Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Genome-wide association meta-analysis for total thyroid hormone levels in Croatian population


Thyroid hormones (THs) are key regulators of cellular growth, development, and metabolism. The thyroid gland secretes two THs, thyroxine (T4) and triiodothyronine (T3), into the plasma where they are almost all bound reversibly to plasma proteins. Free forms of THs are metabolically active, however, they represent a very small fraction of total TH levels. No genome-wide studies have been performed to date on total TH levels, comprising of protein-bound and free forms of THs. To detect genetic variants associated with total TH levels, we carried out the first GWAS meta-analysis of total T4 levels in 1121 individuals from two Croatian cohorts (Split and Korcula). We also performed GWAS analyses of total T3 levels in 577 individuals and T3/T4 ratio in 571 individuals from the Split cohort. The top association in GWAS meta-analysis of total T4 was detected for an intronic variant within SLC22A9 gene (rs12282281, P = 4.00 × 10−7). Within the same region, a genome-wide significant variant (rs11822642, P = 2.50 × 10−8) for the T3/T4 ratio was identified. SLC22A9 encodes for an organic anion transporter protein expressed predominantly in the liver and belongs to the superfamily of solute carriers (SLC), a large group of transport membrane proteins. The transport of THs across the plasma membrane in peripheral tissues is facilitated by the membrane proteins, and all TH transport proteins known to date belong to the same SLC superfamily as SLC22A9. These results suggest a potential role for SLC22A9 as a novel transporter protein of THs.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3


  1. Panicker V. Genetics of thyroid function and disease. Clin Biochem Rev. 2011;32:165–75.

    PubMed  PubMed Central  Google Scholar 

  2. Mondal S, Raja K, Schweizer U, Mugesh G. Chemistry and biology in the biosynthesis and action of thyroid hormones. Angew Chem Int Ed Engl. 2016;55:7606–30.

    Article  CAS  PubMed  Google Scholar 

  3. Hoermann R, Midgley JE, Larisch R, Dietrich JW. Relational stability in the expression of normality, variation, and control of thyroid function. Front Endocrinol. 2016;7:142.

    Article  Google Scholar 

  4. Dayan CM, Panicker V. Novel insights into thyroid hormones from the study of common genetic variation. Nat Rev Endocrinol. 2009;5:211–8.

    Article  CAS  PubMed  Google Scholar 

  5. Larsen PR, Zavacki AM. Role of the iodothyronine deiodinases in the physiology and pathophysiology of thyroid hormone action. Eur Thyroid J. 2013;1:232–42.

    Google Scholar 

  6. Wilkin TJ, Isles TE. The behavior of the triiodothyronine/thyroxine (T3/T4) ratio in normal individuals, and its implications for the regulation of euthyroidism. J Endocrinol Investig. 1984;7:319–22.

    Article  CAS  Google Scholar 

  7. Mortoglou A, Candiloros H. The serum triiodothyronine to thyroxine (T3/T4) ratio in various thyroid disorders and after Levothyroxine replacement therapy. Hormones. 2004;3:120–6.

    Article  CAS  PubMed  Google Scholar 

  8. Medici M, van der Deure WM, Verbiest M, Vermeulen SH, Hansen PS, Kiemeney LA, et al. A large-scale association analysis of 68 thyroid hormone pathway genes with serum TSH and FT4 levels. Eur J Endocrinol. 2011;164:781–8.

    Article  CAS  PubMed  Google Scholar 

  9. Panicker V, Wilson SG, Spector TD, Brown SJ, Falchi M, Richards JB, et al. Heritability of serum TSH, free T4 and free T3 concentrations: a study of a large UK twin cohort. Clin Endocrinol. 2008;68:652–9.

    Article  CAS  Google Scholar 

  10. Martin LJ, Crawford MH. Genetic and environmental components of thyroxine variation in Mennonites from Kansas and Nebraska. Hum Biol. 1998;70:745–60.

    CAS  PubMed  Google Scholar 

  11. Samollow PB, Perez G, Kammerer CM, Finegold D, Zwartjes PW, Havill LM, et al. Genetic and environmental influences on thyroid hormone variation in Mexican Americans. J Clin Endocrinol Metab. 2004;89:3276–84.

