A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function

Eleonora Porcu; Marco Medici; Giorgio Pistis; Claudia B Volpato; Scott G Wilson; Anne R Cappola; Steffan D Bos; Joris Deelen; Martin den Heijer; Rachel M Freathy; Jari Lahti; Chunyu Liu; Lorna M Lopez; Ilja M Nolte; Jeffrey R O'Connell; Toshiko Tanaka; Stella Trompet; Alice Arnold; Stefania Bandinelli; Marian Beekman; Stefan Böhringer; Suzanne J Brown; Brendan M Buckley; Clara Camaschella; Anton J M de Craen; Gail Davies; Marieke C H de Visser; Ian Ford; Tom Forsen; Timothy M Frayling; Laura Fugazzola; Martin Gögele; Andrew T Hattersley; Ad R Hermus; Albert Hofman; Jeanine J Houwing-Duistermaat; Richard A Jensen; Eero Kajantie; Margreet Kloppenburg; Ee M Lim; Corrado Masciullo; Stefano Mariotti; Cosetta Minelli; Braxton D Mitchell; Ramaiah Nagaraja; Romana T Netea-Maier; Aarno Palotie; Luca Persani; Maria G Piras; Bruce M Psaty; Katri Räikkönen; J Brent Richards; Fernando Rivadeneira; Cinzia Sala; Mona M Sabra; Naveed Sattar; Beverley M Shields; Nicole Soranzo; John M Starr; David J Stott; Fred C G J Sweep; Gianluca Usala; Melanie M van der Klauw; Diana van Heemst; Alies van Mullem; Sita H Vermeulen; W Edward Visser; John P Walsh; Rudi G J Westendorp; Elisabeth Widen; Guangju Zhai; Francesco Cucca; Ian J Deary; Johan G Eriksson; Luigi Ferrucci; Caroline S Fox; J Wouter Jukema; Lambertus A Kiemeney; Peter P Pramstaller; David Schlessinger; Alan R Shuldiner; Eline P Slagboom; André G Uitterlinden; Bijay Vaidya; Theo J Visser; Bruce H R Wolffenbuttel; Ingrid Meulenbelt; Jerome I Rotter; Tim D Spector; Andrew A Hicks; Daniela Toniolo; Serena Sanna; Robin P Peeters; Silvia Naitza

doi:10.1371/journal.pgen.1003266

A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function

Eleonora Porcu^*, Marco Medici, Giorgio Pistis, Claudia B Volpato, Scott G Wilson, Anne R Cappola, Steffan D Bos, Joris Deelen, Martin den Heijer, Rachel M Freathy, Jari Lahti, Chunyu Liu, Lorna M Lopez, Ilja M Nolte, Jeffrey R O'Connell, Toshiko Tanaka, Stella Trompet, Alice Arnold, Stefania Bandinelli, Marian BeekmanStefan Böhringer, Suzanne J Brown, Brendan M Buckley, Clara Camaschella, Anton J M de Craen, Gail Davies, Marieke C H de Visser, Ian Ford, Tom Forsen, Timothy M Frayling, Laura Fugazzola, Martin Gögele, Andrew T Hattersley, Ad R Hermus, Albert Hofman, Jeanine J Houwing-Duistermaat, Richard A Jensen, Eero Kajantie, Margreet Kloppenburg, Ee M Lim, Corrado Masciullo, Stefano Mariotti, Cosetta Minelli, Braxton D Mitchell, Ramaiah Nagaraja, Romana T Netea-Maier, Aarno Palotie, Luca Persani, Maria G Piras, Bruce M Psaty, Katri Räikkönen, J Brent Richards, Fernando Rivadeneira, Cinzia Sala, Mona M Sabra, Naveed Sattar, Beverley M Shields, Nicole Soranzo, John M Starr, David J Stott, Fred C G J Sweep, Gianluca Usala, Melanie M van der Klauw, Diana van Heemst, Alies van Mullem, Sita H Vermeulen, W Edward Visser, John P Walsh, Rudi G J Westendorp, Elisabeth Widen, Guangju Zhai, Francesco Cucca, Ian J Deary, Johan G Eriksson, Luigi Ferrucci, Caroline S Fox, J Wouter Jukema, Lambertus A Kiemeney, Peter P Pramstaller, David Schlessinger, Alan R Shuldiner, Eline P Slagboom, André G Uitterlinden, Bijay Vaidya, Theo J Visser, Bruce H R Wolffenbuttel, Ingrid Meulenbelt, Jerome I Rotter, Tim D Spector, Andrew A Hicks, Daniela Toniolo, Serena Sanna, Robin P Peeters, Silvia Naitza

