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

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.

SUBMITTER: Medici M

PROVIDER: S-EPMC3937134 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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

Medici Marco M Porcu Eleonora E Pistis Giorgio G Teumer Alexander A Brown Suzanne J SJ Jensen Richard A RA Rawal Rajesh R Roef Greet L GL Plantinga Theo S TS Vermeulen Sita H SH Lahti Jari J Simmonds Matthew J MJ Husemoen Lise Lotte N LL Freathy Rachel M RM Shields Beverley M BM Pietzner Diana D Nagy Rebecca R Broer Linda L Chaker Layal L Korevaar Tim I M TI Plia Maria Grazia MG Sala Cinzia C Völker Uwe U Richards J Brent JB Sweep Fred C FC Gieger Christian C Corre Tanguy T Kajantie Eero E Thuesen Betina B Taes Youri E YE Visser W Edward WE Hattersley Andrew T AT Kratzsch Jürgen J Hamilton Alexander A Li Wei W Homuth Georg G Lobina Monia M Mariotti Stefano S Soranzo Nicole N Cocca Massimiliano M Nauck Matthias M Spielhagen Christin C Ross Alec A Arnold Alice A van de Bunt Martijn M Liyanarachchi Sandya S Heier Margit M Grabe Hans Jörgen HJ Masciullo Corrado C Galesloot Tessel E TE Lim Ee M EM Reischl Eva E Leedman Peter J PJ Lai Sandra S Delitala Alessandro A Bremner Alexandra P AP Philips David I W DI Beilby John P JP Mulas Antonella A Vocale Matteo M Abecasis Goncalo G Forsen Tom T James Alan A Widen Elisabeth E Hui Jennie J Prokisch Holger H Rietzschel Ernst E EE Palotie Aarno A Feddema Peter P Fletcher Stephen J SJ Schramm Katharina K Rotter Jerome I JI Kluttig Alexander A Radke Dörte D Traglia Michela M Surdulescu Gabriela L GL He Huiling H Franklyn Jayne A JA Tiller Daniel D Vaidya Bijay B de Meyer Tim T Jørgensen Torben T Eriksson Johan G JG O'Leary Peter C PC Wichmann Eric E Hermus Ad R AR Psaty Bruce M BM Ittermann Till T Hofman Albert A Bosi Emanuele E Schlessinger David D Wallaschofski Henri H Pirastu Nicola N Aulchenko Yurii S YS de la Chapelle Albert A Netea-Maier Romana T RT Gough Stephen C L SC Meyer Zu Schwabedissen Henriette H Frayling Timothy M TM Kaufman Jean-Marc JM Linneberg Allan A Räikkönen Katri K Smit Johannes W A JW Kiemeney Lambertus A LA Rivadeneira Fernando F Uitterlinden André G AG Walsh John P JP Meisinger Christa C den Heijer Martin M Visser Theo J TJ Spector Timothy D TD Wilson Scott G SG Völzke Henry H Cappola Anne A Toniolo Daniela D Sanna Serena S Naitza Silvia S Peeters Robin P RP

PLoS genetics 20140227 2

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, ...[more]

PMID: 24586183

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Project description:RATIONALE:Coronary artery disease (CAD) is a complex phenotype driven by genetic and environmental factors. Ninety-seven genetic risk loci have been identified to date, but the identification of additional susceptibility loci might be important to enhance our understanding of the genetic architecture of CAD. OBJECTIVE:To expand the number of genome-wide significant loci, catalog functional insights, and enhance our understanding of the genetic architecture of CAD. METHODS AND RESULTS:We performed a genome-wide association study in 34?541 CAD cases and 261?984 controls of UK Biobank resource followed by replication in 88?192 cases and 162?544 controls from CARDIoGRAMplusC4D. We identified 75 loci that replicated and were genome-wide significant (P<5×10-8) in meta-analysis, 13 of which had not been reported previously. Next, to further identify novel loci, we identified all promising (P<0.0001) loci in the CARDIoGRAMplusC4D data and performed reciprocal replication and meta-analyses with UK Biobank. This led to the identification of 21 additional novel loci reaching genome-wide significance (P<5×10-8) in meta-analysis. Finally, we performed a genome-wide meta-analysis of all available data revealing 30 additional novel loci (P<5×10-8) without further replication. The increase in sample size by UK Biobank raised the number of reconstituted gene sets from 4.2% to 13.9% of all gene sets to be involved in CAD. For the 64 novel loci, 155 candidate causal genes were prioritized, many without an obvious connection to CAD. Fine mapping of the 161 CAD loci generated lists of credible sets of single causal variants and genes for functional follow-up. Genetic risk variants of CAD were linked to development of atrial fibrillation, heart failure, and death. CONCLUSIONS:We identified 64 novel genetic risk loci for CAD and performed fine mapping of all 161 risk loci to obtain a credible set of causal variants. The large expansion of reconstituted gene sets argues in favor of an expanded omnigenic model view on the genetic architecture of CAD.

Dataset Information

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

Publications

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

Similar Datasets

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