Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

Rosalie B. T. M. Sterenborg; Inga Steinbrenner; Yong Li; Melissa N. Bujnis; Tatsuhiko Naito; Eirini Marouli; Tessel E. Galesloot; Oladapo Babajide; Laura Andreasen; Arne Astrup; Bjørn Olav Åsvold; Stefania Bandinelli; Marian Beekman; John P. Beilby; Jette Bork-Jensen; Thibaud Boutin; Jennifer A. Brody; Suzanne J. Brown; Ben Brumpton; Purdey J. Campbell; Anne R. Cappola; Graziano Ceresini; Layal Chaker; Daniel I. Chasman; Maria Pina Concas; Rodrigo Coutinho de Almeida; Simone M. Cross; Francesco Cucca; Ian J. Deary; Alisa Devedzic Kjaergaard; Justin B. Echouffo Tcheugui; Christina Ellervik; Johan G. Eriksson; Luigi Ferrucci; Jan Freudenberg; Christian Fuchsberger; Christian Gieger; Franco Giulianini; Martin Gögele; Sarah E. Graham; Niels Grarup; Ivana Gunjača; Torben Hansen; Barbara N. Harding; Sarah E. Harris; Stig Haunsø; Caroline Hayward; Jennie Hui; Till Ittermann; J. Wouter Jukema; Eero Kajantie; Jørgen K. Kanters; Line L. Kårhus; Lambertus A. L. M. Kiemeney; Margreet Kloppenburg; Brigitte Kühnel; Jari Lahti; Claudia Langenberg; Bruno Lapauw; Graham Leese; Shuo Li; David C. M. Liewald; Allan Linneberg; Jesus V. T. Lominchar; Jian’an Luan; Nicholas G. Martin; Antonela Matana; Marcel E. Meima; Thomas Meitinger; Ingrid Meulenbelt; Braxton D. Mitchell; Line T. Møllehave; Samia Mora; Silvia Naitza; Matthias Nauck; Romana T. Netea-Maier; Raymond Noordam; Casia Nursyifa; Yukinori Okada; Stefano Onano; Areti Papadopoulou; Colin N. A. Palmer; Cristian Pattaro; Oluf Pedersen; Annette Peters; Maik Pietzner; Ozren Polašek; Peter P. Pramstaller; Bruce M. Psaty; Ante Punda; Debashree Ray; Paul Redmond; J. Brent Richards; Paul M. Ridker; Tom C. Russ; Kathleen A. Ryan; Morten Salling Olesen; Ulla T. Schultheiss; Elizabeth Selvin; Moneeza K. Siddiqui; Carlo Sidore; P. Eline Slagboom; Thorkild I. A. Sørensen; Enrique Soto-Pedre; Tim D. Spector; Beatrice Spedicati; Sundararajan Srinivasan; John M. Starr; David J. Stott; Toshiko Tanaka; Vesela Torlak; Stella Trompet; Johanna Tuhkanen; André G. Uitterlinden; Erik B. van den Akker; Tibbert van den Eynde; Melanie M. van der Klauw; Diana van Heemst; Charlotte Verroken; W. Edward Visser; Dina Vojinovic; Henry Völzke; Melanie Waldenberger; John P. Walsh; Nicholas J. Wareham; Stefan Weiss; Cristen J. Willer; Scott G. Wilson; Bruce H. R. Wolffenbuttel; Hanneke J. C. M. Wouters; Margaret J. Wright; Qiong Yang; Tatijana Zemunik; Wei Zhou; Gu Zhu; Sebastian Zöllner; Johannes W. A. Smit; Robin P. Peeters; Anna Köttgen; Alexander Teumer; Marco Medici; GHS DiscovEHR; Regeneron Genetics Center

