A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function

English version České info

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.

Vyšlo v časopise: A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function. PLoS Genet 9(2): e32767. doi:10.1371/journal.pgen.1003266
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003266

Souhrn

Zdroje

1. ToftAD (2001) Clinical practice. Subclinical hyperthyroidism. N Engl J Med 345: 512–516.

2. CooperDS (2001) Clinical practice. Subclinical hypothyroidism. N Engl J Med 345: 260–265.

3. Fernandez-RealJM, Lopez-BermejoA, CastroA, CasamitjanaR, RicartW (2006) Thyroid function is intrinsically linked to insulin sensitivity and endothelium-dependent vasodilation in healthy euthyroid subjects. J Clin Endocrinol Metab 91: 3337–3343.

4. BiondiB, CooperDS (2008) The clinical significance of subclinical thyroid dysfunction. Endocr Rev 29: 76–131.

5. ChiamoleraMI, WondisfordFE (2009) Minireview: Thyrotropin-releasing hormone and the thyroid hormone feedback mechanism. Endocrinology 150: 1091–1096.

6. AndersenS, PedersenKM, BruunNH, LaurbergP (2002) Narrow individual variations in serum T(4) and T(3) in normal subjects: a clue to the understanding of subclinical thyroid disease. J Clin Endocrinol Metab 87: 1068–1072.

7. Bulow PedersenI, KnudsenN, JorgensenT, PerrildH, OvesenL, et al. (2002) Large differences in incidences of overt hyper- and hypothyroidism associated with a small difference in iodine intake: a prospective comparative register-based population survey. J Clin Endocrinol Metab 87: 4462–4469.

8. FranklynJA, RamsdenDB, SheppardMC (1985) The influence of age and sex on tests of thyroid function. Ann Clin Biochem 22 (Pt 5) 502–505.

9. BartalenaL, BogazziF, BrogioniS, BurelliA, ScarcelloG, et al. (1996) Measurement of serum free thyroid hormone concentrations: an essential tool for the diagnosis of thyroid dysfunction. Horm Res 45: 142–147.

10. HansenPS, BrixTH, SorensenTI, KyvikKO, HegedusL (2004) Major genetic influence on the regulation of the pituitary-thyroid axis: a study of healthy Danish twins. J Clin Endocrinol Metab 89: 1181–1187.

11. SamollowPB, PerezG, KammererCM, FinegoldD, ZwartjesPW, et al. (2004) Genetic and environmental influences on thyroid hormone variation in Mexican Americans. J Clin Endocrinol Metab 89: 3276–3284.

12. PanickerV, WilsonSG, SpectorTD, BrownSJ, FalchiM, et al. (2008) Heritability of serum TSH, free T4 and free T3 concentrations: a study of a large UK twin cohort. Clin Endocrinol (Oxf) 68: 652–659.

13. Arnaud-LopezL, UsalaG, CeresiniG, MitchellBD, PiliaMG, et al. (2008) Phosphodiesterase 8B gene variants are associated with serum TSH levels and thyroid function. Am J Hum Genet 82: 1270–1280.

14. PanickerV, WilsonSG, WalshJP, RichardsJB, BrownSJ, et al. (2010) A locus on chromosome 1p36 is associated with thyrotropin and thyroid function as identified by genome-wide association study. Am J Hum Genet 87: 430–435.

15. RawalR, TeumerA, VolzkeH, WallaschofskiH, IttermannT, et al. (2012) Meta-analysis of two genome-wide association studies identifies four genetic loci associated with thyroid function. Hum Mol Genet

16. PeetersRP, van ToorH, KlootwijkW, de RijkeYB, KuiperGG, et al. (2003) Polymorphisms in thyroid hormone pathway genes are associated with plasma TSH and iodothyronine levels in healthy subjects. J Clin Endocrinol Metab 88: 2880–2888.

17. PanickerV, CluettC, ShieldsB, MurrayA, ParnellKS, et al. (2008) A common variation in deiodinase 1 gene DIO1 is associated with the relative levels of free thyroxine and triiodothyronine. J Clin Endocrinol Metab 93: 3075–3081.

