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Genetics of thyroid function

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Recent studies show that subtle variations in thyroid function, including subclinical thyroid dysfunction, and even variation in thyroid function within the normal range, are associated with morbidity and mortality. It is estimated that 40–65% of the inter-individual variation in serum TSH and FT4 levels is determined by genetic factors. To identify these factors, various linkage and candidate gene studies have been performed in the past, which have identified only a few genes. In the last decade, genome-wide association studies identified many new genes, while recent whole-genome sequencing efforts have also been proven to be effective. In the current review, we provide a systematic overview of these studies, including strengths and limitations. We discuss new techniques which will further clarify the genetic basis of thyroid function in the near future, as well as the potential use of these genetic markers in personalizing the management of thyroid disease patients.

Introduction

Thyroid hormone (TH) is essential for the development and function of virtually all human tissues. Its importance is illustrated by the effects of hypo- and hyperthyroidism, which are among the most common diseases in the general population and have been associated with substantial morbidity, as well as mortality. In a seminal study published in 2002 by Andersen et al., it was shown that the intra-individual variability in TSH and FT4 levels is within a narrow range, whereas the inter-individual variability is large (Fig. 1) [1]. This suggests that every individual has its own unique hypothalamic-pituitary thyroid (HPT) axis setpoint. This is relevant because not only subclinical thyroid dysfunction, but even variation in thyroid function within the normal range is associated with various adverse outcomes, including cardiovascular disease, depression and mortality [2], [3], [4], [5], [6]. It is estimated that 45–65% of the total variation in thyroid function is determined by genetic factors, while the rest of the variation is thought to be due to environmental factors (e.g., iodine status) and individual characteristics (e.g., age and BMI) [7], [8], [9], [10]. These findings were followed by an era in which many candidate gene studies were performed, aiming to decipher the genetic basis of thyroid function. These studies have unfortunately identified only a limited number of genetic loci. More recently, the introduction of large-scale genome wide association studies has been very successful in identifying many genetic loci associated with thyroid function. These genetic variants cannot only provide new insights into thyroid (patho)physiology, but have also been suggested to play a future role in the management of thyroid disease.

In the current review, we provide a systematic overview of the genes identified in the above mentioned studies, with special emphasis on the more recent genome-wide association and whole-genome sequencing studies. We will specifically focus on the genetic determinants of normal-range thyroid function, as various reviews have been published about the genetic basis of hypo- and hyperthyroidism. Furthermore, we will discuss new techniques that are expected to further decipher the genetic basis of thyroid function in the near future. Finally, we discuss future directions for research, including the use of these markers in the prediction and treatment of thyroid disease.

Section snippets

Candidate gene studies

In the last 20 years, many candidate gene studies have been performed to investigate the genetic basis of the HPT axis. These studies typically investigate the relation between TH parameters or the risk of thyroid diseases, and common (i.e., minor allele frequency (MAF) > 5%) variants in genes with a known role in TH synthesis, metabolism, transport or action. Especially the earlier studies were limited by the fact that only a few genetic variants were tested, which only covered a minor part of

Genome-wide association studies (GWAS)

Genome-wide association studies follow a hypothesis-free approach in which typically 550,000 genetic variants across the entire genome are genotyped in each subject of the study. Depending on the reference panel used, up to 9 million additional genetic variants can then be imputed. Subsequently, each individual variant is tested against the phenotype of interest. Given the many statistical tests performed, a multiple-testing corrected p-value threshold of 5 × 10−8 is used to minimize the risk

Whole genome sequencing studies

Whole genome sequencing (WGS) studies result in much more information than GWAS, where only 0.1% of the nucleotides is assessed. Therefore, in order to identify rarer variants (with possibly larger effects), Taylor et al. performed the first WGS of serum TSH and FT4 levels in a total of 16,335 individuals [68]. For TSH, they identified new variants in PDE8B and SYN2, and replicated many of the loci previously identified in GWAS (Fig. 2). SYN2 is a neuron-specific phosphoprotein regulating

Discussion

In the previous sections, we have provided an overview of the current state of knowledge concerning the genetic basis of thyroid function. In the final section of this review, we will discuss how the remaining heritability can be uncovered, as well as directions for future research.

Summary

Understanding the genetic basis of thyroid function is important as recent studies have shown that even subtle variations in thyroid function can have substantial clinical effects. In the last few years, hypothesis-free genome-wide approaches have been very successful in identifying new genetic determinants of thyroid function (Fig. 2). Still, the largest part of the genetic variation in thyroid function remains unexplained, part of which is expected to be clarified by promising new techniques

Disclosure statement

The authors declare that none have either any financial interest or conflicts of interest.

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