doi:10.1038/s41467-024-44701-9

Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

Rosalie B. T. M. Sterenborg, Inga Steinbrenner, Yong Li, Melissa N. Bujnis, Tatsuhiko Naito, Eirini Marouli, Tessel E. Galesloot, Oladapo Babajide, Laura Andreasen, Arne Astrup, Bjørn Olav Åsvold, Stefania Bandinelli, Marian Beekman, John P. Beilby, Jette Bork-Jensen, Thibaud Boutin, Jennifer A. Brody, Suzanne J. Brown, Ben Brumpton, Purdey J. CampbellAnne R. Cappola, Graziano Ceresini, Layal Chaker, Daniel I. Chasman, Maria Pina Concas, Rodrigo Coutinho de Almeida, Simone M. Cross, Francesco Cucca, Ian J. Deary, Alisa Devedzic Kjaergaard, Justin B. Echouffo Tcheugui, Christina Ellervik, Johan G. Eriksson, Luigi Ferrucci, Jan Freudenberg, Christian Fuchsberger, Christian Gieger, Franco Giulianini, Martin Gögele, Sarah E. Graham, Niels Grarup, Ivana Gunjača, Torben Hansen, Barbara N. Harding, Sarah E. Harris, Stig Haunsø, Caroline Hayward, Jennie Hui, Till Ittermann, J. Wouter Jukema, Eero Kajantie, Jørgen K. Kanters, Line L. Kårhus, Lambertus A. L. M. Kiemeney, Margreet Kloppenburg, Brigitte Kühnel, Jari Lahti, Claudia Langenberg, Bruno Lapauw, Graham Leese, Shuo Li, David C. M. Liewald, Allan Linneberg, Jesus V. T. Lominchar, Jian’an Luan, Nicholas G. Martin, Antonela Matana, Marcel E. Meima, Thomas Meitinger, Ingrid Meulenbelt, Braxton D. Mitchell, Line T. Møllehave, Samia Mora, Silvia Naitza, Matthias Nauck, Romana T. Netea-Maier, Raymond Noordam, Casia Nursyifa, Yukinori Okada, Stefano Onano, Areti Papadopoulou, Colin N. A. Palmer, Cristian Pattaro, Oluf Pedersen, Annette Peters, Maik Pietzner, Ozren Polašek, Peter P. Pramstaller, Bruce M. Psaty, Ante Punda, Debashree Ray, Paul Redmond, J. Brent Richards, Paul M. Ridker, Tom C. Russ, Kathleen A. Ryan, Morten Salling Olesen, Ulla T. Schultheiss, Elizabeth Selvin, Moneeza K. Siddiqui, Carlo Sidore, P. Eline Slagboom, Thorkild I. A. Sørensen, Enrique Soto-Pedre, Tim D. Spector, Beatrice Spedicati, Sundararajan Srinivasan, John M. Starr, David J. Stott, Toshiko Tanaka, Vesela Torlak, Stella Trompet, Johanna Tuhkanen, André G. Uitterlinden, Erik B. van den Akker, Tibbert van den Eynde, Melanie M. van der Klauw, Diana van Heemst, Charlotte Verroken, W. Edward Visser, Dina Vojinovic, Henry Völzke, Melanie Waldenberger, John P. Walsh, Nicholas J. Wareham, Stefan Weiss, Cristen J. Willer, Scott G. Wilson, Bruce H. R. Wolffenbuttel, Hanneke J. C. M. Wouters, Margaret J. Wright, Qiong Yang, Tatijana Zemunik, Wei Zhou, Gu Zhu, Sebastian Zöllner, Johannes W. A. Smit, Robin P. Peeters, Anna Köttgen, Alexander Teumer^*, Marco Medici^*, GHS DiscovEHR, Regeneron Genetics Center

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

Original language	English
Article number	888
Number of pages	18
Journal	Nature Communications
Volume	15
Issue number	1
Early online date	30 Jan 2024
DOIs	https://doi.org/10.1038/s41467-024-44701-9
Publication status	Published - 2024

Keywords / Materials (for Non-textual outputs)

genome-wide association studies
thyroid diseases

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10.1038/s41467-024-44701-9Licence: Creative Commons: Attribution (CC-BY)

SterenborgEtalNC2024Multi-TraitAnalysisMulti-TraitAnalysisCharacterizesTheGeneticsFinal published version, 9.71 MBLicence: Creative Commons: Attribution (CC-BY)

