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. Korevaar & 98 others Maria 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

Research output: Contribution to journalArticle

78 Citations (Scopus)

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.

Original languageEnglish
Article numbere1004123
Pages (from-to)1-13
Number of pages13
JournalPLoS Genetics
Volume10
Issue number2
DOIs
Publication statusPublished - Feb 2014

Cite this

Medici, M., Porcu, E., Pistis, G., Teumer, A., Brown, S. J., Jensen, R. A., ... Peeters, R. P. (2014). Identification of novel genetic loci associated with thyroid peroxidase antibodies and clinical thyroid disease. PLoS Genetics, 10(2), 1-13. [e1004123]. https://doi.org/10.1371/journal.pgen.1004123
Medici, Marco ; Porcu, Eleonora ; Pistis, Giorgio ; Teumer, Alexander ; Brown, Suzanne J. ; Jensen, Richard A. ; Rawal, Rajesh ; Roef, Greet L. ; Plantinga, Theo S. ; Vermeulen, Sita H. ; Lahti, Jari ; Simmonds, Matthew J. ; Husemoen, Lise Lotte N. ; Freathy, Rachel M. ; Shields, Beverley M. ; Pietzner, Diana ; Nagy, Rebecca ; Broer, Linda ; Chaker, Layal ; Korevaar, Tim I. M. ; Plia, Maria Grazia ; Sala, Cinzia ; Voelker, Uwe ; Richards, J. Brent ; Sweep, Fred C. ; Gieger, Christian ; Corre, Tanguy ; Kajantie, Eero ; Thuesen, Betina ; Taes, Youri E. ; Visser, W. Edward ; Hattersley, Andrew T. ; Kratzsch, Juergen ; Hamilton, Alexander ; Li, Wei ; Homuth, Georg ; Lobina, Monia ; Mariotti, Stefano ; Soranzo, Nicole ; Cocca, Massimiliano ; Nauck, Matthias ; Spielhagen, Christin ; Ross, Alec ; Arnold, Alice ; van de Bunt, Martijn ; Liyanarachchi, Sandya ; Heier, Margit ; Grabe, Hans Joergen ; Masciullo, Corrado ; Galesloot, Tessel E. ; Lim, Ee M. ; Reischl, Eva ; Leedman, Peter J. ; Lai, Sandra ; Delitala, Alessandro ; Bremner, Alexandra P. ; Philips, David I. W. ; Beilby, John P. ; Mulas, Antonella ; Vocale, Matteo ; Abecasis, Goncalo ; Forsen, Tom ; James, Alan ; Widen, Elisabeth ; Hui, Jennie ; Prokisch, Holger ; Rietzschel, Ernst E. ; Palotie, Aarno ; Feddema, Peter ; Fletcher, Stephen J. ; Schramm, Katharina ; Rotter, Jerome I. ; Kluttig, Alexander ; Radke, Doerte ; Traglia, Michela ; Surdulescu, Gabriela L. ; He, Huiling ; Franklyn, Jayne A. ; Tiller, Daniel ; Vaidya, Bijay ; de Meyer, Tim ; Jorgensen, Torben ; Eriksson, Johan G. ; O'Leary, Peter C. ; Wichmann, Eric ; Hermus, Ad R. ; Psaty, Bruce M. ; Ittermann, Till ; Hofman, Albert ; Bosi, Emanuele ; Schlessinger, David ; Wallaschofski, Henri ; Pirastu, Nicola ; Aulchenko, Yurii S. ; de la Chapelle, Albert ; Netea-Maier, Romana T. ; Gough, Stephen C. L. ; Meyer zu Schwabedissen, Henriette ; Frayling, Timothy M. ; Kaufman, Jean-Marc ; Linneberg, Allan ; Raeikkoenen, Katri ; Smit, Johannes W. A. ; Kiemeney, Lambertus A. ; Rivadeneira, Fernando ; Uitterlinden, Andre G. ; Walsh, John P. ; Meisinger, Christa ; Den Heijer, Martin ; Visser, Theo J. ; Spector, Timothy D. ; Wilson, Scott G. ; Voelzke, Henry ; Cappola, Anne ; Toniolo, Daniela ; Sanna, Serena ; Naitza, Silvia ; Peeters, Robin P. / Identification of novel genetic loci associated with thyroid peroxidase antibodies and clinical thyroid disease. In: PLoS Genetics. 2014 ; Vol. 10, No. 2. pp. 1-13.
