Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications
Authors: 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 
Published: January 2024

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.