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Sterenborg, R. B. T. M., Steinbrenner, I., Li, Y., Bujnis, M. N., Naito, T., Marouli, E., Galesloot, T. E., Babajide, O., Andreasen, L., Astrup, A., Åsvold, B. O., Bandinelli, S., Beekman, M., Beilby, J. P., Bork-Jensen, J., Boutin, T., Brody, J. A., Brown, S. J., Brumpton, B., ... Center, R. G. (2024). Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications. Nature Communications, 15(1), Article 888. https://doi.org/10.1038/s41467-024-44701-9

@article{deff79a0d117488ab499a3cb1f344562,

title = "Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications",

abstract = "To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.",

keywords = "genome-wide association studies, thyroid diseases",

author = "Sterenborg, {Rosalie B. T. M.} and Inga Steinbrenner and Yong Li and Bujnis, {Melissa N.} and Tatsuhiko Naito and Eirini Marouli and Galesloot, {Tessel E.} and Oladapo Babajide and Laura Andreasen and Arne Astrup and {\AA}svold, {Bj{\o}rn Olav} and Stefania Bandinelli and Marian Beekman and Beilby, {John P.} and Jette Bork-Jensen and Thibaud Boutin and Brody, {Jennifer A.} and Brown, {Suzanne J.} and Ben Brumpton and Campbell, {Purdey J.} and Cappola, {Anne R.} and Graziano Ceresini and Layal Chaker and Chasman, {Daniel I.} and Concas, {Maria Pina} and {Coutinho de Almeida}, Rodrigo and Cross, {Simone M.} and Francesco Cucca and Deary, {Ian J.} and Kjaergaard, {Alisa Devedzic} and {Echouffo Tcheugui}, {Justin B.} and Christina Ellervik and Eriksson, {Johan G.} and Luigi Ferrucci and Jan Freudenberg and Christian Fuchsberger and Christian Gieger and Franco Giulianini and Martin G{\"o}gele and Graham, {Sarah E.} and Niels Grarup and Ivana Gunja{\v c}a and Torben Hansen and Harding, {Barbara N.} and Harris, {Sarah E.} and Stig Hauns{\o} and Caroline Hayward and Jennie Hui and Till Ittermann and Jukema, {J. Wouter} and Eero Kajantie and Kanters, {J{\o}rgen K.} and K{\aa}rhus, {Line L.} and Kiemeney, {Lambertus A. L. M.} and Margreet Kloppenburg and Brigitte K{\"u}hnel and Jari Lahti and Claudia Langenberg and Bruno Lapauw and Graham Leese and Shuo Li and Liewald, {David C. M.} and Allan Linneberg and Lominchar, {Jesus V. T.} and Jian{\textquoteright}an Luan and Martin, {Nicholas G.} and Antonela Matana and Meima, {Marcel E.} and Thomas Meitinger and Ingrid Meulenbelt and Mitchell, {Braxton D.} and M{\o}llehave, {Line T.} and Samia Mora and Silvia Naitza and Matthias Nauck and Netea-Maier, {Romana T.} and Raymond Noordam and Casia Nursyifa and Yukinori Okada and Stefano Onano and Areti Papadopoulou and Palmer, {Colin N. A.} and Cristian Pattaro and Oluf Pedersen and Annette Peters and Maik Pietzner and Ozren Pola{\v s}ek and Pramstaller, {Peter P.} and Psaty, {Bruce M.} and Ante Punda and Debashree Ray and Paul Redmond and Richards, {J. Brent} and Ridker, {Paul M.} and Russ, {Tom C.} and Ryan, {Kathleen A.} and Olesen, {Morten Salling} and Schultheiss, {Ulla T.} and Elizabeth Selvin and Siddiqui, {Moneeza K.} and Carlo Sidore and Slagboom, {P. Eline} and S{\o}rensen, {Thorkild I. A.} and Enrique Soto-Pedre and Spector, {Tim D.} and Beatrice Spedicati and Sundararajan Srinivasan and Starr, {John M.} and Stott, {David J.} and Toshiko Tanaka and Vesela Torlak and Stella Trompet and Johanna Tuhkanen and Uitterlinden, {Andr{\'e} G.} and {van den Akker}, {Erik B.} and {van den Eynde}, Tibbert and {van der Klauw}, {Melanie M.} and {van Heemst}, Diana and Charlotte Verroken and Visser, {W. Edward} and Dina Vojinovic and Henry V{\"o}lzke and Melanie Waldenberger and Walsh, {John P.} and Wareham, {Nicholas J.} and Stefan Weiss and Willer, {Cristen J.} and Wilson, {Scott G.} and Wolffenbuttel, {Bruce H. R.} and Wouters, {Hanneke J. C. M.} and Wright, {Margaret J.} and Qiong Yang and Tatijana Zemunik and Wei Zhou and Gu Zhu and Sebastian Z{\"o}llner and Smit, {Johannes W. A.} and Peeters, {Robin P.} and Anna K{\"o}ttgen and Alexander Teumer and Marco Medici and GHS DiscovEHR and Center, {Regeneron Genetics}",