^*Corresponding author voor dit werk

Life Course Epidemiology (LCE)

Onderzoeksoutput › Academic › peer review

186 Citaten (Scopus)

528 Downloads (Pure)

Samenvatting

Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.

Originele taal-2	English
Artikelnummer	e1003266
Aantal pagina's	20
Tijdschrift	PLoS genetics
Volume	9
Nummer van het tijdschrift	2
DOI's	https://doi.org/10.1371/journal.pgen.1003266
Status	Published - feb.-2013

Toegang tot document

10.1371/journal.pgen.1003266Licentie: CC BY

Porcu_2013_Plos_Genet.pdfFinal publisher's version, 1,69 MBLicentie: CC BY

Handle.net

Permanente koppeling

Lifelines Biobank
Bakker, S. (Creator), Dotinga, A. (Creator), Vonk, J. M. (Creator), Smidt, N. (Creator), Scholtens, S. (Creator), Swertz, M. (Creator), Wijmenga, C. (Creator), Wolffenbutel, B. H. (Creator), Stolk, R. (Creator), van Zon, S. (Creator), Rosmalen, J. (Creator), Postma, D. S. (Creator), de Boer, R. (Creator), Navis, G. (Creator), Slaets, J. (Creator), Ormel, J. (Creator), van Dijk, F. (Creator) & Bolmer, B. (Data Manager), Lifelines, 2006
https://www.lifelines.nl/ en nog één link, https://catalogue.lifelines.nl/ (minder tonen)
Dataset

Citeer dit

Porcu, E., Medici, M., Pistis, G., Volpato, C. B., Wilson, S. G., Cappola, A. R., Bos, S. D., Deelen, J., den Heijer, M., Freathy, R. M., Lahti, J., Liu, C., Lopez, L. M., Nolte, I. M., O'Connell, J. R., Tanaka, T., Trompet, S., Arnold, A., Bandinelli, S., ... Naitza, S. (2013). A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function. PLoS genetics, 9(2), Artikel e1003266. https://doi.org/10.1371/journal.pgen.1003266

@article{579b08601fbd44cc8ab3d9f799636c92,

title = "A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function",

abstract = "Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.",

keywords = "GENOME-WIDE ASSOCIATION, FACTOR BINDING PROTEIN-5, HORMONE PATHWAY GENES, SERUM TSH, COMMON VARIATION, CLEFT-PALATE, EXPRESSION, GROWTH, HYPOTHYROIDISM, THYROTROPIN",

