Meta-Analysis

. 2014 Feb 27;10(2):e1004123.

doi: 10.1371/journal.pgen.1004123. eCollection 2014 Feb.

Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease

Marco Medici¹, Eleonora Porcu², Giorgio Pistis³, Alexander Teumer⁴, Suzanne J Brown⁵, Richard A Jensen⁶, Rajesh Rawal⁷, Greet L Roef⁸, Theo S Plantinga⁹, Sita H Vermeulen¹⁰, Jari Lahti¹¹, Matthew J Simmonds¹², Lise Lotte N Husemoen¹³, Rachel M Freathy¹⁴, Beverley M Shields¹⁵, Diana Pietzner¹⁶, Rebecca Nagy¹⁷, Linda Broer¹⁸, Layal Chaker¹, Tim I M Korevaar¹, Maria Grazia Plia¹⁹, Cinzia Sala³, Uwe Völker⁴, J Brent Richards²⁰, Fred C Sweep¹⁰, Christian Gieger⁷, Tanguy Corre³, Eero Kajantie²¹, Betina Thuesen¹³, Youri E Taes⁸, W Edward Visser¹, Andrew T Hattersley¹⁵, Jürgen Kratzsch²², Alexander Hamilton¹², Wei Li¹⁷, Georg Homuth⁴, Monia Lobina¹⁹, Stefano Mariotti²³, Nicole Soranzo²⁴, Massimiliano Cocca³, Matthias Nauck²⁵, Christin Spielhagen²⁵, Alec Ross¹⁰, Alice Arnold²⁶, Martijn van de Bunt¹², Sandya Liyanarachchi¹⁷, Margit Heier²⁷, Hans Jörgen Grabe²⁸, Corrado Masciullo³, Tessel E Galesloot¹⁰, Ee M Lim²⁹, Eva Reischl³⁰, Peter J Leedman³¹, Sandra Lai¹⁹, Alessandro Delitala²³, Alexandra P Bremner³², David I W Philips³³, John P Beilby³⁴, Antonella Mulas¹⁹, Matteo Vocale³⁵, Goncalo Abecasis³⁶, Tom Forsen³⁷, Alan James³⁸, Elisabeth Widen³⁹, Jennie Hui²⁹, Holger Prokisch⁴⁰, Ernst E Rietzschel⁴¹, Aarno Palotie⁴², Peter Feddema⁴³, Stephen J Fletcher²⁹, Katharina Schramm⁴⁴, Jerome I Rotter⁴⁵, Alexander Kluttig¹⁶, Dörte Radke⁴⁶, Michela Traglia³, Gabriela L Surdulescu⁴⁷, Huiling He¹⁷, Jayne A Franklyn⁴⁸, Daniel Tiller¹⁶, Bijay Vaidya⁴⁹, Tim de Meyer⁵⁰, Torben Jørgensen⁵¹, Johan G Eriksson⁵², Peter C O'Leary⁵³, Eric Wichmann⁵⁴, Ad R Hermus⁹, Bruce M Psaty⁵⁵, Till Ittermann⁴⁶, Albert Hofman¹⁸, Emanuele Bosi⁵⁶, David Schlessinger⁵⁷, Henri Wallaschofski²², Nicola Pirastu⁵⁸, Yurii S Aulchenko¹⁸, Albert de la Chapelle¹⁷, Romana T Netea-Maier⁹, Stephen C L Gough¹², Henriette Meyer Zu Schwabedissen⁵⁹, Timothy M Frayling¹⁴, Jean-Marc Kaufman⁸, Allan Linneberg¹³, Katri Räikkönen¹¹, Johannes W A Smit⁹, Lambertus A Kiemeney¹⁰, Fernando Rivadeneira⁶⁰, André G Uitterlinden⁶⁰, John P Walsh⁶¹, Christa Meisinger²⁷, Martin den Heijer⁶², Theo J Visser¹, Timothy D Spector⁴⁷, Scott G Wilson⁶³, Henry Völzke⁴⁶, Anne Cappola⁶⁴, Daniela Toniolo⁶⁵, Serena Sanna¹⁹, Silvia Naitza¹⁹, Robin P Peeters¹

