期刊
PLOS GENETICS
卷 10, 期 2, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1004123
关键词
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资金
- Fonds voor Wetenschappelijk Onderzoek-Vlaanderen FWO [G. 0427.03, G. 0838.10N]
- Healthway, Western Australia
- National Health and Medical Research Council of Australia
- Great Wine Estates Auctions
- NHLBI [HHSN268201200036C, N01HC85239, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HL080295, HL087652, HL105756]
- National Institute of Neurological Disorders and Stroke (NINDS)
- National Institute on Aging (NIA) [AG023629]
- National Center for Research Resources [UL1RR033176]
- CTSI [UL1TR000124]
- National Institute of Diabetes and Digestive and Kidney Disease [DK063491]
- Cedars-Sinai Board of Governors' Chair in Medical Genetics
- Deutsche Forschungsgemeinschaft as part of the Collaborative Research Center 598
- Wilhelm-Roux Programme of the Martin-Luther-University Halle-Wittenberg
- Ministry of Education and Cultural Affairs of Saxony-Anhalt
- Federal Employment Office
- South West NHS Research and Development
- Exeter NHS Research and Development
- Darlington Trust
- Peninsula NIHR Clinical Research Facility at the University of Exeter
- Endocrine Research Fund
- Sir Henry Wellcome Postdoctoral Fellowship (Wellcome Trust) [085541/Z/08/Z]
- The Velux Foundation
- Danish Medical Research Council
- Danish Agency for Science, Technology and Innovation
- Aase and Ejner Danielsens Foundation
- ALK-Abello A/S (Horsholm, Denmark)
- Timber Merchant Vilhelm Bangs Foundation
- MEKOS Laboratories (Denmark)
- Health Insurance Foundation
- Research Centre for Prevention and Health
- Capital Region of Denmark
- Academy of Finland
- Finnish Diabetes Research Society
- Finnish Society for Cardiovascular Research
- Folkhalsan Research Foundation
- Novo Nordisk Foundation
- Finska Lakaresallskapet
- Signe and Ane Gyllenberg Foundation
- University of Helsinki
- European Science Foundation (EUROSTRESS)
- Ministry of Education
- Ahokas Foundation
- Emil Aaltonen Foundation
- Juho Vainio Foundation
- Wellcome Trust [WT089062]
- KORA
- Helmholtz Center Munich
- German Research Center for Environmental Health
- German Federal Ministry of Education and Research
- State of Bavaria
- German Federal Ministry of Education and Research (BMBF)
- Munich Center of Health Sciences (MC Health) as part of LMUinnovativ
- Sanofi-Aventis
- European Commission [POLYGENE: LSHC-CT-2005018827]
- Radboud University Nijmegen Medical Centre
- National Computing Facilities Foundation (NCF)
- NWO
- National Cancer Institute, USA [P30 CA16058, P01 CA124570]
- Research Institute for Diseases in the Elderly [014-93-015]
- Netherlands Genomics Initiative (NGI)/ Netherlands Organisation for Scientific Research (NWO) [050-060-810]
- Erasmus Medical Center
- Erasmus University, Rotterdam
- Netherlands Organization for the Health Research and Development (ZonMw)
- Research Institute for Diseases in the Elderly (RIDE)
- Ministry of Education, Culture and Science
- Ministry for Health, Welfare and Sports
- European Commission
- Municipality of Rotterdam
- National Institute on Aging (NIA), National Institutes of Health (NIH)
- NIA [NO1-AG-1-2109, 263-MA-410953]
- Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03IS2061A, 03ZIK012]
- Ministry of Cultural Affairs
- Social Ministry of the Federal State of Mecklenburg-West Pomerania
- network Greifswald Approach to Individualized Medicine (GANI_MED)
- Siemens Healthcare, Erlangen, Germany
- Federal State of Mecklenburg-West Pomerania
- German Research Foundation [DFG Vo 955/10-2, SPP 1629: THYROID TRANS ACT WA 1328/5-1]
- Federal Ministry of Nutrition, Agriculture and Consumer's Safety [BMELV 07 HS 003]
- German Research Foundation
- Federal State of Mecklenburg, West Pomerania
- Chronic Disease Research Foundation
- European Community [HEALTH-F4-2007-201413]
- Department of Health via the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre
- Canadian Institutes of Health Research
- Canadian Foundation for Innovation
- Fonds de la Recherche en Sante Quebec
- Ministere du Developpement Economique, de l'Innovation et de l'Exportation Quebec
- Lady Davis Institute of the Jewish General Hospital
- Australian National Health and Medical Research Council [1010494, 1031422]
- Sir Charles Gairdner Hospital Research Fund
- Compagnia di San Paolo, Torino, Italy
- Fondazione Cariplo, Italy
- Ministry of Health
- Ricerca Finalizzata
- [HG002651]
- Wellcome Trust [085541/Z/08/Z] Funding Source: Wellcome Trust
- National Institute for Health Research [NF-SI-0611-10219] Funding Source: researchfish
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<5x10(-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 = 8.1x10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, P = 2.9x10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, P = 6.5x10(-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 = 1.2x10(-7) and OR: 1.25, 95% CI 1.12-1.39, P = 6.2x10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, P = 1.9x10(-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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