title: A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function.
abstract: 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.
authors: Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy.
authors: Eleonora
authors: E
authors: Porcu
authors: Marco
authors: M
authors: Medici
authors: Giorgio
authors: G
authors: Pistis
authors: Claudia B
authors: CB
authors: Volpato
authors: Scott G
authors: SG
authors: Wilson
authors: Anne R
authors: AR
authors: Cappola
authors: Steffan D
authors: SD
authors: Bos
authors: Joris
authors: J
authors: Deelen
authors: Martin
authors: M
authors: den Heijer
authors: Rachel M
authors: RM
authors: Freathy
authors: Jari
authors: J
authors: Lahti
authors: Chunyu
authors: C
authors: Liu
authors: Lorna M
authors: LM
authors: Lopez
authors: Ilja M
authors: IM
authors: Nolte
authors: Jeffrey R
authors: JR
authors: O'Connell
authors: Toshiko
authors: T
authors: Tanaka
authors: Stella
authors: S
authors: Trompet
authors: Alice
authors: A
authors: Arnold
authors: Stefania
authors: S
authors: Bandinelli
authors: Marian
authors: M
authors: Beekman
authors: Stefan
authors: S
authors: Böhringer
authors: Suzanne J
authors: SJ
authors: Brown
authors: Brendan M
authors: BM
authors: Buckley
authors: Clara
authors: C
authors: Camaschella
authors: Anton J M
authors: AJ
authors: de Craen
authors: Gail
authors: G
authors: Davies
authors: Marieke C H
authors: MC
authors: de Visser
authors: Ian
authors: I
authors: Ford
authors: Tom
authors: T
authors: Forsen
authors: Timothy M
authors: TM
authors: Frayling
authors: Laura
authors: L
authors: Fugazzola
authors: Martin
authors: M
authors: Gögele
authors: Andrew T
authors: AT
authors: Hattersley
authors: Ad R
authors: AR
authors: Hermus
authors: Albert
authors: A
authors: Hofman
authors: Jeanine J
authors: JJ
authors: Houwing-Duistermaat
authors: Richard A
authors: RA
authors: Jensen
authors: Eero
authors: E
authors: Kajantie
authors: Margreet
authors: M
authors: Kloppenburg
authors: Ee M
authors: EM
authors: Lim
authors: Corrado
authors: C
authors: Masciullo
authors: Stefano
authors: S
authors: Mariotti
authors: Cosetta
authors: C
authors: Minelli
authors: Braxton D
authors: BD
authors: Mitchell
authors: Ramaiah
authors: R
authors: Nagaraja
authors: Romana T
authors: RT
authors: Netea-Maier
authors: Aarno
authors: A
authors: Palotie
authors: Luca
authors: L
authors: Persani
authors: Maria G
authors: MG
authors: Piras
authors: Bruce M
authors: BM
authors: Psaty
authors: Katri
authors: K
authors: Räikkönen
authors: J Brent
authors: JB
authors: Richards
authors: Fernando
authors: F
authors: Rivadeneira
authors: Cinzia
authors: C
authors: Sala
authors: Mona M
authors: MM
authors: Sabra
authors: Naveed
authors: N
authors: Sattar
authors: Beverley M
authors: BM
authors: Shields
authors: Nicole
authors: N
authors: Soranzo
authors: John M
authors: JM
authors: Starr
authors: David J
authors: DJ
authors: Stott
authors: Fred C G J
authors: FC
authors: Sweep
authors: Gianluca
authors: G
authors: Usala
authors: Melanie M
authors: MM
authors: van der Klauw
authors: Diana
authors: D
authors: van Heemst
authors: Alies
authors: A
authors: van Mullem
authors: Sita H
authors: SH
authors: Vermeulen
authors: W Edward
authors: WE
authors: Visser
authors: John P
authors: JP
authors: Walsh
authors: Rudi G J
authors: RG
authors: Westendorp
authors: Elisabeth
authors: E
authors: Widen
authors: Guangju
authors: G
authors: Zhai
authors: Francesco
authors: F
authors: Cucca
authors: Ian J
authors: IJ
authors: Deary
authors: Johan G
authors: JG
authors: Eriksson
authors: Luigi
authors: L
authors: Ferrucci
authors: Caroline S
authors: CS
authors: Fox
authors: J Wouter
authors: JW
authors: Jukema
authors: Lambertus A
authors: LA
authors: Kiemeney
authors: Peter P
authors: PP
authors: Pramstaller
authors: David
authors: D
authors: Schlessinger
authors: Alan R
authors: AR
authors: Shuldiner
authors: Eline P
authors: EP
authors: Slagboom
authors: André G
authors: AG
authors: Uitterlinden
authors: Bijay
authors: B
authors: Vaidya
authors: Theo J
authors: TJ
authors: Visser
authors: Bruce H R
authors: BH
authors: Wolffenbuttel
authors: Ingrid
authors: I
authors: Meulenbelt
authors: Jerome I
authors: JI
authors: Rotter
authors: Tim D
authors: TD
authors: Spector
authors: Andrew A
authors: AA
authors: Hicks
authors: Daniela
authors: D
authors: Toniolo
authors: Serena
authors: S
authors: Sanna
authors: Robin P
authors: RP
authors: Peeters
authors: Silvia
authors: S
authors: Naitza
mesh_terms: D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D006980:Hyperthyroidism / Q000097:blood / Q000235:genetics*; D007037:Hypothyroidism / Q000097:blood / Q000235:genetics*; D008297:Male; D010641:Phenotype; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012727:Sex Characteristics; D015398:Signal Transduction / Q000235:genetics; D013961:Thyroid Gland / Q000378:metabolism / Q000503:physiopathology; D013972:Thyrotropin / Q000097:blood / Q000235:genetics*; D013974:Thyroxine / Q000097:blood* / Q000235:genetics
chemical_list: D013972:Thyrotropin; D013974:Thyroxine