Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

Sterenborg, Rosalie B. T. M.; Steinbrenner, Inga; Yong, Li; Bujnis, Melissa N.; Naito, Tatsuhiko; Marouli, Eirini; Galesloot, Tessel E.; Babajide, Oladapo; Andreasen, Laura; Astrup, Arne; Bjørn Olav Åsvold,; 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; Rodrigo Coutinho de Almeida,; Cross, Simone M.; Cucca, Francesco; Deary, Ian J.; Alisa Devedzic Kjaergaard,; Echouffo Tcheugui, Justin B.; Ellervik, Christina; Eriksson, Johan G.; Ferrucci, Luigi; Freudenberg, Jan; Discovehr, Ghs; 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; Wouter Jukema, J.; 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; Shuo, Li; 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; Brent Richards, J.; Ridker, Paul M.; Russ, Tom C.; Ryan, Kathleen A.; Morten Salling Olesen,; Schultheiss, Ulla T.; Selvin, Elizabeth; Siddiqui, Moneeza K.; Sidore, Carlo; Eline Slagboom, P.; 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.; Tibbert van den Eynde,; van der Klauw, Melanie M.; Diana van Heemst,; Verroken, Charlotte; Edward Visser, W.; 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

doi:10.1038/s41467-024-44701-9

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.