note = "Acknowledgements: This work was supported by funding from the European and American Thyroid Associations, the Erasmus University Rotterdam, the Dutch Organization for Scientific Research (NWO) (M.Med.), and the NIH (grants R35GM118335 and T32DK110966). Acknowledgments and study-specific acknowledgments are provided in the Supplementary Note. We conducted this research using the UK Biobank resource under the application numbers 53723 and 20272. Lothian Birth Cohorts: We thank the cohort participants and team members who contributed to these studies. Phenotype collection in the Lothian Birth Cohort 1921 was supported by the UK{\textquoteright}s Biotechnology and Biological Sciences Research Council (BBSRC), The Royal Society, and The Chief Scientist Office of the Scottish Government. LBC1936 is supported by the BBSRC, and the Economic and Social Research Council [BB/W008793/1], Age UK (Disconnected Mind project), and the University of Edinburgh. Genotyping of the cohorts was funded by the BBSRC (BB/F019394/1). Ethics permission for the LBC1936 was obtained from the Multi- Centre Research Ethics Committee for Scotland (MREC/01/0/56) and the Lothian Research Ethics Committee (LREC/2003/2/29). Ethics permission for the LBC1921 was obtained from the Lothian Research Ethics Committee (LREC/1998/4/183). All persons gave their informed consent prior to their inclusion in the study. We gratefully acknowledge the contribution of LBC co-author Professor John M. Starr, who died prior to the publication of this manuscript.",

year = "2024",

doi = "10.1038/s41467-024-44701-9",

language = "English",

volume = "15",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Sterenborg, RBTM, Steinbrenner, I, Li, Y, Bujnis, MN, Naito, T, Marouli, E, Galesloot, TE, Babajide, O, Andreasen, L, Astrup, A, Åsvold, BO, Bandinelli, S, Beekman, M, Beilby, JP, Bork-Jensen, J, Boutin, T, Brody, JA, Brown, SJ, Brumpton, B, Campbell, PJ, Cappola, AR, Ceresini, G, Chaker, L, Chasman, DI, Concas, MP, Coutinho de Almeida, R, Cross, SM, Cucca, F, Deary, IJ, Kjaergaard, AD, Echouffo Tcheugui, JB, Ellervik, C, Eriksson, JG, Ferrucci, L, Freudenberg, J, Fuchsberger, C, Gieger, C, Giulianini, F, Gögele, M, Graham, SE, Grarup, N, Gunjača, I, Hansen, T, Harding, BN, Harris, SE, Haunsø, S, Hayward, C, Hui, J, Ittermann, T, Jukema, JW, Kajantie, E, Kanters, JK, Kårhus, LL, Kiemeney, LALM, Kloppenburg, M, Kühnel, B, Lahti, J, Langenberg, C, Lapauw, B, Leese, G, Li, S, Liewald, DCM, Linneberg, A, Lominchar, JVT, Luan, J, Martin, NG, Matana, A, Meima, ME, Meitinger, T, Meulenbelt, I, Mitchell, BD, Møllehave, LT, Mora, S, Naitza, S, Nauck, M, Netea-Maier, RT, Noordam, R, Nursyifa, C, Okada, Y, Onano, S, Papadopoulou, A, Palmer, CNA, Pattaro, C, Pedersen, O, Peters, A, Pietzner, M, Polašek, O, Pramstaller, PP, Psaty, BM, Punda, A, Ray, D, Redmond, P, Richards, JB, Ridker, PM, Russ, TC, Ryan, KA, Olesen, MS, Schultheiss, UT, Selvin, E, Siddiqui, MK, Sidore, C, Slagboom, PE, Sørensen, TIA, Soto-Pedre, E, Spector, TD, Spedicati, B, Srinivasan, S, Starr, JM, Stott, DJ, Tanaka, T, Torlak, V, Trompet, S, Tuhkanen, J, Uitterlinden, AG, van den Akker, EB, van den Eynde, T, van der Klauw, MM, van Heemst, D, Verroken, C, Visser, WE, Vojinovic, D, Völzke, H, Waldenberger, M, Walsh, JP, Wareham, NJ, Weiss, S, Willer, CJ, Wilson, SG, Wolffenbuttel, BHR, Wouters, HJCM, Wright, MJ, Yang, Q, Zemunik, T, Zhou, W, Zhu, G, Zöllner, S, Smit, JWA, Peeters, RP, Köttgen, A, Teumer, A, Medici, M, DiscovEHR, GHS & Center, RG 2024, 'Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications', Nature Communications, vol. 15, no. 1, 888. https://doi.org/10.1038/s41467-024-44701-9

