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 - Völker, 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, Jürgen

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 Jörgen

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, Dörte

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 - Jørgensen, 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 - Räikkönen, Katri

AU - Smit, Johannes W A

AU - Kiemeney, Lambertus A

AU - Rivadeneira, Fernando

AU - Uitterlinden, André 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 - Völzke, 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 - Autoantibodies

KW - Genetic Loci

KW - Genome-Wide Association Study

KW - Graves Disease

KW - Hashimoto Disease

KW - Humans

KW - Iodide Peroxidase

KW - Risk Factors

KW - Thyrotropin

U2 - 10.1371/journal.pgen.1004123

DO - 10.1371/journal.pgen.1004123

M3 - Journal article

C2 - 24586183

VL - 10

SP - 1

EP - 13

JO - P L o S Genetics

JF - P L o S Genetics

SN - 1553-7390

IS - 2

M1 - e1004123

ER -