05787nas a2201681 4500008004100000022001400041245009400055210006900149260001500218300000900233490000600242520110000248100002201348700001801370700002201388700001301410700002001423700002301443700002501466700002101491700002801512700002001540700002701560700001901587700001801606700001701624700002001641700002001661700001901681700002101700700002201721700002101743700002401764700002301788700002501811700002101836700001801857700001801875700002101893700001901914700002301933700002101956700001501977700002201992700001402014700002102028700002702049700002502076700002202101700002002123700002602143700001802169700002702187700001802214700001902232700002102251700002202272700002402294700002102318700002702339700001802366700001602384700002002400700002002420700002302440700001902463700001902482700001902501700002302520700001902543700002302562700002702585700002602612700002402638700001902662700001602681700001802697700001302715700002402728700001702752700002102769700002002790700002402810700002002834700002202854700002302876700002302899700001802922700004102940700002402981700001903005700002703024700001903051700002003070700001603090700002203106700001903128700002303147700002003170700001803190700002603208700002003234700002403254700001803278700001803296700002003314700002503334700002603359700001603385700002203401700002003423700002403443700002203467700002003489700002003509700002903529700002403558700001903582700002003601700001603621700001903637700002003656700002003676700001903696700002103715700002803736700001903764700001903783700002103802700003003823700001603853700002003869700001803889700002203907700001903929700001903948700001803967700001903985700002004004700001804024710002704042856003604069 2018 eng d a2041-172300aGenome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation.0 aGenomewide analyses identify a role for SLC17A4 and AADAT in thy c2018 10 26 a44550 v93 a
Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.
1 aTeumer, Alexander1 aChaker, Layal1 aGroeneweg, Stefan1 aLi, Yong1 aDi Munno, Celia1 aBarbieri, Caterina1 aSchultheiss, Ulla, T1 aTraglia, Michela1 aAhluwalia, Tarunveer, S1 aAkiyama, Masato1 aAppel, Emil, Vincent R1 aArking, Dan, E1 aArnold, Alice1 aAstrup, Arne1 aBeekman, Marian1 aBeilby, John, P1 aBekaert, Sofie1 aBoerwinkle, Eric1 aBrown, Suzanne, J1 aDe Buyzere, Marc1 aCampbell, Purdey, J1 aCeresini, Graziano1 aCerqueira, Charlotte1 aCucca, Francesco1 aDeary, Ian, J1 aDeelen, Joris1 aEckardt, Kai-Uwe1 aEkici, Arif, B1 aEriksson, Johan, G1 aFerrrucci, Luigi1 aFiers, Tom1 aFiorillo, Edoardo1 aFord, Ian1 aFox, Caroline, S1 aFuchsberger, Christian1 aGalesloot, Tessel, E1 aGieger, Christian1 aGögele, Martin1 aDe Grandi, Alessandro1 aGrarup, Niels1 aGreiser, Karin, Halina1 aHaljas, Kadri1 aHansen, Torben1 aHarris, Sarah, E1 avan Heemst, Diana1 aHeijer, Martin, den1 aHicks, Andrew, A1 aHollander, Wouter, den1 aHomuth, Georg1 aHui, Jennie1 aIkram, Arfan, M1 aIttermann, Till1 aJensen, Richard, A1 aJing, Jiaojiao1 aJukema, Wouter1 aKajantie, Eero1 aKamatani, Yoichiro1 aKasbohm, Elisa1 aKaufman, Jean-Marc1 aKiemeney, Lambertus, A1 aKloppenburg, Margreet1 aKronenberg, Florian1 aKubo, Michiaki1 aLahti, Jari1 aLapauw, Bruno1 aLi, Shuo1 aLiewald, David, C M1 aLim, Ee, Mun1 aLinneberg, Allan1 aMarina, Michela1 aMascalzoni, Deborah1 aMatsuda, Koichi1 aMedenwald, Daniel1 aMeisinger, Christa1 aMeulenbelt, Ingrid1 aDe Meyer, Tim1 aMeyer zu Schwabedissen, Henriette, E1 aMikolajczyk, Rafael1 aMoed, Matthijs1 aNetea-Maier, Romana, T1 aNolte, Ilja, M1 aOkada, Yukinori1 aPala, Mauro1 aPattaro, Cristian1 aPedersen, Oluf1 aPetersmann, Astrid1 aPorcu, Eleonora1 aPostmus, Iris1 aPramstaller, Peter, P1 aPsaty, Bruce, M1 aRamos, Yolande, F M1 aRawal, Rajesh1 aRedmond, Paul1 aRichards, Brent1 aRietzschel, Ernst, R1 aRivadeneira, Fernando1 aRoef, Greet1 aRotter, Jerome, I1 aSala, Cinzia, F1 aSchlessinger, David1 aSelvin, Elizabeth1 aSlagboom, Eline1 aSoranzo, Nicole1 aSørensen, Thorkild, I A1 aSpector, Timothy, D1 aStarr, John, M1 aStott, David, J1 aTaes, Youri1 aTaliun, Daniel1 aTanaka, Toshiko1 aThuesen, Betina1 aTiller, Daniel1 aToniolo, Daniela1 aUitterlinden, André, G1 aVisser, Edward1 aWalsh, John, P1 aWilson, Scott, G1 aWolffenbuttel, Bruce, H R1 aYang, Qiong1 aZheng, Hou-Feng1 aCappola, Anne1 aPeeters, Robin, P1 aNaitza, Silvia1 aVölzke, Henry1 aSanna, Serena1 aKöttgen, Anna1 aVisser, Theo, J1 aMedici, Marco1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/7927