A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function.
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 change...
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2013-01-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1003266&type=printable |
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| author | Eleonora Porcu Marco Medici Giorgio Pistis Claudia B Volpato Scott G Wilson Anne R Cappola Steffan D Bos Joris Deelen Martin den Heijer Rachel M Freathy Jari Lahti Chunyu Liu Lorna M Lopez Ilja M Nolte Jeffrey R O'Connell Toshiko Tanaka Stella Trompet Alice Arnold Stefania Bandinelli Marian Beekman Stefan Böhringer Suzanne J Brown Brendan M Buckley Clara Camaschella Anton J M de Craen Gail Davies Marieke C H de Visser Ian Ford Tom Forsen Timothy M Frayling Laura Fugazzola Martin Gögele Andrew T Hattersley Ad R Hermus Albert Hofman Jeanine J Houwing-Duistermaat Richard A Jensen Eero Kajantie Margreet Kloppenburg Ee M Lim Corrado Masciullo Stefano Mariotti Cosetta Minelli Braxton D Mitchell Ramaiah Nagaraja Romana T Netea-Maier Aarno Palotie Luca Persani Maria G Piras Bruce M Psaty Katri Räikkönen J Brent Richards Fernando Rivadeneira Cinzia Sala Mona M Sabra Naveed Sattar Beverley M Shields Nicole Soranzo John M Starr David J Stott Fred C G J Sweep Gianluca Usala Melanie M van der Klauw Diana van Heemst Alies van Mullem Sita H Vermeulen W Edward Visser John P Walsh Rudi G J Westendorp Elisabeth Widen Guangju Zhai Francesco Cucca Ian J Deary Johan G Eriksson Luigi Ferrucci Caroline S Fox J Wouter Jukema Lambertus A Kiemeney Peter P Pramstaller David Schlessinger Alan R Shuldiner Eline P Slagboom André G Uitterlinden Bijay Vaidya Theo J Visser Bruce H R Wolffenbuttel Ingrid Meulenbelt Jerome I Rotter Tim D Spector Andrew A Hicks Daniela Toniolo Serena Sanna Robin P Peeters Silvia Naitza |
| author_facet | Eleonora Porcu Marco Medici Giorgio Pistis Claudia B Volpato Scott G Wilson Anne R Cappola Steffan D Bos Joris Deelen Martin den Heijer Rachel M Freathy Jari Lahti Chunyu Liu Lorna M Lopez Ilja M Nolte Jeffrey R O'Connell Toshiko Tanaka Stella Trompet Alice Arnold Stefania Bandinelli Marian Beekman Stefan Böhringer Suzanne J Brown Brendan M Buckley Clara Camaschella Anton J M de Craen Gail Davies Marieke C H de Visser Ian Ford Tom Forsen Timothy M Frayling Laura Fugazzola Martin Gögele Andrew T Hattersley Ad R Hermus Albert Hofman Jeanine J Houwing-Duistermaat Richard A Jensen Eero Kajantie Margreet Kloppenburg Ee M Lim Corrado Masciullo Stefano Mariotti Cosetta Minelli Braxton D Mitchell Ramaiah Nagaraja Romana T Netea-Maier Aarno Palotie Luca Persani Maria G Piras Bruce M Psaty Katri Räikkönen J Brent Richards Fernando Rivadeneira Cinzia Sala Mona M Sabra Naveed Sattar Beverley M Shields Nicole Soranzo John M Starr David J Stott Fred C G J Sweep Gianluca Usala Melanie M van der Klauw Diana van Heemst Alies van Mullem Sita H Vermeulen W Edward Visser John P Walsh Rudi G J Westendorp Elisabeth Widen Guangju Zhai Francesco Cucca Ian J Deary Johan G Eriksson Luigi Ferrucci Caroline S Fox J Wouter Jukema Lambertus A Kiemeney Peter P Pramstaller David Schlessinger Alan R Shuldiner Eline P Slagboom André G Uitterlinden Bijay Vaidya Theo J Visser Bruce H R Wolffenbuttel Ingrid Meulenbelt Jerome I Rotter Tim D Spector Andrew A Hicks Daniela Toniolo Serena Sanna Robin P Peeters Silvia Naitza |
| author_sort | Eleonora Porcu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e69c66d7aa444da8a3bac096f4be9764 |
| institution | DOAJ |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-e69c66d7aa444da8a3bac096f4be97642025-08-20T03:10:39ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042013-01-0192e100326610.1371/journal.pgen.1003266A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function.Eleonora PorcuMarco MediciGiorgio PistisClaudia B VolpatoScott G WilsonAnne R CappolaSteffan D BosJoris DeelenMartin den HeijerRachel M FreathyJari LahtiChunyu LiuLorna M LopezIlja M NolteJeffrey R O'ConnellToshiko TanakaStella TrompetAlice ArnoldStefania BandinelliMarian BeekmanStefan BöhringerSuzanne J BrownBrendan M BuckleyClara CamaschellaAnton J M de CraenGail DaviesMarieke C H de VisserIan FordTom ForsenTimothy M FraylingLaura FugazzolaMartin GögeleAndrew T HattersleyAd R HermusAlbert HofmanJeanine J Houwing-DuistermaatRichard A JensenEero KajantieMargreet KloppenburgEe M LimCorrado MasciulloStefano MariottiCosetta MinelliBraxton D MitchellRamaiah NagarajaRomana T Netea-MaierAarno PalotieLuca PersaniMaria G PirasBruce M PsatyKatri RäikkönenJ Brent RichardsFernando RivadeneiraCinzia SalaMona M SabraNaveed SattarBeverley M ShieldsNicole SoranzoJohn M StarrDavid J StottFred C G J SweepGianluca UsalaMelanie M van der KlauwDiana van HeemstAlies van MullemSita H VermeulenW Edward VisserJohn P WalshRudi G J WestendorpElisabeth WidenGuangju ZhaiFrancesco CuccaIan J DearyJohan G ErikssonLuigi FerrucciCaroline S FoxJ Wouter JukemaLambertus A KiemeneyPeter P PramstallerDavid SchlessingerAlan R ShuldinerEline P SlagboomAndré G UitterlindenBijay VaidyaTheo J VisserBruce H R WolffenbuttelIngrid MeulenbeltJerome I RotterTim D SpectorAndrew A HicksDaniela TonioloSerena SannaRobin P PeetersSilvia NaitzaThyroid 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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1003266&type=printable |
