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; Torben Hansen; Stig Haunsø; Jørgen K Kanters; Line L Kårhus; Allan Linneberg; Line T Møllehave; Oluf Pedersen; Morten Salling Olesen; Thorkild I A Sørensen; GHS DiscovEHR

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, Torben Hansen, Stig Haunsø, Jørgen K Kanters, Line L Kårhus, Allan Linneberg, Line T Møllehave, Oluf Pedersen, Morten Salling Olesen, Thorkild I A Sørensen, GHS DiscovEHR

15 Citationer (Scopus)

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
ISSN	2041-1722
DOI	https://doi.org/10.1038/s41467-024-44701-9
Status	Udgivet - 30 jan. 2024

Adgang til dokumentet

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

Andre filer og links

Link to publication in Scopus

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

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, Hansen, T, Haunsø, S, Kanters, JK, Kårhus, LL , Linneberg, A , Møllehave, LT , Pedersen, O , Olesen, MS, Sørensen, TIA & GHS DiscovEHR 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

@article{cecdd587628f452b8b85766a94017a34,

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 Torben Hansen and Stig Hauns{\o} and Kanters, {J{\o}rgen K} and K{\aa}rhus, {Line L} and Allan Linneberg and M{\o}llehave, {Line T} and Oluf Pedersen and Olesen, {Morten Salling} and S{\o}rensen, {Thorkild I A} and {GHS DiscovEHR}",

note = "{\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 = "2041-1722",

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 - Hansen, Torben

AU - Haunsø, Stig

AU - Kanters, Jørgen K

AU - Kårhus, Line L

AU - Linneberg, Allan

AU - Møllehave, Line T

AU - Pedersen, Oluf

AU - Olesen, Morten Salling

AU - Sørensen, Thorkild I A

AU - GHS DiscovEHR

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.

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 - Journal article

C2 - 38291025

SN - 2041-1722

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

Adgang til dokumentet

Andre filer og links

Fingeraftryk

Citationsformater