Identification of Novel Genetic Loci Associated with Thyroid Peroxidase Antibodies and Clinical Thyroid Disease

Marco Medici*, Eleonora Porcu, Giorgio Pistis, Alexander Teumer, Suzanne J. Brown, Richard A. Jensen, Rajesh Rawal, Greet L. Roef, Theo S. Plantinga, Sita H. Vermeulen, Jari Lahti, Matthew J. Simmonds, Lise Lotte N. Husemoen, Rachel M. Freathy, Beverley M. Shields, Diana Pietzner, Rebecca Nagy, Linda Broer, Layal Chaker, Tim I. M. KorevaarMaria Grazia Plia, Cinzia Sala, Uwe Voelker, J. Brent Richards, Fred C. Sweep, Christian Gieger, Tanguy Corre, Eero Kajantie, Betina Thuesen, Youri E. Taes, W. Edward Visser, Andrew T. Hattersley, Juergen Kratzsch, Alexander Hamilton, Wei Li, Georg Homuth, Monia Lobina, Stefano Mariotti, Nicole Soranzo, Massimiliano Cocca, Matthias Nauck, Christin Spielhagen, Alec Ross, Alice Arnold, Martijn van de Bunt, Sandya Liyanarachchi, Margit Heier, Hans Joergen Grabe, Corrado Masciullo, Tessel E. Galesloot, Ee M. Lim, Eva Reischl, Peter J. Leedman, Sandra Lai, Alessandro Delitala, Alexandra P. Bremner, David I. W. Philips, John P. Beilby, Antonella Mulas, Matteo Vocale, Goncalo Abecasis, Tom Forsen, Alan James, Elisabeth Widen, Jennie Hui, Holger Prokisch, Ernst E. Rietzschel, Aarno Palotie, Peter Feddema, Stephen J. Fletcher, Katharina Schramm, Jerome I. Rotter, Alexander Kluttig, Doerte Radke, Michela Traglia, Gabriela L. Surdulescu, Huiling He, Jayne A. Franklyn, Daniel Tiller, Bijay Vaidya, Tim de Meyer, Torben Jorgensen, Johan G. Eriksson, Peter C. O'Leary, Eric Wichmann, Ad R. Hermus, Bruce M. Psaty, Till Ittermann, Albert Hofman, Emanuele Bosi, David Schlessinger, Henri Wallaschofski, Nicola Pirastu, Yurii S. Aulchenko, Albert de la Chapelle, Romana T. Netea-Maier, Stephen C. L. Gough, Henriette Meyer zu Schwabedissen, Timothy M. Frayling, Jean-Marc Kaufman, Allan Linneberg, Katri Raeikkoenen, Johannes W. A. Smit, Lambertus A. Kiemeney, Fernando Rivadeneira, Andre G. Uitterlinden, John P. Walsh, Christa Meisinger, Martin Den Heijer, Theo J. Visser, Timothy D. Spector, Scott G. Wilson, Henry Voelzke, Anne Cappola, Daniela Toniolo, Serena Sanna, Silvia Naitza, Robin P. Peeters

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Author Summary

Individuals with thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune thyroid diseases (AITD), which are common in the general population and associated with increased cardiovascular, metabolic and psychiatric morbidity and mortality. As the causative genes of TPOAbs and AITD remain largely unknown, we performed a genome-wide scan for TPOAbs in 18,297 individuals, with replication in 8,990 individuals. Significant associations were detected with variants at TPO, ATXN2, BACH2, MAGI3, and KALRN. Individuals carrying multiple risk variants also had a higher risk of increased thyroid-stimulating hormone levels (including subclinical and overt hypothyroidism), and a decreased risk of goiter. The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, and the MAGI3 variant was also associated with an increased risk of hypothyroidism. This first genome-wide scan for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. These results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which individuals are particularly at risk of developing clinical thyroid dysfunction.

Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P

This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.

Original languageEnglish
Number of pages13
JournalPLoS Genetics
Volume10
Issue number2
DOIs
Publication statusPublished - 27 Feb 2014

Keywords

  • GENOME-WIDE ASSOCIATION
  • IODIDE ORGANIFICATION DEFECTS
  • SYSTEMIC-LUPUS-ERYTHEMATOSUS
  • GRAVES-DISEASE
  • RHEUMATOID-ARTHRITIS
  • SUSCEPTIBILITY LOCI
  • FEMALE RELATIVES
  • COMMON VARIANTS
  • WHICKHAM SURVEY
  • HEART-FAILURE

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