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

Nature communications（2024）

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摘要

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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Thyroid Hormone

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