18. MediciM, van der DeureWM, VerbiestM, VermeulenSH, HansenPS, et al. (2011) A large-scale association analysis of 68 thyroid hormone pathway genes with serum TSH and FT4 levels. Eur J Endocrinol 164: 781–788.

19. GudmundssonJ, SulemP, GudbjartssonDF, JonassonJG, SigurdssonA, et al. (2009) Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations. Nat Genet 41: 460–464.

20. DennyJC, CrawfordDC, RitchieMD, BielinskiSJ, BasfordMA, et al. (2011) Variants near FOXE1 are associated with hypothyroidism and other thyroid conditions: using electronic medical records for genome- and phenome-wide studies. Am J Hum Genet 89: 529–542.

21. BoucaiL, HollowellJG, SurksMI (2011) An approach for development of age-, gender-, and ethnicity-specific thyrotropin reference limits. Thyroid 21: 5–11.

22. McGroganA, SeamanHE, WrightJW, de VriesCS (2008) The incidence of autoimmune thyroid disease: a systematic review of the literature. Clin Endocrinol (Oxf) 69: 687–696.

23. HollowellJG, StaehlingNW, FlandersWD, HannonWH, GunterEW, et al. (2002) Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 87: 489–499.

24. BenjaminiY, HochbergY (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society Series B 57: 289–300.

25. Ben-AharonI, BrownPR, EtkovitzN, EddyEM, ShalgiR (2005) The expression of calpain 1 and calpain 2 in spermatogenic cells and spermatozoa of the mouse. Reproduction 129: 435–442.

26. PiliaG, ChenWM, ScuteriA, OrruM, AlbaiG, et al. (2006) Heritability of cardiovascular and personality traits in 6,148 Sardinians. PLoS Genet 2: e132 doi:10.1371/journal.pgen.0020132.

27. ShieldsBM, FreathyRM, KnightBA, HillA, WeedonMN, et al. (2009) Phosphodiesterase 8B gene polymorphism is associated with subclinical hypothyroidism in pregnancy. J Clin Endocrinol Metab 94: 4608–4612.

28. Montero-PedrazuelaA, Fernandez-LamoI, AlievaM, Pereda-PerezI, VeneroC, et al. (2011) Adult-onset hypothyroidism enhances fear memory and upregulates mineralocorticoid and glucocorticoid receptors in the amygdala. PLoS ONE 6: e26582 doi:10.1371/journal.pone.0026582.

29. ErikssonN, TungJY, KieferAK, HindsDA, FranckeU, et al. (2012) Novel Associations for Hypothyroidism Include Known Autoimmune Risk Loci. PLoS ONE 7: e34442 doi:10.1371/journal.pone.0034442.

30. ShengHZ, ZhadanovAB, MosingerBJr, FujiiT, BertuzziS, et al. (1996) Specification of pituitary cell lineages by the LIM homeobox gene Lhx3. Science 272: 1004–1007.

31. NetchineI, SobrierML, KrudeH, SchnabelD, MaghnieM, et al. (2000) Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency. Nat Genet 25: 182–186.

32. GudmundssonJ, SulemP, GudbjartssonDF, JonassonJG, MassonG, et al. (2012) Discovery of common variants associated with low TSH levels and thyroid cancer risk. Nat Genet 44: 319–322.

33. TaylorPN, PanickerV, SayersA, ShieldsB, IqbalA, et al. (2011) A meta-analysis of the associations between common variation in the PDE8B gene and thyroid hormone parameters, including assessment of longitudinal stability of associations over time and effect of thyroid hormone replacement. Eur J Endocrinol 164: 773–780.

34. VolpatoCB, De GrandiA, GogeleM, TaliunD, FuchsbergerC, et al. (2011) Linkage and association analysis of hyperthyrotropinaemia in an Alpine population reveal two novel loci on chromosomes 3q28–29 and 6q26–27. J Med Genet 48: 549–556.