Affiliations

¹ Department of Internal Medicine, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
² Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy ; Dipartimento di Scienze Biomediche, Universita di Sassari, Sassari, Italy.
³ Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
⁴ Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.
⁵ Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
⁶ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, Washington, United States of America.
⁷ Institute for Genetic Epidemiology, Helmholtz Zentrum Munich, Munich/Neuherberg, Germany.
⁸ Department of Endocrinology and Internal Medicine, University Hospital Ghent and Faculty of Medicine, Ghent University, Ghent, Belgium.
⁹ Internal Medicine, Division of Endocrinology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
¹⁰ Department for Health Evidence, Radboud University Medical Centre, Nijmegen, The Netherlands.
¹¹ Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland.
¹² Oxford Centre for Diabetes, Endocrinology and Metabolism and NIHR Oxford Biomedical Research Centre, Oxford, UK Churchill Hospital, Headington, Oxford, United Kingdom.
¹³ Research Centre for Prevention and Health, Glostrup University Hospital, the Capital Region of Denmark, Glostrup, Denmark.
¹⁴ Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, United Kingdom.
¹⁵ Peninsula NIHR Clinical Research Facility, University of Exeter Medical School, University of Exeter, Exeter, United Kingdom.
¹⁶ Institute of Medical Epidemiology, Biostatistics, and Informatics, Martin-Luther-University Halle-Wittenberg, Halle, Germany.
¹⁷ Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, United States of America.
¹⁸ Department of Epidemiology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
¹⁹ Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy.
²⁰ Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, Lady Davis Institute, McGill University, Montreal, Canada ; Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
²¹ National Institute for Health and Welfare, Helsinki, Finland ; Hospital for Children and Adolescents, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
²² Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany.
²³ Dipartimento di Scienze Biomediche, Universita di Sassari, Sassari, Italy.
²⁴ Wellcome Trust Sanger Institute, Hixton, United Kingdom.
²⁵ Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
²⁶ Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
²⁷ Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Institute of Epidemiology II, Neuherberg, Germany.
²⁸ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, HELIOS Hospital Stralsund, Greifswald, Germany.
²⁹ Pathwest Laboratory Medicine WA, Nedlands, Western Australia, Australia.
³⁰ Research Unit of Molecular Epidemiology Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
³¹ School of Medicine and Pharmacology, the University of Western Australia, Crawley, Western Australia, Australia ; UWA Centre for Medical Research, Western Australian Institute for Medical Research, Perth, Western Australia, Australia.
³² School of Population Health, University of Western Australia, Nedlands, Western Australia, Australia.
³³ MRC Lifecourse Epidemiology Unit, Southampton General Hospital, Southampton, United Kingdom.
³⁴ Pathwest Laboratory Medicine WA, Nedlands, Western Australia, Australia ; School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia.
³⁵ High Performance Computing and Network, CRS4, Parco Tecnologico della Sardegna, Pula, Italy.
³⁶ Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, United States of America.
³⁷ Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland ; Vaasa Health Care Centre, Diabetes Unit, Vaasa, Finland.
³⁸ School of Medicine and Pharmacology, the University of Western Australia, Crawley, Western Australia, Australia ; Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
³⁹ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
⁴⁰ Institute of Human Genetics, Helmholtz Zentrum Munich, Munich, Germany ; Institute of Human Genetics, Technische Universität München, Munich, Germany.
⁴¹ Department of Cardiology and Internal Medicine, University Hospital Ghent and Faculty of Medicine, Ghent University, Ghent, Belgium.
⁴² Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland ; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom ; Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland.
⁴³ Diagnostica Stago, Doncaster, Victoria, Australia.
⁴⁴ Institute of Human Genetics, Helmholtz Zentrum Munich, Munich, Germany.
⁴⁵ Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Torrance, California, United States of America ; Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, United States of America.
⁴⁶ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
⁴⁷ Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
⁴⁸ School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, Univeristy of Birmingham, Edgbaston, Birmingham, United Kingdom.
⁴⁹ Diabetes, Endocrinology and Vascular Health Centre, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom.
⁵⁰ BIOBIX Lab. for Bioinformatics and Computational Genomics, Dept. of Mathematical Modelling, Statistics and Bioinformatics. Faculty of Bioscience Engineering, Ghent University, Ghent, Belgium.
⁵¹ Research Centre for Prevention and Health, Glostrup University Hospital, the Capital Region of Denmark, Glostrup, Denmark ; Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark.
⁵² National Institute for Health and Welfare, Helsinki, Finland ; Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland ; Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland ; Folkhalsan Research Centre, Helsinki, Finland ; Vasa Central Hospital, Vasa, Finland.
⁵³ School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia ; Curtin Health Innovation Research Institute, Curtin University of Technology, Bentley, Western Australia, Australia.
⁵⁴ Institute of Epidemiology I, Helmholtz Zentrum Munich, Munich, Germany.
⁵⁵ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, Washington, United States of America ; Group Health Research Institute, Group Health Cooperative, Seattle, Washington, United States of America.
⁵⁶ Department of Internal Medicine, Diabetes & Endocrinology Unit, San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, Italy.
⁵⁷ Laboratory of Genetics, National Institute on Aging, Baltimore, Maryland, United States of America.
⁵⁸ Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy ; University of Trieste, Trieste, Italy.
⁵⁹ Biopharmacy, Department of Pharmaceutical Sciences, University Basel, Basel, Switzerland.
⁶⁰ Department of Internal Medicine, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands ; Department of Epidemiology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands ; Netherlands Consortium for Healthy Aging, Netherlands Genomics Initiative, Leiden, The Netherlands.
⁶¹ Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia ; School of Medicine and Pharmacology, the University of Western Australia, Crawley, Western Australia, Australia.
⁶² Department of Internal Medicine, VU Medical Center, Amsterdam, The Netherlands.
⁶³ Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia ; School of Medicine and Pharmacology, the University of Western Australia, Crawley, Western Australia, Australia ; Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
⁶⁴ Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
⁶⁵ Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy ; Institute of Molecular Genetics-CNR, Pavia, Italy.