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title = "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.",
keywords = "GENOME-WIDE ASSOCIATION, IODIDE ORGANIFICATION DEFECTS, SYSTEMIC-LUPUS-ERYTHEMATOSUS, GRAVES-DISEASE, RHEUMATOID-ARTHRITIS, SUSCEPTIBILITY LOCI, FEMALE RELATIVES, COMMON VARIANTS, WHICKHAM SURVEY, HEART-FAILURE",
author = "Marco Medici and Eleonora Porcu and Giorgio Pistis and Alexander Teumer and Brown, {Suzanne J.} and Jensen, {Richard A.} and Rajesh Rawal and Roef, {Greet L.} and Plantinga, {Theo S.} and Vermeulen, {Sita H.} and Jari Lahti and Simmonds, {Matthew J.} and Husemoen, {Lise Lotte N.} and Freathy, {Rachel M.} and Shields, {Beverley M.} and Diana Pietzner and Rebecca Nagy and Linda Broer and Layal Chaker and Korevaar, {Tim I. M.} and Plia, {Maria Grazia} and Cinzia Sala and Uwe Voelker and Richards, {J. Brent} and Sweep, {Fred C.} and Christian Gieger and Tanguy Corre and Eero Kajantie and Betina Thuesen and Taes, {Youri E.} and Visser, {W. Edward} and Hattersley, {Andrew T.} and Juergen Kratzsch and Alexander Hamilton and Wei Li and Georg Homuth and Monia Lobina and Stefano Mariotti and Nicole Soranzo and Massimiliano Cocca and Matthias Nauck and Christin Spielhagen and Alec Ross and Alice Arnold and {van de Bunt}, Martijn and Sandya Liyanarachchi and Margit Heier and Grabe, {Hans Joergen} and Corrado Masciullo and Galesloot, {Tessel E.} and Lim, {Ee M.} and Eva Reischl and Leedman, {Peter J.} and Sandra Lai and Alessandro Delitala and Bremner, {Alexandra P.} and Philips, {David I. W.} and Beilby, {John P.} and Antonella Mulas and Matteo Vocale and Goncalo Abecasis and Tom Forsen and Alan James and Elisabeth Widen and Jennie Hui and Holger Prokisch and Rietzschel, {Ernst E.} and Aarno Palotie and Peter Feddema and Fletcher, {Stephen J.} and Katharina Schramm and Rotter, {Jerome I.} and Alexander Kluttig and Doerte Radke and Michela Traglia and Surdulescu, {Gabriela L.} and Huiling He and Franklyn, {Jayne A.} and Daniel Tiller and Bijay Vaidya and {de Meyer}, Tim and Torben Jorgensen and Eriksson, {Johan G.} and O'Leary, {Peter C.} and Eric Wichmann and Hermus, {Ad R.} and Psaty, {Bruce M.} and Till Ittermann and Albert Hofman and Emanuele Bosi and David Schlessinger and Henri Wallaschofski and Nicola Pirastu and Aulchenko, {Yurii S.} and {de la Chapelle}, Albert and Netea-Maier, {Romana T.} and Gough, {Stephen C. L.} and {Meyer zu Schwabedissen}, Henriette and Frayling, {Timothy M.} and Jean-Marc Kaufman and Allan Linneberg and Katri Raeikkoenen and Smit, {Johannes W. A.} and Kiemeney, {Lambertus A.} and Fernando Rivadeneira and Uitterlinden, {Andre G.} and Walsh, {John P.} and Christa Meisinger and {Den Heijer}, Martin and Visser, {Theo J.} and Spector, {Timothy D.} and Wilson, {Scott G.} and Henry Voelzke and Anne Cappola and Daniela Toniolo and Serena Sanna and Silvia Naitza and Peeters, {Robin P.}",
year = "2014",
month = "2",
doi = "10.1371/journal.pgen.1004123",
language = "English",
volume = "10",
pages = "1--13",
journal = "PLoS Genetics",
issn = "1553-7390",
publisher = "Public Library of Science (PLoS)",
number = "2",

