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; GHS DiscovEHR; Regeneron Genetics Center; 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 (2024-01-30)
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
GHS DiscovEHR
Regeneron Genetics Center
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
Springer
30.01.2024
Sterenborg, R.B.T.M., Steinbrenner, I., Li, Y. et al. Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications. Nat Commun 15, 888 (2024). https://doi.org/10.1038/s41467-024-44701-9.
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© The Author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
https://creativecommons.org/licenses/by/4.0/
© The Author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
https://creativecommons.org/licenses/by/4.0/
Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:oulu-202402151798
https://urn.fi/URN:NBN:fi:oulu-202402151798
Tiivistelmä
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.
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.
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