35. KitazawaM, YamakuniT, SongSY, KatoC, TsuchiyaR, et al. (2005) Intracellular cAMP controls a physical association of V-1 with CapZ in cultured mammalian endocrine cells. Biochem Biophys Res Commun 331: 181–186.

36. TeumerA, RawalR, HomuthG, ErnstF, HeierM, et al. (2011) Genome-wide association study identifies four genetic loci associated with thyroid volume and goiter risk. Am J Hum Genet 88: 664–673.

37. DuanC, ClemmonsDR (1995) Transcription factor AP-2 regulates human insulin-like growth factor binding protein-5 gene expression. J Biol Chem 270: 24844–24851.

38. de JongFJ, PeetersRP, den HeijerT, van der DeureWM, HofmanA, et al. (2007) The association of polymorphisms in the type 1 and 2 deiodinase genes with circulating thyroid hormone parameters and atrophy of the medial temporal lobe. J Clin Endocrinol Metab 92: 636–640.

39. GerebenB, ZavackiAM, RibichS, KimBW, HuangSA, et al. (2008) Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling. Endocr Rev 29: 898–938.

40. De FeliceM, OvittC, BiffaliE, Rodriguez-MallonA, ArraC, et al. (1998) A mouse model for hereditary thyroid dysgenesis and cleft palate. Nat Genet 19: 395–398.

41. Clifton-BlighRJ, WentworthJM, HeinzP, CrispMS, JohnR, et al. (1998) Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate and choanal atresia. Nat Genet 19: 399–401.

42. PfaeffleRW, SavageJJ, HunterCS, PalmeC, AhlmannM, et al. (2007) Four novel mutations of the LHX3 gene cause combined pituitary hormone deficiencies with or without limited neck rotation. J Clin Endocrinol Metab 92: 1909–1919.

43. RajabA, KelbermanD, de CastroSC, BiebermannH, ShaikhH, et al. (2008) Novel mutations in LHX3 are associated with hypopituitarism and sensorineural hearing loss. Hum Mol Genet 17: 2150–2159.

44. OkadaY, KamataniY, TakahashiA, MatsudaK, HosonoN, et al. (2010) A genome-wide association study in 19 633 Japanese subjects identified LHX3-QSOX2 and IGF1 as adult height loci. Hum Mol Genet 19: 2303–2312.

45. HelmreichDL, ParfittDB, LuXY, AkilH, WatsonSJ (2005) Relation between the hypothalamic-pituitary-thyroid (HPT) axis and the hypothalamic-pituitary-adrenal (HPA) axis during repeated stress. Neuroendocrinology 81: 183–192.

46. VamosE, PardutzA, KlivenyiP, ToldiJ, VecseiL (2009) The role of kynurenines in disorders of the central nervous system: possibilities for neuroprotection. J Neurol Sci 283: 21–27.

47. GohDL, PatelA, ThomasGH, SalomonsGS, SchorDS, et al. (2002) Characterization of the human gene encoding alpha-aminoadipate aminotransferase (AADAT). Mol Genet Metab 76: 172–180.

48. de SouzaFR, FontesFL, da SilvaTA, CoutinhoLG, LeibSL, et al. (2010) Association of kynurenine aminotransferase II gene C401T polymorphism with immune response in patients with meningitis. BMC Med Genet 12: 51.

49. HanQ, CaiT, TagleDA, LiJ (2009) Structure, expression, and function of kynurenine aminotransferases in human and rodent brains. Cell Mol Life Sci 67: 353–368.

50. SegrèAV, GroopL, MoothaVK, DalyMJ, AltshulerD (2010) Common inherited variation in mitochondrial genes is not enriched for associations with type 2 diabetes or related glycemic traits. PLoS Genet 6: e1001058 doi:10.1371/journal.pgen.1001058.

51. RaychaudhuriS, PlengeRM, RossinEJ, NgAC, PurcellSM, et al. (2009) Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions. PLoS Genet 5: e1000534 doi:10.1371/journal.pgen.1000534.

52. SeneeV, ChelalaC, DuchateletS, FengD, BlancH, et al. (2006) Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism. Nat Genet 38: 682–687.

