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

Marco Medici; E Porcu; G Pistis; A Teumer; SJ Brown; RA Jensen; R Rawal; GL Roef; TS Plantinga; SH Vermeulen; J Lahti; MJ Simmonds; LLN Husemoen; RM Freathy; BM Shields; D Pietzner; R Nagy; Linda Broer; Layal Chaker; Tim Korevaar; MG Plia; C Sala; U Volker; JB Richards; FC Sweep; C Gieger; T Corre; E Kajantie; B Thuesen; YE Taes; Edward Visser; AT Hattersley; J Kratzsch; A Hamilton; W (Wenguang) Li; G Homuth; M Lobina; S Mariotti; N Soranzo; M Cocca; M Nauck; C Spielhagen; A Ross; A Arnold; M van de Bunt; S Liyanarachchi; M Heier; HJ Grabe; C Masciullo; TE Galesloot; EM Lim; E Reischl; PJ Leedman; S Lai; A Delitala; AP Bremner; DIW Philips; JP Beilby; A Mulas; M Vocale; G Abecasis; T Forsen; A James; E Widen; J Hui; H Prokisch; EE Rietzschel; A Palotie; P Feddema; SJ Fletcher; K Schramm; JI Rotter; A Kluttig; D Radke; M Traglia; GL Surdulescu; HL He; JA Franklyn; D Tiller; B Vaidya; T Meyer; T Jorgensen; JG Eriksson; PC O'Leary; E Wichmann; AR Hermus; BM Psaty; T Ittermann; Bert Hofman; E Bosi; D Schlessinger; H Wallaschofski; N Pirastu; YS Aulchenko; A de la Chapelle; RT Netea-Maier; SCL Gough; H Meyer zu Schwabedissen; TM Frayling; JM Kaufman; A Linneberg; K Raikkonen; JWA Smit; LA Kiemeney; Fernando Rivadeneira; André Uitterlinden; JP Walsh; C Meisinger; Mariska Heijer; Theo Visser; TD Spector; SG Wilson; H Voelzke; A Cappola; D Toniolo; S Sanna; S Naitza; Robin Peeters

doi:10.1371/journal.pgen.1004123

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

Marco Medici, E Porcu, G Pistis, A Teumer, SJ Brown, RA Jensen, R Rawal, GL Roef, TS Plantinga, SH Vermeulen, J Lahti, MJ Simmonds, LLN Husemoen, RM Freathy, BM Shields, D Pietzner, R Nagy, Linda Broer, Layal Chaker, Tim KorevaarMG Plia, C Sala, U Volker, JB Richards, FC Sweep, C Gieger, T Corre, E Kajantie, B Thuesen, YE Taes, Edward Visser, AT Hattersley, J Kratzsch, A Hamilton, W (Wenguang) Li, G Homuth, M Lobina, S Mariotti, N Soranzo, M Cocca, M Nauck, C Spielhagen, A Ross, A Arnold, M van de Bunt, S Liyanarachchi, M Heier, HJ Grabe, C Masciullo, TE Galesloot, EM Lim, E Reischl, PJ Leedman, S Lai, A Delitala, AP Bremner, DIW Philips, JP Beilby, A Mulas, M Vocale, G Abecasis, T Forsen, A James, E Widen, J Hui, H Prokisch, EE Rietzschel, A Palotie, P Feddema, SJ Fletcher, K Schramm, JI Rotter, A Kluttig, D Radke, M Traglia, GL Surdulescu, HL He, JA Franklyn, D Tiller, B Vaidya, T Meyer, T Jorgensen, JG Eriksson, PC O'Leary, E Wichmann, AR Hermus, BM Psaty, T Ittermann, Bert Hofman, E Bosi, D Schlessinger, H Wallaschofski, N Pirastu, YS Aulchenko, A de la Chapelle, RT Netea-Maier, SCL Gough, H Meyer zu Schwabedissen, TM Frayling, JM Kaufman, A Linneberg, K Raikkonen, JWA Smit, LA Kiemeney, Fernando Rivadeneira, André Uitterlinden, JP Walsh, C Meisinger, Mariska Heijer, Theo Visser, TD Spector, SG Wilson, H Voelzke, A Cappola, D Toniolo, S Sanna, S Naitza, Robin Peeters

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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<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.

