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

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^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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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.

Originalsprog	Engelsk
Artikelnummer	888
Tidsskrift	Nature Communications
Vol/bind	15
Udgave nummer	1
Antal sider	18
ISSN	2041-1723
DOI	https://doi.org/10.1038/s41467-024-44701-9
Status	Udgivet - 2024

Bibliografisk note

Funding Information:
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.

Funding Information:
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.

Publisher Copyright:
© 2024, The Author(s).

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10.1038/s41467-024-44701-9Licens: CC BY

FulltextForlagets udgivne version, 9,71 MBLicens: CC BY

Citationsformater

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., ... Medici, M. (2024). Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications. Nature Communications, 15(1), [888]. https://doi.org/10.1038/s41467-024-44701-9

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

I: Nature Communications, Bind 15, Nr. 1, 888, 2024.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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 2024, 'Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications', Nature Communications, bind 15, nr. 1, 888. https://doi.org/10.1038/s41467-024-44701-9

Sterenborg, Rosalie B.T.M. ; Steinbrenner, Inga ; Li, Yong ; Bujnis, Melissa N. ; Naito, Tatsuhiko ; Marouli, Eirini ; Galesloot, Tessel E. ; Babajide, Oladapo ; Andreasen, Laura ; Astrup, Arne ; Åsvold, Bjørn Olav ; Bandinelli, Stefania ; Beekman, Marian ; Beilby, John P. ; Bork-Jensen, Jette ; Boutin, Thibaud ; Brody, Jennifer A. ; Brown, Suzanne J. ; Brumpton, Ben ; Campbell, Purdey J. ; Cappola, Anne R. ; Ceresini, Graziano ; Chaker, Layal ; Chasman, Daniel I. ; Concas, Maria Pina ; Coutinho de Almeida, Rodrigo ; Cross, Simone M. ; Cucca, Francesco ; Deary, Ian J. ; Kjaergaard, Alisa Devedzic ; Echouffo Tcheugui, Justin B. ; Ellervik, Christina ; Eriksson, Johan G. ; Ferrucci, Luigi ; Freudenberg, Jan ; Fuchsberger, Christian ; Gieger, Christian ; Giulianini, Franco ; Gögele, Martin ; Graham, Sarah E. ; Grarup, Niels ; Gunjača, Ivana ; Hansen, Torben ; Harding, Barbara N. ; Harris, Sarah E. ; Haunsø, Stig ; Hayward, Caroline ; Hui, Jennie ; Ittermann, Till ; Jukema, J. Wouter ; Kajantie, Eero ; Kanters, Jørgen K. ; Kårhus, Line L. ; Kiemeney, Lambertus A.L.M. ; Kloppenburg, Margreet ; Kühnel, Brigitte ; Lahti, Jari ; Langenberg, Claudia ; Lapauw, Bruno ; Leese, Graham ; Li, Shuo ; Liewald, David C.M. ; Linneberg, Allan ; Lominchar, Jesus V.T. ; Luan, Jian’an ; Martin, Nicholas G. ; Matana, Antonela ; Meima, Marcel E. ; Meitinger, Thomas ; Meulenbelt, Ingrid ; Mitchell, Braxton D. ; Møllehave, Line T. ; Mora, Samia ; Naitza, Silvia ; Nauck, Matthias ; Netea-Maier, Romana T. ; Noordam, Raymond ; Nursyifa, Casia ; Okada, Yukinori ; Onano, Stefano ; Papadopoulou, Areti ; Palmer, Colin N.A. ; Pattaro, Cristian ; Pedersen, Oluf ; Peters, Annette ; Pietzner, Maik ; Polašek, Ozren ; Pramstaller, Peter P. ; Psaty, Bruce M. ; Punda, Ante ; Ray, Debashree ; Redmond, Paul ; Richards, J. Brent ; Ridker, Paul M. ; Russ, Tom C. ; Ryan, Kathleen A. ; Olesen, Morten Salling ; Schultheiss, Ulla T. ; Selvin, Elizabeth ; Siddiqui, Moneeza K. ; Sidore, Carlo ; Slagboom, P. Eline ; Sørensen, Thorkild I.A. ; Soto-Pedre, Enrique ; Spector, Tim D. ; Spedicati, Beatrice ; Srinivasan, Sundararajan ; Starr, John M. ; Stott, David J. ; Tanaka, Toshiko ; Torlak, Vesela ; Trompet, Stella ; Tuhkanen, Johanna ; Uitterlinden, André G. ; van den Akker, Erik B. ; van den Eynde, Tibbert ; van der Klauw, Melanie M. ; van Heemst, Diana ; Verroken, Charlotte ; Visser, W. Edward ; Vojinovic, Dina ; Völzke, Henry ; Waldenberger, Melanie ; Walsh, John P. ; Wareham, Nicholas J. ; Weiss, Stefan ; Willer, Cristen J. ; Wilson, Scott G. ; Wolffenbuttel, Bruce H.R. ; Wouters, Hanneke J.C.M. ; Wright, Margaret J. ; Yang, Qiong ; Zemunik, Tatijana ; Zhou, Wei ; Zhu, Gu ; Zöllner, Sebastian ; Smit, Johannes W.A. ; Peeters, Robin P. ; Köttgen, Anna ; Teumer, Alexander ; Medici, Marco. / Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications. I: Nature Communications. 2024 ; Bind 15, Nr. 1.

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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.",

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",

note = "Publisher Copyright: {\textcopyright} 2024, The Author(s).",

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",

}

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

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.

U2 - 10.1038/s41467-024-44701-9

DO - 10.1038/s41467-024-44701-9

M3 - Journal article

C2 - 38291025

AN - SCOPUS:85183777430

VL - 15

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 888

ER -