Best Practice & Research Clinical Endocrinology & Metabolism
1Genetics of thyroid function
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.
References (97)
- et al.
Subclinical thyroid disease
Lancet
(2012) - et al.
Functional significance of the thyrotropin receptor germline polymorphism D727E
Biochem Biophys Res Commun
(2003) - et al.
Phosphodiesterase 8B gene variants are associated with serum TSH levels and thyroid function
Am J Hum Genet
(2008) - et al.
A locus on chromosome 1p36 is associated with thyrotropin and thyroid function as identified by genome-wide association study
Am J Hum Genet
(2010) - et al.
Associations between single nucleotide polymorphisms in thyroid hormone transporter genes (MCT8, MCT10 and OATP1C1) and circulating thyroid hormones
Clin Chim Acta
(2013) - et al.
Genetic variation in thyroid hormone transporters
Best Pract Res Clin Endocrinol Metab
(2007) - et al.
Genome-wide association study identifies four genetic loci associated with thyroid volume and goiter risk
Am J Hum Genet
(2011) - et al.
Variants near FOXE1 are associated with hypothyroidism and other thyroid conditions: using electronic medical records for genome- and phenome-wide studies
Am J Hum Genet
(2011) - et al.
The interaction between the forkhead thyroid transcription factor TTF-2 and the constitutive factor CTF/NF-1 is required for efficient hormonal regulation of the thyroperoxidase gene transcription
J Biol Chem
(1999) - et al.
Thyroxine downregulates Sox9 and promotes chondrocyte hypertrophy
Biochem Biophys Res Commun
(2003)
Rare-variant association testing for sequencing data with the sequence kernel association test
Am J Hum Genet
Epigenome-wide association of DNA methylation markers in peripheral blood from Indian Asians and Europeans with incident type 2 diabetes: a nested case-control study
Lancet Diabetes Endocrinol
Long-term residual complaints and psychosocial sequelae after remission of hyperthyroidism
Psychoneuroendocrinology
Polygenic risk and the development and course of asthma: an analysis of data from a four-decade longitudinal study
Lancet Respir Med
Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials
Lancet
Narrow individual variations in serum T(4) and T(3) in normal subjects: a clue to the understanding of subclinical thyroid disease
J Clin Endocrinol Metab
Thyroid function in the euthyroid range and adverse outcomes in older adults
J Clin Endocrinol Metab
Thyroid function within the reference range and the risk of stroke: an individual participant data analysis
J Clin Endocrinol Metab
Normal thyroid function and the risk of atrial fibrillation: the Rotterdam study
J Clin Endocrinol Metab
Thyroid function within the normal range and the risk of depression: a population-based cohort study
J Clin Endocrinol Metab
Smoking reduces the risk of hypothyroidism and increases the risk of hyperthyroidism: evidence from 450842 mothers giving birth in Denmark
Clin Endocrinol
Major genetic influence on the regulation of the pituitary-thyroid axis: a study of healthy Danish twins
J Clin Endocrinol Metab
Heritability of serum TSH, free T4 and free T3 concentrations: a study of a large UK twin cohort
Clin Endocrinol
Genetic and environmental influences on thyroid hormone variation in Mexican Americans
J Clin Endocrinol Metab
The impact of a TSH receptor gene polymorphism on thyroid-related phenotypes in a healthy Danish twin population
Clin Endocrinol
Polymorphisms in thyroid hormone pathway genes are associated with plasma TSH and iodothyronine levels in healthy subjects
J Clin Endocrinol Metab
Effects of serum TSH and FT4 levels and the TSHR-Asp727Glu polymorphism on bone: the Rotterdam study
Clin Endocrinol
Germline polymorphism of codon 727 of human thyroid-stimulating hormone receptor is associated with toxic multinodular goiter
J Clin Endocrinol Metab
Thyrotropin receptor mutations in hyperfunctioning thyroid adenomas from Brazil
Thyroid
Discovery of common variants associated with low TSH levels and thyroid cancer risk
Nat Genet
A large-scale association analysis of 68 thyroid hormone pathway genes with serum TSH and FT4 levels
Eur J Endocrinol
A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function
PLoS Genet
A genome-wide association study on thyroid function and anti-thyroid peroxidase antibodies in Koreans
Hum Mol Genet
Meta-analysis of two genome-wide association studies identifies four genetic loci associated with thyroid function
Hum Mol Genet
Genome-wide association study identifies a novel susceptibility gene for serum TSH levels in Chinese populations
Hum Mol Genet
Minireview: thyroid hormone transporters: the knowns and the unknowns
Mol Endocrinol
Prevalence and functional analysis of the S107P polymorphism (rs6647476) of the monocarboxylate transporter 8 (SLC16A2) gene in the male population of north-west Spain (Galicia)
Clin Endocrinol
Organic anion transporter 1B1: an important factor in hepatic thyroid hormone and estrogen transport and metabolism
Endocrinology
Thyroid hormone transport and metabolism by organic anion transporter 1C1 and consequences of genetic variation
Endocrinology
Molecular aspects of thyroid hormone transporters, including MCT8, MCT10, and OATPs, and the effects of genetic variation in these transporters
J Mol Endocrinol
Different causes of reduced sensitivity to thyroid hormone: diagnosis and clinical management
Clin Endocrinol
Scanning of estrogen receptor alpha (ERalpha) and thyroid hormone receptor alpha (TRalpha) genes in patients with psychiatric diseases: four missense mutations identified in ERalpha gene
Am J Med Genet
Identification and consequences of polymorphisms in the thyroid hormone receptor alpha and beta genes
Thyroid
The association of polymorphisms in the type 1 and 2 deiodinase genes with circulating thyroid hormone parameters and atrophy of the medial temporal lobe
J Clin Endocrinol Metab
A common variation in deiodinase 1 gene DIO1 is associated with the relative levels of free thyroxine and triiodothyronine
J Clin Endocrinol Metab
A polymorphism in type I deiodinase is associated with circulating free insulin-like growth factor I levels and body composition in humans
J Clin Endocrinol Metab
The relationship of deiodinase 1 genotype and thyroid function to lifetime history of major depression in three independent populations
Am J Med Genet Part B Neuropsychiatr Genet
The effect of the D1-C785T polymorphism in the type 1 iodothyronine deiodinase gene on the circulating thyroid hormone levels in Romanian women with preeclampsia. Association with the degree of severity and pregnancy outcome of preeclampsia
Gynecol Endocrinol
Cited by (21)
The Effects of Common Genetic Variation in 96 Genes Involved in Thyroid Hormone Regulation on TSH and FT4 Concentrations
2022, Journal of Clinical Endocrinology and MetabolismGenetics of congenital hypothyroidism: Modern concepts
2022, Pediatric InvestigationClassification of maternal thyroid function in early pregnancy using repeated blood samples
2022, European Thyroid JournalSecondary Hyperlipidemia and Atherosclerosis in Patients with Thyroid Pathology
2022, Kardiologija v BelarusiGenetic Variation and Mendelian Randomization Approaches
2022, Advances in Experimental Medicine and Biology