candidate genes included SNPs that were associated with either thyrotropin or FT4 concentrations, and none of the SNPs was associated with both thyrotropin and FT4 concentrations.
All common SNPs (minor allele frequency >1%) in the entire genome accounted for 21.2% (SD 1.64) of the variance in thyrotropin concentrations and 20.8% (SD 1.73) of the variance in FT4 serum concentrations. The common SNPs in or near all 96 candidate genes accounted for 1.9% (SD 0.35) of the variation in thyrotropin and 2.6% (SD 0.41) of the variation in FT4.
The researchers noted that their findings cannot be generalized to non-European populations, and some of the results are potentially false positive. Also, the results could not be confirmed in a replication analysis in a well-powered, independent cohort.
“While this approach yielded a number of novel independently associated variants, we also showed that genetic variation in the currently known [thyroid hormone]-regulating genes only explains a remarkable small part of the variation in thyroid function,” concluded the study authors. “Therefore, large-scale genetic studies focusing on both common and rare variation are needed, together with in vitro studies, to identify yet unknown pathways and elucidating the missing heritability in thyroid function.”
Sterenborg RBTM, Galesloot TE, Teumer A, et al. The effects of common genetic variation in 96 genes involved in thyroid hormone regulation on TSH and FT4 concentrations. J Clin Endocrinol Metab. Published online March 9, 2022. doi:10.1210/clinem/dgac136