| Title: |
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; 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 |
| Contributors: |
Clinicum; Johan Eriksson / Principal Investigator; Department of General Practice and Primary Health Care; HUS Group; HUS Children and Adolescents; Lastentautien yksikkö; Children's Hospital; Department of Psychology and Logopedics; Faculty of Medicine |
| Publisher Information: |
Nature Publishing Group |
| Publication Year: |
2024 |
| Collection: |
Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto |
| Subject Terms: |
General medicine; internal medicine and other clinical medicine |
| Description: |
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. ; Peer reviewed |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
This work was supported by funding from the European and American Thyroid Associations, the Erasmus University Rotterdam, the Dutch Organization for Scientific Research (NWO) (M.Med.), and the NIH (grants R35GM118335 and T32DK110966). Acknowledgments and study-specific acknowledgments are provided in the Supplementary Note. We conducted this research using the UK Biobank resource under the application numbers 53723 and 20272. This work was supported by funding from the European and American Thyroid Associations, the Erasmus University Rotterdam, the Dutch Organization for Scientific Research (NWO) (M.Med.), and the NIH (grants R35GM118335 and T32DK110966). Acknowledgments and study-specific acknowledgments are provided in the Supplementary Note. We conducted this research using the UK Biobank resource under the application numbers 53723 and 20272.; https://hdl.handle.net/10138/574604; 85183777430; 001188050100001 |
| Availability: |
https://hdl.handle.net/10138/574604 |
| Rights: |
cc_by ; info:eu-repo/semantics/openAccess ; openAccess |
| Accession Number: |
edsbas.487CFF2 |
| Database: |
BASE |