Genetics of Thyroid Function: Relevance for Biology and Disease Management

Genetic factors are a major contributor to variation in thyroid function. Recent studies have partly identified the responsible common genetic variants and studied their application in unraveling thyroid (patho)physiology as well as their potential clinical use.

This review summarizes the current state of knowledge regarding the genetic architecture of thyroid function as well as its applications to improve (patho)physiological understanding and clinical management of thyroid (dys)function.

Genome-wide association studies (GWAS) have been successful in detecting numerous genetic variants affecting variation in thyrotropin (TSH), free thyroxine, and triiodothyronine concentrations. Subsequent emerging high-throughput in silico and in vitro strategies are of particular value in unraveling functionality of these novel genes and its genetic variants. Translational methods such as mendelian randomization (MR) and polygenic scores (PGSs) can provide important insights into causal associations or susceptibility to disease. Moreover, PGSs show potential in adjusting personalized TSH reference ranges by distinguishing between individual hypothalamic-pituitary-thyroid-axis set-point effects and (subclinical) thyroid dysfunction.

Functional characterization of the associated genes and variants in GWAS is warranted as the majority are located in genes with a yet unknown role in thyroid hormone physiology. Integration of multi-omics data and optimalization of translational applications such as MR and PGS show potential to further unravel the underlying molecular mechanisms and pave the way for incorporation of genetics in personalized management of thyroid diseases.