Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications.
Rosalie B T M SterenborgInga SteinbrennerYong LiMelissa N BujnisTatsuhiko NaitoEirini MarouliTessel E GaleslootOladapo BabajideLaura AndreasenArnie AstrupBjørn Olav ÅsvoldStefania BandinelliMarian BeekmanJohn P BeilbyJette Bork-JensenThibaud BoutinJennifer A BrodySuzanne J BrownBen Michael BrumptonPurdey J CampbellAnne R CappolaGraziano CeresiniLayal ChakerDaniel I ChasmanMaria Pina ConcasRodrigo Coutinho de AlmeidaSimone M CrossFrancesco CuccaIan J DearyAlisa Devedzic KjaergaardJustin B Echouffo TcheuguiChristina EllervikJohan G ErikssonLuigi FerruciJan Freudenbergnull nullnull nullChristian FuchsbergerChristian GiegerFranco GiulianiniMartin GögeleSarah E GrahamNiels GrarupIvana GunjačaTorben HansenBarbara N HardingSarah E HarrisStig HaunsøCaroline HaywardJennie HuiTill IttermannJohan Wouter JukemaKajantie EeroJørgen Kim KantersLine L KårhusLambertus A L M KiemeneyMargreet KloppenburgBrigitte KühnelJari M T LahtiClaudia LangenbergBruno LapauwGraham P LeeseShuo LiDavid C M LiewaldAllan LinnebergJesus V T LomincharJian'an LuanNicholas G MartinAntonela MatanaMarcel E MeimaThomas MeitingerIngrid MeulenbeltBraxton D MitchellLine T MøllehaveSamia MoraSilvia NaitzaMatthias NauckRomana T Netea-MaierRaymond NoordamCasia NursyifaYukinori OkadaStefano OnanoAreti PapadopoulouColin Neil Alexander PalmerCristian PattaroOluf PedersenAnnette PetersMaik PietznerOzren PolašekPeter P PramstallerBruce M PsatyAnte PundaDebashree RayPaul RedmondJohn Brent RichardsPaul M RidkerTom Charles RussKathleen A RyanMorten Salling OlesenUlla T SchultheißElizabeth SelvinMoneeza K SiddiquiCarlo SidorePieternella Eline SlagboomThorkild I A SørensenEnrique Soto-PedreTimothy D SpectorBeatrice SpedicatiSundararajan SrinivasanJohn M StarrDavid J StottToshiko TanakaVesela TorlakStella TrompetJohanna TuhkanenAndre G UitterlindenErik Ben van den AkkerTibbert van den EyndeMelanie M van der KlauwDiana van HeemstCharlotte VerrokenW. Edward VisserDina VojinovicHenry VölzkeMelanie WaldenbergerJohn P WalshNicholas J WarehamStefan WeissCristen J WillerScott G WilsonBruce H R WolffenbuttelHanneke J C M WoutersMargaret J WrightQiong YangTatijana ZemunikWei ZhouGu ZhuSebastian ZöllnerJohannes W A SmitRobin P PeetersAnna KottgenAlexander TeumerMarco MediciPublished in: Nature communications (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.