05839nas a2201429 4500008004100000022001400041245013600055210006900191260000900260300001300269490000600282520178500288653001102073653003402084653001102118653002002129653001902149653000902168653001402177653002602191653003602217653002402253653002402277653001802301653001602319653001402335100002002349700001802369700002002387700002402407700002102431700002102452700002002473700001802493700002402511700002302535700001602558700001602574700002002590700001902610700002602629700002002655700002002675700001802695700002502713700002002738700002302758700002202781700002402803700002302827700002502850700001702875700002802892700001402920700001602934700002502950700002102975700002002996700002603016700001803042700001903060700003603079700002303115700001903138700002603157700001503183700002303198700002203221700002103243700002503264700002203289700002703311700001903338700001803357700002003375700002003395700002303415700002003438700002603458700001703484700001903501700001903520700002503539700002003564700001903584700002003603700002303623700002003646700003003666700002203696700002203718700002303740700001903763700001903782700002603801700002103827700001803848700002103866700001803887700002303905700002003928700002103948700001903969700002703988700002604015700002404041700002304065700002304088700002804111700001804139700002004157700003004177700002304207700002204230700002004252700002104272700002104293700001804314700002204332700001904354856003604373 2013 eng d a1553-740400aA meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function.0 ametaanalysis of thyroidrelated traits reveals novel loci and gen c2013 ae10032660 v93 a
Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.
10aFemale10aGenome-Wide Association Study10aHumans10aHyperthyroidism10aHypothyroidism10aMale10aPhenotype10aPolymorphism, Genetic10aPolymorphism, Single Nucleotide10aSex Characteristics10aSignal Transduction10aThyroid Gland10aThyrotropin10aThyroxine1 aPorcu, Eleonora1 aMedici, Marco1 aPistis, Giorgio1 aVolpato, Claudia, B1 aWilson, Scott, G1 aCappola, Anne, R1 aBos, Steffan, D1 aDeelen, Joris1 aHeijer, Martin, den1 aFreathy, Rachel, M1 aLahti, Jari1 aLiu, Chunyu1 aLopez, Lorna, M1 aNolte, Ilja, M1 aO'Connell, Jeffrey, R1 aTanaka, Toshiko1 aTrompet, Stella1 aArnold, Alice1 aBandinelli, Stefania1 aBeekman, Marian1 aBöhringer, Stefan1 aBrown, Suzanne, J1 aBuckley, Brendan, M1 aCamaschella, Clara1 ade Craen, Anton, J M1 aDavies, Gail1 ade Visser, Marieke, C H1 aFord, Ian1 aForsen, Tom1 aFrayling, Timothy, M1 aFugazzola, Laura1 aGögele, Martin1 aHattersley, Andrew, T1 aHermus, Ad, R1 aHofman, Albert1 aHouwing-Duistermaat, Jeanine, J1 aJensen, Richard, A1 aKajantie, Eero1 aKloppenburg, Margreet1 aLim, Ee, M1 aMasciullo, Corrado1 aMariotti, Stefano1 aMinelli, Cosetta1 aMitchell, Braxton, D1 aNagaraja, Ramaiah1 aNetea-Maier, Romana, T1 aPalotie, Aarno1 aPersani, Luca1 aPiras, Maria, G1 aPsaty, Bruce, M1 aRäikkönen, Katri1 aRichards, Brent1 aRivadeneira, Fernando1 aSala, Cinzia1 aSabra, Mona, M1 aSattar, Naveed1 aShields, Beverley, M1 aSoranzo, Nicole1 aStarr, John, M1 aStott, David, J1 aSweep, Fred, C G J1 aUsala, Gianluca1 avan der Klauw, Melanie, M1 avan Heemst, Diana1 avan Mullem, Alies1 aVermeulen, Sita, H1 aVisser, Edward1 aWalsh, John, P1 aWestendorp, Rudi, G J1 aWiden, Elisabeth1 aZhai, Guangju1 aCucca, Francesco1 aDeary, Ian, J1 aEriksson, Johan, G1 aFerrucci, Luigi1 aFox, Caroline, S1 aJukema, Wouter1 aKiemeney, Lambertus, A1 aPramstaller, Peter, P1 aSchlessinger, David1 aShuldiner, Alan, R1 aSlagboom, Eline, P1 aUitterlinden, André, G1 aVaidya, Bijay1 aVisser, Theo, J1 aWolffenbuttel, Bruce, H R1 aMeulenbelt, Ingrid1 aRotter, Jerome, I1 aSpector, Tim, D1 aHicks, Andrew, A1 aToniolo, Daniela1 aSanna, Serena1 aPeeters, Robin, P1 aNaitza, Silvia uhttps://chs-nhlbi.org/node/5877