PMID: 24586183
PMCID: PMC3937134
DOI: 10.1371/journal.pgen.1004123

Meta-Analysis

Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease

Marco Medici et al. PLoS Genet. 2014.

. 2014 Feb 27;10(2):e1004123.

doi: 10.1371/journal.pgen.1004123. eCollection 2014 Feb.

Authors

Affiliations

¹ Department of Internal Medicine, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
² Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy ; Dipartimento di Scienze Biomediche, Universita di Sassari, Sassari, Italy.
³ Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
⁴ Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.
⁵ Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
⁶ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, Washington, United States of America.
⁷ Institute for Genetic Epidemiology, Helmholtz Zentrum Munich, Munich/Neuherberg, Germany.
⁸ Department of Endocrinology and Internal Medicine, University Hospital Ghent and Faculty of Medicine, Ghent University, Ghent, Belgium.
⁹ Internal Medicine, Division of Endocrinology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
¹⁰ Department for Health Evidence, Radboud University Medical Centre, Nijmegen, The Netherlands.
¹¹ Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland.
¹² Oxford Centre for Diabetes, Endocrinology and Metabolism and NIHR Oxford Biomedical Research Centre, Oxford, UK Churchill Hospital, Headington, Oxford, United Kingdom.
¹³ Research Centre for Prevention and Health, Glostrup University Hospital, the Capital Region of Denmark, Glostrup, Denmark.
¹⁴ Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, United Kingdom.
¹⁵ Peninsula NIHR Clinical Research Facility, University of Exeter Medical School, University of Exeter, Exeter, United Kingdom.
¹⁶ Institute of Medical Epidemiology, Biostatistics, and Informatics, Martin-Luther-University Halle-Wittenberg, Halle, Germany.
¹⁷ Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, United States of America.
¹⁸ Department of Epidemiology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
¹⁹ Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy.
²⁰ Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, Lady Davis Institute, McGill University, Montreal, Canada ; Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
²¹ National Institute for Health and Welfare, Helsinki, Finland ; Hospital for Children and Adolescents, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
²² Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany.
²³ Dipartimento di Scienze Biomediche, Universita di Sassari, Sassari, Italy.
²⁴ Wellcome Trust Sanger Institute, Hixton, United Kingdom.
²⁵ Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
²⁶ Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
²⁷ Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Institute of Epidemiology II, Neuherberg, Germany.
²⁸ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, HELIOS Hospital Stralsund, Greifswald, Germany.
²⁹ Pathwest Laboratory Medicine WA, Nedlands, Western Australia, Australia.
³⁰ Research Unit of Molecular Epidemiology Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
³¹ School of Medicine and Pharmacology, the University of Western Australia, Crawley, Western Australia, Australia ; UWA Centre for Medical Research, Western Australian Institute for Medical Research, Perth, Western Australia, Australia.
³² School of Population Health, University of Western Australia, Nedlands, Western Australia, Australia.
³³ MRC Lifecourse Epidemiology Unit, Southampton General Hospital, Southampton, United Kingdom.
³⁴ Pathwest Laboratory Medicine WA, Nedlands, Western Australia, Australia ; School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia.
³⁵ High Performance Computing and Network, CRS4, Parco Tecnologico della Sardegna, Pula, Italy.
³⁶ Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, United States of America.
³⁷ Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland ; Vaasa Health Care Centre, Diabetes Unit, Vaasa, Finland.
³⁸ School of Medicine and Pharmacology, the University of Western Australia, Crawley, Western Australia, Australia ; Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
³⁹ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
⁴⁰ Institute of Human Genetics, Helmholtz Zentrum Munich, Munich, Germany ; Institute of Human Genetics, Technische Universität München, Munich, Germany.
⁴¹ Department of Cardiology and Internal Medicine, University Hospital Ghent and Faculty of Medicine, Ghent University, Ghent, Belgium.
⁴² Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland ; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom ; Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland.
⁴³ Diagnostica Stago, Doncaster, Victoria, Australia.
⁴⁴ Institute of Human Genetics, Helmholtz Zentrum Munich, Munich, Germany.
⁴⁵ Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Torrance, California, United States of America ; Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, United States of America.
⁴⁶ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
⁴⁷ Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
⁴⁸ School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, Univeristy of Birmingham, Edgbaston, Birmingham, United Kingdom.
⁴⁹ Diabetes, Endocrinology and Vascular Health Centre, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom.
⁵⁰ BIOBIX Lab. for Bioinformatics and Computational Genomics, Dept. of Mathematical Modelling, Statistics and Bioinformatics. Faculty of Bioscience Engineering, Ghent University, Ghent, Belgium.
⁵¹ Research Centre for Prevention and Health, Glostrup University Hospital, the Capital Region of Denmark, Glostrup, Denmark ; Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark.
⁵² National Institute for Health and Welfare, Helsinki, Finland ; Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland ; Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland ; Folkhalsan Research Centre, Helsinki, Finland ; Vasa Central Hospital, Vasa, Finland.
⁵³ School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia ; Curtin Health Innovation Research Institute, Curtin University of Technology, Bentley, Western Australia, Australia.
⁵⁴ Institute of Epidemiology I, Helmholtz Zentrum Munich, Munich, Germany.
⁵⁵ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, Washington, United States of America ; Group Health Research Institute, Group Health Cooperative, Seattle, Washington, United States of America.
⁵⁶ Department of Internal Medicine, Diabetes & Endocrinology Unit, San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, Italy.
⁵⁷ Laboratory of Genetics, National Institute on Aging, Baltimore, Maryland, United States of America.
⁵⁸ Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy ; University of Trieste, Trieste, Italy.
⁵⁹ Biopharmacy, Department of Pharmaceutical Sciences, University Basel, Basel, Switzerland.
⁶⁰ Department of Internal Medicine, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands ; Department of Epidemiology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands ; Netherlands Consortium for Healthy Aging, Netherlands Genomics Initiative, Leiden, The Netherlands.
⁶¹ Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia ; School of Medicine and Pharmacology, the University of Western Australia, Crawley, Western Australia, Australia.
⁶² Department of Internal Medicine, VU Medical Center, Amsterdam, The Netherlands.
⁶³ Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia ; School of Medicine and Pharmacology, the University of Western Australia, Crawley, Western Australia, Australia ; Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
⁶⁴ Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
⁶⁵ Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy ; Institute of Molecular Genetics-CNR, Pavia, Italy.