}

Medici, M, Porcu, E, Pistis, G, Teumer, A, Brown, SJ, Jensen, RA, Rawal, R, Roef, GL, Plantinga, TS, Vermeulen, SH, Lahti, J, Simmonds, MJ, Husemoen, LLN, Freathy, RM, Shields, BM, Pietzner, D, Nagy, R, Broer, L, Chaker, L, Korevaar, TIM, Plia, MG, Sala, C, Voelker, U, Richards, JB, Sweep, FC, Gieger, C, Corre, T, Kajantie, E, Thuesen, B, Taes, YE, Visser, WE, Hattersley, AT, Kratzsch, J, Hamilton, A, Li, W, Homuth, G, Lobina, M, Mariotti, S, Soranzo, N, Cocca, M, Nauck, M, Spielhagen, C, Ross, A, Arnold, A, van de Bunt, M, Liyanarachchi, S, Heier, M, Grabe, HJ, Masciullo, C, Galesloot, TE, Lim, EM, Reischl, E, Leedman, PJ, Lai, S, Delitala, A, Bremner, AP, Philips, DIW, Beilby, JP, Mulas, A, Vocale, M, Abecasis, G, Forsen, T, James, A, Widen, E, Hui, J, Prokisch, H, Rietzschel, EE, Palotie, A, Feddema, P, Fletcher, SJ, Schramm, K, Rotter, JI, Kluttig, A, Radke, D, Traglia, M, Surdulescu, GL, He, H, Franklyn, JA, Tiller, D, Vaidya, B, de Meyer, T, Jorgensen, T, Eriksson, JG, O'Leary, PC, Wichmann, E, Hermus, AR, Psaty, BM, Ittermann, T, Hofman, A, Bosi, E, Schlessinger, D, Wallaschofski, H, Pirastu, N, Aulchenko, YS, de la Chapelle, A, Netea-Maier, RT, Gough, SCL, Meyer zu Schwabedissen, H, Frayling, TM, Kaufman, J-M, Linneberg, A, Raeikkoenen, K, Smit, JWA, Kiemeney, LA, Rivadeneira, F, Uitterlinden, AG, Walsh, JP, Meisinger, C, Den Heijer, M, Visser, TJ, Spector, TD, Wilson, SG, Voelzke, H, Cappola, A, Toniolo, D, Sanna, S, Naitza, S & Peeters, RP 2014, 'Identification of novel genetic loci associated with thyroid peroxidase antibodies and clinical thyroid disease' PLoS Genetics, vol. 10, no. 2, e1004123, pp. 1-13. https://doi.org/10.1371/journal.pgen.1004123

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

In: PLoS Genetics, Vol. 10, No. 2, e1004123, 02.2014, p. 1-13.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Identification of novel genetic loci associated with thyroid peroxidase antibodies and clinical thyroid disease

AU - Medici, Marco

AU - Porcu, Eleonora

AU - Pistis, Giorgio

AU - Teumer, Alexander

AU - Brown, Suzanne J.

AU - Jensen, Richard A.

AU - Rawal, Rajesh

AU - Roef, Greet L.

AU - Plantinga, Theo S.

AU - Vermeulen, Sita H.

AU - Lahti, Jari

AU - Simmonds, Matthew J.

AU - Husemoen, Lise Lotte N.

AU - Freathy, Rachel M.

AU - Shields, Beverley M.

AU - Pietzner, Diana

AU - Nagy, Rebecca

AU - Broer, Linda

AU - Chaker, Layal

AU - Korevaar, Tim I. M.

AU - Plia, Maria Grazia

AU - Sala, Cinzia

AU - Voelker, Uwe

AU - Richards, J. Brent

AU - Sweep, Fred C.