53. SalajeghehA, SmithRA, KasemK, GopalanV, NassiriMR, et al. (2011) Single nucleotide polymorphisms and mRNA expression of VEGF-A in papillary thyroid carcinoma: potential markers for aggressive phenotypes. Eur J Surg Oncol 37: 93–99.

54. StolfBS, CarvalhoAF, MartinsWK, RunzaFB, BrunM, et al. (2003) Differential expression of IGFBP-5 and two human ESTs in thyroid glands with goiter, adenoma and papillary or follicular carcinomas. Cancer Lett 191: 193–202.

55. VellaV, PandiniG, SciaccaL, MineoR, VigneriR, et al. (2002) A novel autocrine loop involving IGF-II and the insulin receptor isoform-A stimulates growth of thyroid cancer. J Clin Endocrinol Metab 87: 245–254.

56. BraunschweigT, KasererK, ChungJY, BilkeS, KrizmanD, et al. (2007) Proteomic expression profiling of thyroid neoplasms. Proteomics Clin Appl 1: 264–271.

57. WillerCJ, LiY, AbecasisGR (2010) METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26: 2190–2191.

58. LiY, WillerCJ, DingJ, ScheetP, AbecasisGR (2010) MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol 34: 816–834.

59. MarchiniJ, HowieB, MyersS, McVeanG, DonnellyP (2007) A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet 39: 906–913.

60. HowieBN, DonnellyP, MarchiniJ (2009) A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet 5: e1000529 doi:10.1371/journal.pgen.1000529.

61. PruimRJ, WelchRP, SannaS, TeslovichTM, ChinesPS, et al. (2010) LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26: 2336–2337.

62. KleinM, CatargiB (2007) VEGF in physiological process and thyroid disease. Ann Endocrinol (Paris) 68: 438–448.

63. GerardAC, PoncinS, CaetanoB, SonveauxP, AudinotJN, et al. (2008) Iodine deficiency induces a thyroid stimulating hormone-independent early phase of microvascular reshaping in the thyroid. Am J Pathol 172: 748–760.

64. YamadaE, YamazakiK, TakanoK, ObaraT, SatoK (2006) Iodide inhibits vascular endothelial growth factor-A expression in cultured human thyroid follicles: a microarray search for effects of thyrotropin and iodide on angiogenesis factors. Thyroid 16: 545–554.

65. ZhangL, Cooper-KuhnCM, NannmarkU, BlomgrenK, KuhnHG (2010) Stimulatory effects of thyroid hormone on brain angiogenesis in vivo and in vitro. J Cereb Blood Flow Metab 30: 323–335.

66. YuH, RohanT (2000) Role of the insulin-like growth factor family in cancer development and progression. J Natl Cancer Inst 92: 1472–1489.

67. EggoMC, KingWJ, BlackEG, SheppardMC (1996) Functional human thyroid cells and their insulin-like growth factor-binding proteins: regulation by thyrotropin, cyclic 3′,5′ adenosine monophosphate, and growth factors. J Clin Endocrinol Metab 81: 3056–3062.

68. BackeljauwPF, DaiZ, ClemmonsDR, D'ErcoleAJ (1993) Synthesis and regulation of insulin-like growth factor binding protein-5 in FRTL-5 cells. Endocrinology 132: 1677–1681.

69. PepeneCE, KasperkCH, PfeilschifterJ, BorcsokI, GozariuL, et al. (2001) Effects of triiodothyronine on the insulin-like growth factor system in primary human osteoblastic cells in vitro. Bone 29: 540–546.

70. ZhouR, BonneaudN, YuanCX, de Santa BarbaraP, BoizetB, et al. (2002) SOX9 interacts with a component of the human thyroid hormone receptor-associated protein complex. Nucleic Acids Res 30: 3245–3252.

71. das NevesL, DuchalaCS, Tolentino-SilvaF, HaxhiuMA, ColmenaresC, et al. (1999) Disruption of the murine nuclear factor I-A gene (Nfia) results in perinatal lethality, hydrocephalus, and agenesis of the corpus callosum. Proc Natl Acad Sci U S A 96: 11946–11951.