PMID: 24586183
PMCID: PMC3937134
DOI: 10.1371/journal.pgen.1004123

Abstract

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<5×10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68-2.81, P = 8.1×10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, P = 2.9×10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, P = 6.5×10(-4)). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22-1.54, P = 1.2×10(-7) and OR: 1.25, 95% CI 1.12-1.39, P = 6.2×10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, P = 1.9×10(-3)). 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.

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Conflict of interest statement

I have read the journal's policy and have the following conflicts: Dr. Bruce M Psaty reported serving on a DSMB for a clinical trial of a device funded by the manufacturer (Zoll LifeCor) and on the Yale Open Data Access Project funded by Medtronic. All other authors have declared that no competing interests exist.

Figures

**Figure 1. Genome wide association studies meta-analyses: Loci associated with TPOAb-positivity (a–c) and TPOAb levels (d–f) on a genome-wide level of significance.**
Regional association plots of the genome-wide significant loci associated with TPOAb positivity (a–c) and TPOAb levels (d–f). The y-axis on the left indicates the – log₁₀ P value for the association with TPOAb –positivity (a–c) or TPOAb levels (d–f). SNPs are plotted on the x-axis according to their chromosomal position against the association with the phenotype on the y-axis. The most significant stage 1 SNP is indicated in purple. The combined stage 1 and 2 result of this SNP is indicated in yellow. The SNPs surrounding the most significant SNP are color-coded to reflect their LD with this SNP. Symbols reflect functional genomic annotation, as indicated in the legend. The blue y-axes on the right of each plot indicate the estimated recombination rates (based on HapMap Phase II); the bottom of each panel shows the respective annotated genes at the locus and their transcriptional direction. Mb, megabases.

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Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease

Affiliations

Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease

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