AU - Gieger, Christian

AU - Corre, Tanguy

AU - Kajantie, Eero

AU - Thuesen, Betina

AU - Taes, Youri E.

AU - Visser, W. Edward

AU - Hattersley, Andrew T.

AU - Kratzsch, Juergen

AU - Hamilton, Alexander

AU - Li, Wei

AU - Homuth, Georg

AU - Lobina, Monia

AU - Mariotti, Stefano

AU - Soranzo, Nicole

AU - Cocca, Massimiliano

AU - Nauck, Matthias

AU - Spielhagen, Christin

AU - Ross, Alec

AU - Arnold, Alice

AU - van de Bunt, Martijn

AU - Liyanarachchi, Sandya

AU - Heier, Margit

AU - Grabe, Hans Joergen

AU - Masciullo, Corrado

AU - Galesloot, Tessel E.

AU - Lim, Ee M.

AU - Reischl, Eva

AU - Leedman, Peter J.

AU - Lai, Sandra

AU - Delitala, Alessandro

AU - Bremner, Alexandra P.

AU - Philips, David I. W.

AU - Beilby, John P.

AU - Mulas, Antonella

AU - Vocale, Matteo

AU - Abecasis, Goncalo

AU - Forsen, Tom

AU - James, Alan

AU - Widen, Elisabeth

AU - Hui, Jennie

AU - Prokisch, Holger

AU - Rietzschel, Ernst E.

AU - Palotie, Aarno

AU - Feddema, Peter

AU - Fletcher, Stephen J.

AU - Schramm, Katharina

AU - Rotter, Jerome I.

AU - Kluttig, Alexander

AU - Radke, Doerte

AU - Traglia, Michela

AU - Surdulescu, Gabriela L.

AU - He, Huiling

AU - Franklyn, Jayne A.

AU - Tiller, Daniel

AU - Vaidya, Bijay

AU - de Meyer, Tim

AU - Jorgensen, Torben

AU - Eriksson, Johan G.

AU - O'Leary, Peter C.

AU - Wichmann, Eric

AU - Hermus, Ad R.

AU - Psaty, Bruce M.

AU - Ittermann, Till

AU - Hofman, Albert

AU - Bosi, Emanuele

AU - Schlessinger, David

AU - Wallaschofski, Henri

AU - Pirastu, Nicola

AU - Aulchenko, Yurii S.

AU - de la Chapelle, Albert

AU - Netea-Maier, Romana T.

AU - Gough, Stephen C. L.

AU - Meyer zu Schwabedissen, Henriette

AU - Frayling, Timothy M.

AU - Kaufman, Jean-Marc

AU - Linneberg, Allan

AU - Raeikkoenen, Katri

AU - Smit, Johannes W. A.

AU - Kiemeney, Lambertus A.

AU - Rivadeneira, Fernando

AU - Uitterlinden, Andre G.

AU - Walsh, John P.

AU - Meisinger, Christa

AU - Den Heijer, Martin

AU - Visser, Theo J.

AU - Spector, Timothy D.

AU - Wilson, Scott G.

AU - Voelzke, Henry

AU - Cappola, Anne

AU - Toniolo, Daniela

AU - Sanna, Serena

AU - Naitza, Silvia

AU - Peeters, Robin P.

PY - 2014/2

Y1 - 2014/2

N2 - 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.

AB - 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.

KW - GENOME-WIDE ASSOCIATION

KW - IODIDE ORGANIFICATION DEFECTS

KW - SYSTEMIC-LUPUS-ERYTHEMATOSUS

KW - GRAVES-DISEASE

KW - RHEUMATOID-ARTHRITIS

KW - SUSCEPTIBILITY LOCI

KW - FEMALE RELATIVES

KW - COMMON VARIANTS

KW - WHICKHAM SURVEY

KW - HEART-FAILURE

U2 - 10.1371/journal.pgen.1004123

DO - 10.1371/journal.pgen.1004123

M3 - Article

VL - 10

SP - 1

EP - 13

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 2

M1 - e1004123

ER -