TY - JOUR

T1 - Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

AU - Sterenborg, Rosalie B. T. M.

AU - Steinbrenner, Inga

AU - Li, Yong

AU - Bujnis, Melissa N.

AU - Naito, Tatsuhiko

AU - Marouli, Eirini

AU - Galesloot, Tessel E.

AU - Babajide, Oladapo

AU - Andreasen, Laura

AU - Astrup, Arne

AU - Åsvold, Bjørn Olav

AU - Bandinelli, Stefania

AU - Beekman, Marian

AU - Beilby, John P.

AU - Bork-Jensen, Jette

AU - Boutin, Thibaud

AU - Brody, Jennifer A.

AU - Brown, Suzanne J.

AU - Brumpton, Ben

AU - Campbell, Purdey J.

AU - Cappola, Anne R.

AU - Ceresini, Graziano

AU - Chaker, Layal

AU - Chasman, Daniel I.

AU - Concas, Maria Pina

AU - Coutinho de Almeida, Rodrigo

AU - Cross, Simone M.

AU - Cucca, Francesco

AU - Deary, Ian J.

AU - Kjaergaard, Alisa Devedzic

AU - Echouffo Tcheugui, Justin B.

AU - Ellervik, Christina

AU - Eriksson, Johan G.

AU - Ferrucci, Luigi

AU - Freudenberg, Jan

AU - Fuchsberger, Christian

AU - Gieger, Christian

AU - Giulianini, Franco

AU - Gögele, Martin

AU - Graham, Sarah E.

AU - Grarup, Niels

AU - Gunjača, Ivana

AU - Hansen, Torben

AU - Harding, Barbara N.

AU - Harris, Sarah E.

AU - Haunsø, Stig

AU - Hayward, Caroline

AU - Hui, Jennie

AU - Ittermann, Till

AU - Jukema, J. Wouter

AU - Kajantie, Eero

AU - Kanters, Jørgen K.

AU - Kårhus, Line L.

AU - Kiemeney, Lambertus A. L. M.

AU - Kloppenburg, Margreet

AU - Kühnel, Brigitte

AU - Lahti, Jari

AU - Langenberg, Claudia

AU - Lapauw, Bruno

AU - Leese, Graham

AU - Li, Shuo

AU - Liewald, David C. M.

AU - Linneberg, Allan

AU - Lominchar, Jesus V. T.

AU - Luan, Jian’an

AU - Martin, Nicholas G.

AU - Matana, Antonela

AU - Meima, Marcel E.

AU - Meitinger, Thomas

AU - Meulenbelt, Ingrid

AU - Mitchell, Braxton D.

AU - Møllehave, Line T.

AU - Mora, Samia

AU - Naitza, Silvia

AU - Nauck, Matthias

AU - Netea-Maier, Romana T.

AU - Noordam, Raymond

AU - Nursyifa, Casia

AU - Okada, Yukinori

AU - Onano, Stefano

AU - Papadopoulou, Areti

AU - Palmer, Colin N. A.

AU - Pattaro, Cristian

AU - Pedersen, Oluf

AU - Peters, Annette

AU - Pietzner, Maik

AU - Polašek, Ozren

AU - Pramstaller, Peter P.