author = "Eleonora Porcu and Marco Medici and Giorgio Pistis and Volpato, {Claudia B} and Wilson, {Scott G} and Cappola, {Anne R} and Bos, {Steffan D} and Joris Deelen and {den Heijer}, Martin and Freathy, {Rachel M} and Jari Lahti and Chunyu Liu and Lopez, {Lorna M} and Nolte, {Ilja M} and O'Connell, {Jeffrey R} and Toshiko Tanaka and Stella Trompet and Alice Arnold and Stefania Bandinelli and Marian Beekman and Stefan B{\"o}hringer and Brown, {Suzanne J} and Buckley, {Brendan M} and Clara Camaschella and {de Craen}, {Anton J M} and Gail Davies and {de Visser}, {Marieke C H} and Ian Ford and Tom Forsen and Frayling, {Timothy M} and Laura Fugazzola and Martin G{\"o}gele and Hattersley, {Andrew T} and Hermus, {Ad R} and Albert Hofman and Houwing-Duistermaat, {Jeanine J} and Jensen, {Richard A} and Eero Kajantie and Margreet Kloppenburg and Lim, {Ee M} and Corrado Masciullo and Stefano Mariotti and Cosetta Minelli and Mitchell, {Braxton D} and Ramaiah Nagaraja and Netea-Maier, {Romana T} and Aarno Palotie and Luca Persani and Piras, {Maria G} and Psaty, {Bruce M} and Katri R{\"a}ikk{\"o}nen and Richards, {J Brent} and Fernando Rivadeneira and Cinzia Sala and Sabra, {Mona M} and Naveed Sattar and Shields, {Beverley M} and Nicole Soranzo and Starr, {John M} and Stott, {David J} and Sweep, {Fred C G J} and Gianluca Usala and {van der Klauw}, {Melanie M} and {van Heemst}, Diana and {van Mullem}, Alies and Vermeulen, {Sita H} and Visser, {W Edward} and Walsh, {John P} and Westendorp, {Rudi G J} and Elisabeth Widen and Guangju Zhai and Francesco Cucca and Deary, {Ian J} and Eriksson, {Johan G} and Luigi Ferrucci and Fox, {Caroline S} and Jukema, {J Wouter} and Kiemeney, {Lambertus A} and Pramstaller, {Peter P} and David Schlessinger and Shuldiner, {Alan R} and Slagboom, {Eline P} and Uitterlinden, {Andr{\'e} G} and Bijay Vaidya and Visser, {Theo J} and Wolffenbuttel, {Bruce H R} and Ingrid Meulenbelt and Rotter, {Jerome I} and Spector, {Tim D} and Hicks, {Andrew A} and Daniela Toniolo and Serena Sanna and Peeters, {Robin P} and Silvia Naitza",

year = "2013",

month = feb,

doi = "10.1371/journal.pgen.1003266",

language = "English",

volume = "9",

journal = "PLoS genetics",

issn = "1553-7404",

publisher = "PUBLIC LIBRARY SCIENCE",

number = "2",

}

Porcu, E, Medici, M, Pistis, G, Volpato, CB, Wilson, SG, Cappola, AR, Bos, SD, Deelen, J, den Heijer, M, Freathy, RM, Lahti, J, Liu, C, Lopez, LM, Nolte, IM, O'Connell, JR, Tanaka, T, Trompet, S, Arnold, A, Bandinelli, S, Beekman, M, Böhringer, S, Brown, SJ, Buckley, BM, Camaschella, C, de Craen, AJM, Davies, G, de Visser, MCH, Ford, I, Forsen, T, Frayling, TM, Fugazzola, L, Gögele, M, Hattersley, AT, Hermus, AR, Hofman, A, Houwing-Duistermaat, JJ, Jensen, RA, Kajantie, E, Kloppenburg, M, Lim, EM, Masciullo, C, Mariotti, S, Minelli, C, Mitchell, BD, Nagaraja, R, Netea-Maier, RT, Palotie, A, Persani, L, Piras, MG, Psaty, BM, Räikkönen, K, Richards, JB, Rivadeneira, F, Sala, C, Sabra, MM, Sattar, N, Shields, BM, Soranzo, N, Starr, JM, Stott, DJ, Sweep, FCGJ, Usala, G, van der Klauw, MM, van Heemst, D, van Mullem, A, Vermeulen, SH, Visser, WE, Walsh, JP, Westendorp, RGJ, Widen, E, Zhai, G, Cucca, F, Deary, IJ, Eriksson, JG, Ferrucci, L, Fox, CS, Jukema, JW, Kiemeney, LA, Pramstaller, PP, Schlessinger, D, Shuldiner, AR, Slagboom, EP, Uitterlinden, AG, Vaidya, B, Visser, TJ, Wolffenbuttel, BHR, Meulenbelt, I, Rotter, JI, Spector, TD, Hicks, AA, Toniolo, D, Sanna, S, Peeters, RP & Naitza, S 2013, 'A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function', PLoS genetics, vol. 9, nr. 2, e1003266. https://doi.org/10.1371/journal.pgen.1003266