Original language	Undefined/Unknown
Journal	PLoS Genetics (print)
Volume	10
Issue number	2
DOIs	https://doi.org/10.1371/journal.pgen.1004123
Publication status	Published - 2014

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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., ... Peeters, R. (2014). Identification of Novel Genetic Loci Associated with Thyroid Peroxidase Antibodies and Clinical Thyroid Disease. PLoS Genetics (print), 10(2). https://doi.org/10.1371/journal.pgen.1004123

@article{4ff482bbc4134f7f870ae4fed659e040,

title = "Identification of Novel Genetic Loci Associated with Thyroid Peroxidase Antibodies and Clinical Thyroid Disease",

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<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.",

author = "Marco Medici and E Porcu and G Pistis and A Teumer and SJ Brown and RA Jensen and R Rawal and GL Roef and TS Plantinga and SH Vermeulen and J Lahti and MJ Simmonds and LLN Husemoen and RM Freathy and BM Shields and D Pietzner and R Nagy and Linda Broer and Layal Chaker and Tim Korevaar and MG Plia and C Sala and U Volker and JB Richards and FC Sweep and C Gieger and T Corre and E Kajantie and B Thuesen and YE Taes and Edward Visser and AT Hattersley and J Kratzsch and A Hamilton and Li, {W (Wenguang)} and G Homuth and M Lobina and S Mariotti and N Soranzo and M Cocca and M Nauck and C Spielhagen and A Ross and A Arnold and {van de Bunt}, M and S Liyanarachchi and M Heier and HJ Grabe and C Masciullo and TE Galesloot and EM Lim and E Reischl and PJ Leedman and S Lai and A Delitala and AP Bremner and DIW Philips and JP Beilby and A Mulas and M Vocale and G Abecasis and T Forsen and A James and E Widen and J Hui and H Prokisch and EE Rietzschel and A Palotie and P Feddema and SJ Fletcher and K Schramm and JI Rotter and A Kluttig and D Radke and M Traglia and GL Surdulescu and HL He and JA Franklyn and D Tiller and B Vaidya and T Meyer and T Jorgensen and JG Eriksson and PC O'Leary and E Wichmann and AR Hermus and BM Psaty and T Ittermann and Bert Hofman and E Bosi and D Schlessinger and H Wallaschofski and N Pirastu and YS Aulchenko and {de la Chapelle}, A and RT Netea-Maier and SCL Gough and {Meyer zu Schwabedissen}, H and TM Frayling and JM Kaufman and A Linneberg and K Raikkonen and JWA Smit and LA Kiemeney and Fernando Rivadeneira and Andr{\'e} Uitterlinden and JP Walsh and C Meisinger and Mariska Heijer and Theo Visser and TD Spector and SG Wilson and H Voelzke and A Cappola and D Toniolo and S Sanna and S Naitza and Robin Peeters",

year = "2014",

doi = "10.1371/journal.pgen.1004123",

language = "Undefined/Unknown",

volume = "10",

journal = "PLoS Genetics (print)",

issn = "1553-7390",

publisher = "Public Library of Science",

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, T, Plia, MG, Sala, C, Volker, U, Richards, JB, Sweep, FC, Gieger, C, Corre, T, Kajantie, E, Thuesen, B, Taes, YE, Visser, E, 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, HL, Franklyn, JA, Tiller, D, Vaidya, B, Meyer, T, Jorgensen, T, Eriksson, JG, O'Leary, PC, Wichmann, E, Hermus, AR, Psaty, BM, Ittermann, T, Hofman, B, 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, JM, Linneberg, A, Raikkonen, K, Smit, JWA, Kiemeney, LA, Rivadeneira, F , Uitterlinden, A, Walsh, JP, Meisinger, C, Heijer, M, Visser, T, Spector, TD, Wilson, SG, Voelzke, H, Cappola, A, Toniolo, D, Sanna, S, Naitza, S & Peeters, R 2014, 'Identification of Novel Genetic Loci Associated with Thyroid Peroxidase Antibodies and Clinical Thyroid Disease', PLoS Genetics (print), vol. 10, no. 2. https://doi.org/10.1371/journal.pgen.1004123

