ETA2023 45th Annual Meeting of the European Thyroid Association ETA 2023 Oral Session 5: Young Investigators / Basic (6 abstracts)
Multi-Trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications
Rosalie Sterenborg 1 , Inga Steinbrenner 2 , Yong Li 2 , Melissa Bujnis 3 , Tatsuhiko Naito 4 , Eirini Marouli 5 , Thyroidomics Consortium 6 , Anna Köttgen 7 , Johannes W.A. Smit 8 , Robin Peeters 9 , Alexander Teumer 10 & Marco Medici 11
1Radboud University Medical Center, Nijmegen, Erasmus Medical Center, Rotterdam, Department of Internal Medicine - Division of Endocrinology, Nijmegen, Netherlands; 2Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany; 3The University of Utah, Salt Lake City, United States; 4Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan; 5William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; 6Thyroidomics Consortium; 7Albert-Ludwigs-Universität Freiburg, Innere Medizin IV, Nephrologie und Allgemeinmedizin, Universitätsklinikum, Institute of Genetic Epidemiology, Department of Biometry, Epidemiology and Medical Bioinformatics, Faculty of Medicine and Medical Center–university of Freiburg, Freiburg, Germany, Germany; 8Radboud University Nijmegen Medical Centre, 463 Internal Medicine, Nijmegen, Netherlands; 9Academic Center for Thyroid Diseases, Department of Endocrinology, Erasmus, Department of Internal Medicine, Rotterdam, Netherlands; 10University Medicine Greifswald, Department of Psychiatry and Psychotherapy, Department of Psychiatry and Psychotherapy, Greifswald, Germany; 11Radboud University Medical Center, Nijmegen, Erasmus Medical Center, Rotterdam, Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands
Introduction: In the last decade, it has become clear that not only overt but also subclinical hypo- and hyperthyroidism are associated with several adverse clinical outcomes, including atrial fibrillation, coronary heart disease, stroke and mortality. More recently, various studies have suggested that even small differences in thyroid function within the reference range are associated with clinical consequences. Genetic factors are responsible for up to 58-71% of the variation in thyrotropin (TSH) and free thyroxine (FT4) levels. However, to date only a fraction of the genetic footprint of TSH and FT4 has been clarified. Furthermore, the genetic background of triiodothyronine (T3) has been understudied, emphasizing the need for agnostic approaches such as genome-wide association studies (GWAS) to further unravel the additional underlying genetic contributors.
Methods: We conducted large GWAS meta-analyses of thyroid function in up to 271,040 individuals of European ancestry from the ThyroidOmics Consortium, including reference range TSH, FT4, free and total T3, and proxies for metabolism (T3/FT4 ratio). Secondary analyses included colocalization with mRNA levels using GTEx, functional enrichment and pathway analyses as well as polygenic risk score and Mendelian randomization analyses on a wide range of clinical endpoints.
Results: We revealed 198 loci associated with TSH (84 novel), 84 loci associated with FT4 (45 novel), and 29 novel loci for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the variation in TSH, FT4, total and free T3 concentrations, respectively. For FT4, the tissue enrichment and colocalization analyses revealed genes expressed in various peripheral tissues, whereas TSH-associated genes were predominantly expressed in the thyroid including multiple genes with a known role in the TSH signaling cascade and thyroid hormone synthesis, such as PDE8B, PDE10A and TPO. Genetically determined variations in reference range thyroid function were associated with a wide range of clinical outcomes including lipids, blood pressure, coronary artery disease, cardiac dysrhythmias, autoimmune diseases, and cancer.
Conclusion: This is the currently largest and most complete genetic analysis of thyroid function. These results leverage impact on understanding thyroid hormone physiology, reveal causal effects of reference range thyroid function on various diseases, and highlight multiple genes involved in thyroid function and metabolism. Furthermore, this study fosters possibilities applying genetics in diagnostics and identifying candidates for therapeutic targets to personalize treatment of thyroid diseases.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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