TY - JOUR

T1 - A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function

AU - Porcu, Eleonora

AU - Medici, Marco

AU - Pistis, Giorgio

AU - Volpato, Claudia B

AU - Wilson, Scott G

AU - Cappola, Anne R

AU - Bos, Steffan D

AU - Deelen, Joris

AU - den Heijer, Martin

AU - Freathy, Rachel M

AU - Lahti, Jari

AU - Liu, Chunyu

AU - Lopez, Lorna M

AU - Nolte, Ilja M

AU - O'Connell, Jeffrey R

AU - Tanaka, Toshiko

AU - Trompet, Stella

AU - Arnold, Alice

AU - Bandinelli, Stefania

AU - Beekman, Marian

AU - Böhringer, Stefan

AU - Brown, Suzanne J

AU - Buckley, Brendan M

AU - Camaschella, Clara

AU - de Craen, Anton J M

AU - Davies, Gail

AU - de Visser, Marieke C H

AU - Ford, Ian

AU - Forsen, Tom

AU - Frayling, Timothy M

AU - Fugazzola, Laura

AU - Gögele, Martin

AU - Hattersley, Andrew T

AU - Hermus, Ad R

AU - Hofman, Albert

AU - Houwing-Duistermaat, Jeanine J

AU - Jensen, Richard A

AU - Kajantie, Eero

AU - Kloppenburg, Margreet

AU - Lim, Ee M

AU - Masciullo, Corrado

AU - Mariotti, Stefano

AU - Minelli, Cosetta

AU - Mitchell, Braxton D

AU - Nagaraja, Ramaiah

AU - Netea-Maier, Romana T

AU - Palotie, Aarno

AU - Persani, Luca

AU - Piras, Maria G

AU - Psaty, Bruce M

AU - Räikkönen, Katri

AU - Richards, J Brent

AU - Rivadeneira, Fernando

AU - Sala, Cinzia

AU - Sabra, Mona M

AU - Sattar, Naveed

AU - Shields, Beverley M

AU - Soranzo, Nicole

AU - Starr, John M

AU - Stott, David J

AU - Sweep, Fred C G J

AU - Usala, Gianluca

AU - van der Klauw, Melanie M

AU - van Heemst, Diana

AU - van Mullem, Alies

AU - Vermeulen, Sita H

AU - Visser, W Edward

AU - Walsh, John P

AU - Westendorp, Rudi G J

AU - Widen, Elisabeth

AU - Zhai, Guangju

AU - Cucca, Francesco

AU - Deary, Ian J

AU - Eriksson, Johan G

AU - Ferrucci, Luigi

AU - Fox, Caroline S

AU - Jukema, J Wouter

AU - Kiemeney, Lambertus A

AU - Pramstaller, Peter P

AU - Schlessinger, David

AU - Shuldiner, Alan R

AU - Slagboom, Eline P

AU - Uitterlinden, André G

AU - Vaidya, Bijay

AU - Visser, Theo J

AU - Wolffenbuttel, Bruce H R

AU - Meulenbelt, Ingrid

AU - Rotter, Jerome I

AU - Spector, Tim D

AU - Hicks, Andrew A

AU - Toniolo, Daniela

AU - Sanna, Serena

AU - Peeters, Robin P

AU - Naitza, Silvia

PY - 2013/2

Y1 - 2013/2

N2 - Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.

AB - Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.

KW - GENOME-WIDE ASSOCIATION

KW - FACTOR BINDING PROTEIN-5

KW - HORMONE PATHWAY GENES

KW - SERUM TSH

KW - COMMON VARIATION

KW - CLEFT-PALATE

KW - EXPRESSION

KW - GROWTH

KW - HYPOTHYROIDISM

KW - THYROTROPIN

U2 - 10.1371/journal.pgen.1003266

DO - 10.1371/journal.pgen.1003266

M3 - Article

C2 - 23408906

SN - 1553-7404

VL - 9

JO - PLoS genetics

JF - PLoS genetics

IS - 2

M1 - e1003266

ER -

A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function

Samenvatting

Toegang tot document

Handle.net

Vingerafdruk

Datasets

Lifelines Biobank

Citeer dit