AU - Psaty, Bruce M.

AU - Punda, Ante

AU - Ray, Debashree

AU - Redmond, Paul

AU - Richards, J. Brent

AU - Ridker, Paul M.

AU - Russ, Tom C.

AU - Ryan, Kathleen A.

AU - Olesen, Morten Salling

AU - Schultheiss, Ulla T.

AU - Selvin, Elizabeth

AU - Siddiqui, Moneeza K.

AU - Sidore, Carlo

AU - Slagboom, P. Eline

AU - Sørensen, Thorkild I. A.

AU - Soto-Pedre, Enrique

AU - Spector, Tim D.

AU - Spedicati, Beatrice

AU - Srinivasan, Sundararajan

AU - Starr, John M.

AU - Stott, David J.

AU - Tanaka, Toshiko

AU - Torlak, Vesela

AU - Trompet, Stella

AU - Tuhkanen, Johanna

AU - Uitterlinden, André G.

AU - van den Akker, Erik B.

AU - van den Eynde, Tibbert

AU - van der Klauw, Melanie M.

AU - van Heemst, Diana

AU - Verroken, Charlotte

AU - Visser, W. Edward

AU - Vojinovic, Dina

AU - Völzke, Henry

AU - Waldenberger, Melanie

AU - Walsh, John P.

AU - Wareham, Nicholas J.

AU - Weiss, Stefan

AU - Willer, Cristen J.

AU - Wilson, Scott G.

AU - Wolffenbuttel, Bruce H. R.

AU - Wouters, Hanneke J. C. M.

AU - Wright, Margaret J.

AU - Yang, Qiong

AU - Zemunik, Tatijana

AU - Zhou, Wei

AU - Zhu, Gu

AU - Zöllner, Sebastian

AU - Smit, Johannes W. A.

AU - Peeters, Robin P.

AU - Köttgen, Anna

AU - Teumer, Alexander

AU - Medici, Marco

AU - DiscovEHR, GHS

AU - Center, Regeneron Genetics

N1 - Acknowledgements: This work was supported by funding from the European and American Thyroid Associations, the Erasmus University Rotterdam, the Dutch Organization for Scientific Research (NWO) (M.Med.), and the NIH (grants R35GM118335 and T32DK110966). Acknowledgments and study-specific acknowledgments are provided in the Supplementary Note. We conducted this research using the UK Biobank resource under the application numbers 53723 and 20272. Lothian Birth Cohorts: We thank the cohort participants and team members who contributed to these studies. Phenotype collection in the Lothian Birth Cohort 1921 was supported by the UK’s Biotechnology and Biological Sciences Research Council (BBSRC), The Royal Society, and The Chief Scientist Office of the Scottish Government. LBC1936 is supported by the BBSRC, and the Economic and Social Research Council [BB/W008793/1], Age UK (Disconnected Mind project), and the University of Edinburgh. Genotyping of the cohorts was funded by the BBSRC (BB/F019394/1). Ethics permission for the LBC1936 was obtained from the Multi- Centre Research Ethics Committee for Scotland (MREC/01/0/56) and the Lothian Research Ethics Committee (LREC/2003/2/29). Ethics permission for the LBC1921 was obtained from the Lothian Research Ethics Committee (LREC/1998/4/183). All persons gave their informed consent prior to their inclusion in the study. We gratefully acknowledge the contribution of LBC co-author Professor John M. Starr, who died prior to the publication of this manuscript.

PY - 2024

Y1 - 2024

N2 - To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

AB - To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

KW - genome-wide association studies

KW - thyroid diseases

UR - https://transfer.sysepi.medizin.uni-greifswald.de/thyroidomics/datasets/

U2 - 10.1038/s41467-024-44701-9

DO - 10.1038/s41467-024-44701-9

M3 - Article

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 888

ER -

Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

Abstract

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The Lothian Birth Cohort 1936 Waves 6 and 7

Disconnected Mind - Phase 4

A genome wide association study of non pathological cognitive ageing

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Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

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Projects

The Lothian Birth Cohort 1936 Waves 6 and 7

Disconnected Mind - Phase 4

A genome wide association study of non pathological cognitive ageing

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