72. NakazatoM, ChungHK, UlianichL, GrassadoniaA, SuzukiK, et al. (2000) Thyroglobulin repression of thyroid transcription factor 1 (TTF-1) gene expression is mediated by decreased DNA binding of nuclear factor I proteins which control constitutive TTF-1 expression. Mol Cell Biol 20: 8499–8512.

73. MoellerLC, KimuraS, KusakabeT, LiaoXH, Van SandeJ, et al. (2003) Hypothyroidism in thyroid transcription factor 1 haploinsufficiency is caused by reduced expression of the thyroid-stimulating hormone receptor. Mol Endocrinol 17: 2295–2302.

74. RevestJM, Spencer-DeneB, KerrK, De MoerloozeL, RosewellI, et al. (2001) Fibroblast growth factor receptor 2-IIIb acts upstream of Shh and Fgf4 and is required for limb bud maintenance but not for the induction of Fgf8, Fgf10, Msx1, or Bmp4. Dev Biol 231: 47–62.

75. JiangGL, HuangS (2000) The yin-yang of PR-domain family genes in tumorigenesis. Histol Histopathol 15: 109–117.

76. NaitzaS, PorcuE, SteriM, TaubDD, MulasA, et al. (2012) A genome-wide association scan on the levels of markers of inflammation in Sardinians reveals associations that underpin its complex regulation. PLoS Genet 8: e1002480 doi:10.1371/journal.pgen.1002480.

77. CarmelR, SpencerCA (1982) Clinical and subclinical thyroid disorders associated with pernicious anemia. Observations on abnormal thyroid-stimulating hormone levels and on a possible association of blood group O with hyperthyroidism. Arch Intern Med 142: 1465–1469.

78. MajerusPW, WilsonDB, ZhangC, NicholasPJ, WilsonMP (2010) Expression of inositol 1,3,4-trisphosphate 5/6-kinase (ITPK1) and its role in neural tube defects. Adv Enzyme Regul 50: 365–372.

79. GrasbergerH, Van SandeJ, Hag-Dahood MahameedA, Tenenbaum-RakoverY, RefetoffS (2007) A familial thyrotropin (TSH) receptor mutation provides in vivo evidence that the inositol phosphates/Ca2+ cascade mediates TSH action on thyroid hormone synthesis. J Clin Endocrinol Metab 92: 2816–2820.

80. FukuyamaK, YoshidaM, YamashitaA, DeyamaT, BabaM, et al. (2000) MAPK upstream kinase (MUK)-binding inhibitory protein, a negative regulator of MUK/dual leucine zipper-bearing kinase/leucine zipper protein kinase. J Biol Chem 275: 21247–21254.

81. JendrzejewskiJ, HeH, RadomskaHS, LiW, TomsicJ, et al. (2012) The polymorphism rs944289 predisposes to papillary thyroid carcinoma through a large intergenic noncoding RNA gene of tumor suppressor type. Proc Natl Acad Sci U S A 109: 8646–8651.

82. DuboisF, VandermoereF, GernezA, MurphyJ, TothR, et al. (2009) Differential 14-3-3 affinity capture reveals new downstream targets of phosphatidylinositol 3-kinase signaling. Mol Cell Proteomics 8: 2487–2499.

83. TakahashiM, SaenkoVA, RogounovitchTI, KawaguchiT, DrozdVM, et al. The FOXE1 locus is a major genetic determinant for radiation-related thyroid carcinoma in Chernobyl. Hum Mol Genet 19: 2516–2523.

84. LandaI, Ruiz-LlorenteS, Montero-CondeC, Inglada-PerezL, SchiaviF, et al. (2009) The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors. PLoS Genet 5: e1000637 doi:10.1371/journal.pgen.1000637.

85. TakahashiM, SaenkoVA, RogounovitchTI, KawaguchiT, DrozdVM, et al. (2010) The FOXE1 locus is a major genetic determinant for radiation-related thyroid carcinoma in Chernobyl. Hum Mol Genet 19: 2516–2523.