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; GHS DiscovEHR; Regeneron Genetics Center; Christian Fuchsberger; Christian Gieger; Franco Giulianini; Martin Gögele; Sarah E Graham; Niels Grarup; Ivana Gunjača; Torben Hansen; Barbara N Harding; Graham Leese; Marcel E Meima; Colin N A Palmer; Moneeza K Siddiqui; Sundararajan Srinivasan; 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; 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, GHS DiscovEHR, Regeneron Genetics Center, Christian Fuchsberger, Christian Gieger, Franco Giulianini, Martin Gögele, Sarah E Graham, Niels Grarup, Ivana Gunjača, Torben Hansen, Barbara N Harding, Graham Leese, Marcel E Meima, Colin N A Palmer, Moneeza K Siddiqui, Sundararajan Srinivasan, 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, Alexander Teumer (Lead / Corresponding author), Marco Medici (Lead / Corresponding author)

Population Health and Genomics

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

20 Citations (Scopus)

83 Downloads (Pure)

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
DOIs	https://doi.org/10.1038/s41467-024-44701-9
Publication status	Published - 30 Jan 2024

Keywords

Humans
Thyroid Gland/metabolism
Thyroxine/metabolism
Genome-Wide Association Study
Triiodothyronine/metabolism
Thyrotropin/metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

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

Final published versionFinal published version, 9.71 MBLicence: CC BY

Cite this

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), Article 888. https://doi.org/10.1038/s41467-024-44701-9

@article{bac193d789fc4bbfad61fe09acfc3de7,

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 = "Humans, Thyroid Gland/metabolism, Thyroxine/metabolism, Genome-Wide Association Study, Triiodothyronine/metabolism, Thyrotropin/metabolism",

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 {GHS DiscovEHR} and {Regeneron Genetics Center} 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 Graham Leese and Meima, {Marcel E} and Palmer, {Colin N A} and Siddiqui, {Moneeza K} and Sundararajan Srinivasan 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 Alexander Teumer and Marco Medici",

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

year = "2024",

month = jan,

day = "30",

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

language = "English",

volume = "15",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

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, GHS DiscovEHR, Regeneron Genetics Center, Fuchsberger, C, Gieger, C, Giulianini, F, Gögele, M, Graham, SE, Grarup, N, Gunjača, I, Hansen, T, Harding, BN, Leese, G, Meima, ME, Palmer, CNA , Siddiqui, MK , Srinivasan, S, Waldenberger, M, Walsh, JP, Wareham, NJ, Weiss, S, Willer, CJ, Wilson, SG, Wolffenbuttel, BHR, Wouters, HJCM, Wright, MJ, Yang, Q, Zemunik, T, Zhou, W, Teumer, A & Medici, M 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 - GHS DiscovEHR

AU - Regeneron Genetics Center

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 - Leese, Graham

AU - Meima, Marcel E

AU - Palmer, Colin N A

AU - Siddiqui, Moneeza K

AU - Srinivasan, Sundararajan

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 - Teumer, Alexander

AU - Medici, Marco

PY - 2024/1/30

Y1 - 2024/1/30

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 - Humans

KW - Thyroid Gland/metabolism

KW - Thyroxine/metabolism

KW - Genome-Wide Association Study

KW - Triiodothyronine/metabolism

KW - Thyrotropin/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85183777430&partnerID=8YFLogxK

U2 - 10.1038/s41467-024-44701-9

DO - 10.1038/s41467-024-44701-9

M3 - Article

C2 - 38291025

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

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this