| spellingShingle | Eleonora Porcu Marco Medici Giorgio Pistis Claudia B Volpato Scott G Wilson Anne R Cappola Steffan D Bos Joris Deelen Martin den Heijer Rachel M Freathy Jari Lahti Chunyu Liu Lorna M Lopez Ilja M Nolte Jeffrey R O'Connell Toshiko Tanaka Stella Trompet Alice Arnold Stefania Bandinelli Marian Beekman Stefan Böhringer Suzanne J Brown Brendan M Buckley Clara Camaschella Anton J M de Craen Gail Davies Marieke C H de Visser Ian Ford Tom Forsen Timothy M Frayling Laura Fugazzola Martin Gögele Andrew T Hattersley Ad R Hermus Albert Hofman Jeanine J Houwing-Duistermaat Richard A Jensen Eero Kajantie Margreet Kloppenburg Ee M Lim Corrado Masciullo Stefano Mariotti Cosetta Minelli Braxton D Mitchell Ramaiah Nagaraja Romana T Netea-Maier Aarno Palotie Luca Persani Maria G Piras Bruce M Psaty Katri Räikkönen J Brent Richards Fernando Rivadeneira Cinzia Sala Mona M Sabra Naveed Sattar Beverley M Shields Nicole Soranzo John M Starr David J Stott Fred C G J Sweep Gianluca Usala Melanie M van der Klauw Diana van Heemst Alies van Mullem Sita H Vermeulen W Edward Visser John P Walsh Rudi G J Westendorp Elisabeth Widen Guangju Zhai Francesco Cucca Ian J Deary Johan G Eriksson Luigi Ferrucci Caroline S Fox J Wouter Jukema Lambertus A Kiemeney Peter P Pramstaller David Schlessinger Alan R Shuldiner Eline P Slagboom André G Uitterlinden Bijay Vaidya Theo J Visser Bruce H R Wolffenbuttel Ingrid Meulenbelt Jerome I Rotter Tim D Spector Andrew A Hicks Daniela Toniolo Serena Sanna Robin P Peeters Silvia Naitza A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function. PLoS Genetics |
| title | A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function. |
| title_full | A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function. |
| title_fullStr | A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function. |
| title_full_unstemmed | A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function. |
| title_short | A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function. |
| title_sort | meta analysis of thyroid related traits reveals novel loci and gender specific differences in the regulation of thyroid function |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1003266&type=printable |
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metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT cosettaminelli metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT braxtondmitchell metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT ramaiahnagaraja metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT romanatneteamaier metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT aarnopalotie metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT lucapersani metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT mariagpiras metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT brucempsaty metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT katriraikkonen metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT jbrentrichards metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT fernandorivadeneira metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT cinziasala metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT monamsabra metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT naveedsattar metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT beverleymshields metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT nicolesoranzo metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT johnmstarr metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT davidjstott metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT fredcgjsweep metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT gianlucausala metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT melaniemvanderklauw metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT dianavanheemst metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT aliesvanmullem metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT sitahvermeulen metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT wedwardvisser metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT johnpwalsh metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT rudigjwestendorp metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT elisabethwiden metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT guangjuzhai metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT francescocucca metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT ianjdeary metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT johangeriksson metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT luigiferrucci metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT carolinesfox metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT jwouterjukema metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT lambertusakiemeney metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT peterppramstaller metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT davidschlessinger metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT alanrshuldiner metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT elinepslagboom metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT andreguitterlinden metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT bijayvaidya metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT theojvisser metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT brucehrwolffenbuttel metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT ingridmeulenbelt metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT jeromeirotter metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT timdspector metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT andrewahicks metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT danielatoniolo metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT serenasanna metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT robinppeeters metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction AT silvianaitza metaanalysisofthyroidrelatedtraitsrevealsnovellociandgenderspecificdifferencesintheregulationofthyroidfunction |