TY - JOUR

T1 - Identification of Novel Genetic Loci Associated with Thyroid Peroxidase Antibodies and Clinical Thyroid Disease

AU - Medici, Marco

AU - Porcu, E

AU - Pistis, G

AU - Teumer, A

AU - Brown, SJ

AU - Jensen, RA

AU - Rawal, R

AU - Roef, GL

AU - Plantinga, TS

AU - Vermeulen, SH

AU - Lahti, J

AU - Simmonds, MJ

AU - Husemoen, LLN

AU - Freathy, RM

AU - Shields, BM

AU - Pietzner, D

AU - Nagy, R

AU - Broer, Linda

AU - Chaker, Layal

AU - Korevaar, Tim

AU - Plia, MG

AU - Sala, C

AU - Volker, U

AU - Richards, JB

AU - Sweep, FC

AU - Gieger, C

AU - Corre, T

AU - Kajantie, E

AU - Thuesen, B

AU - Taes, YE

AU - Visser, Edward

AU - Hattersley, AT

AU - Kratzsch, J

AU - Hamilton, A

AU - Li, W (Wenguang)

AU - Homuth, G

AU - Lobina, M

AU - Mariotti, S

AU - Soranzo, N

AU - Cocca, M

AU - Nauck, M

AU - Spielhagen, C

AU - Ross, A

AU - Arnold, A

AU - van de Bunt, M

AU - Liyanarachchi, S

AU - Heier, M

AU - Grabe, HJ

AU - Masciullo, C

AU - Galesloot, TE

AU - Lim, EM

AU - Reischl, E

AU - Leedman, PJ

AU - Lai, S

AU - Delitala, A

AU - Bremner, AP

AU - Philips, DIW

AU - Beilby, JP

AU - Mulas, A

AU - Vocale, M

AU - Abecasis, G

AU - Forsen, T

AU - James, A

AU - Widen, E

AU - Hui, J

AU - Prokisch, H

AU - Rietzschel, EE

AU - Palotie, A

AU - Feddema, P

AU - Fletcher, SJ

AU - Schramm, K

AU - Rotter, JI

AU - Kluttig, A

AU - Radke, D

AU - Traglia, M

AU - Surdulescu, GL

AU - He, HL

AU - Franklyn, JA

AU - Tiller, D

AU - Vaidya, B

AU - Meyer, T

AU - Jorgensen, T

AU - Eriksson, JG

AU - O'Leary, PC

AU - Wichmann, E

AU - Hermus, AR

AU - Psaty, BM

AU - Ittermann, T

AU - Hofman, Bert

AU - Bosi, E

AU - Schlessinger, D

AU - Wallaschofski, H

AU - Pirastu, N

AU - Aulchenko, YS

AU - de la Chapelle, A

AU - Netea-Maier, RT

AU - Gough, SCL

AU - Meyer zu Schwabedissen, H

AU - Frayling, TM

AU - Kaufman, JM

AU - Linneberg, A

AU - Raikkonen, K

AU - Smit, JWA

AU - Kiemeney, LA

AU - Rivadeneira, Fernando

AU - Uitterlinden, André

AU - Walsh, JP

AU - Meisinger, C

AU - Heijer, Mariska

AU - Visser, Theo

AU - Spector, TD

AU - Wilson, SG

AU - Voelzke, H

AU - Cappola, A

AU - Toniolo, D

AU - Sanna, S

AU - Naitza, S

AU - Peeters, Robin

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

U2 - 10.1371/journal.pgen.1004123

DO - 10.1371/journal.pgen.1004123

M3 - Article

C2 - 24586183

SN - 1553-7390

VL - 10

JO - PLoS Genetics (print)

JF - PLoS Genetics (print)

IS - 2

ER -