    Article  CAS  PubMed  Google Scholar 

  12. Nielsen TR, Appel EV, Svendstrup M, Ohrt JD, Dahl M, Fonvig CE, et al. A genome-wide association study of thyroid stimulating hormone and free thyroxine in Danish children and adolescents. PLoS One. 2017;12:e0174204.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Porcu E, Medici M, Pistis G, Volpato CB, Wilson SG, Cappola AR, et al. A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function. PLoS Genet. 2013;9:e1003266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Rudan I, Marušić A, Janković S, Rotim K, Boban M, Lauc G, et al. “10 001 Dalmatians:” Croatia launches its national biobank. Croat Med J. 2009;50:4–6.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Matana A, Brdar D, Torlak V, Boutin T, Popović M, Gunjača I, et al. Genome-wide meta-analysis identifies novel loci associated with parathyroid hormone level. Mol Med. 2018;24:15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Matana A, Popovic M, Boutin T, Torlak V, Brdar D, Gunjaca I, et al. Genome-wide meta-analysis identifies novel gender specific loci associated with thyroid antibodies level in Croatians. Genomics. 2018;18:30242–8.

  17. Reinehr T, Andler W. Thyroid hormones before and after weight loss in obesity. Arch Dis Child. 2002;87:320–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Aulchenko YS, Ripke S, Isaacs A, van Duijn CM. GenABEL: an R library for genome-wide association analysis. Bioinformatics. 2007;23:1294–6.

    Article  CAS  PubMed  Google Scholar 

  19. Marchini J, Howie B, Myers S, McVean G, Donnelly P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet. 2007;39:906–13.

    Article  CAS  PubMed  Google Scholar 

  20. Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010;26:2190–1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP, et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics. 2010;26:2336–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ruffier M, Kähäri A, Komorowska M, Keenan S, Laird M, Longden I, et al. Ensembl core software resources: storage and programmatic access for DNA sequence and genome annotation. Database. 2017;2017:bax020.

    Article  PubMed Central  CAS  Google Scholar 

  23. Turner SD. qqman: an R package for visualizing GWAS results using Q–Q and Manhattan plots. J Open Source Softw. 2014;3:731.

  24. Koepsell H. The SLC22 family with transporters of organic cations, anions and zwitterions. Mol Asp Med. 2013;34:413–35.

    Article  CAS  Google Scholar 

  25. Shin HJ, Anzai N, Enomoto A, He X, Kim DK, Endou H, et al. Novel liver-specific organic anion transporter OAT7 that operates the exchange of sulfate conjugates for short chain fatty acid butyrate. Hepatology. 2007;45:1046–55.

    Article  CAS  PubMed  Google Scholar 

  26. Schweizer U, Johannes J, Bayer D, Braun D. Structure and function of thyroid hormone plasma membrane transporters. Eur Thyroid J. 2014;3:143–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bernal J, Guadano-Ferraz A, Morte B. Thyroid hormone transporters—functions and clinical implications. Nat Rev. 2015;11:406–17.

    CAS  Google Scholar 

  28. Visser WE, Friesema EC, Visser TJ. Minireview: thyroid hormone transporters: the knowns and the unknowns. Mol Endocrinol. 2011;25:1–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Roth M, Obaidat A, Hagenbuch B. OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies. Br J Pharmacol. 2012;165:1260–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hsiang B, Zhu Y, Wang Z, Wu Y, Sasseville V, Yang WP, et al. A novel human hepatic organic anion transporting polypeptide (OATP2). Identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters. J Biol Chem. 1999;274:37161–8.

    Article  CAS  PubMed  Google Scholar 

  31. Konig J, Cui Y, Nies AT, Keppler D. A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane. Am J Physiol Gastrointest Liver Physiol. 2000;278:G156–64.

    Article  CAS  PubMed  Google Scholar 

  32. Fujiwara K, Adachi H, Nishio T, Unno M, Tokui T, Okabe M, et al. Identification of thyroid hormone transporters in humans: different molecules are involved in a tissue-specific manner. Endocrinology. 2001;142:2005–12.

    Article  CAS  PubMed  Google Scholar 

  33. Kullak-Ublick GA, Ismair MG, Stieger B, Landmann L, Huber R, Pizzagalli F, et al. Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology. 2001;120:525–33.

    Article  CAS  PubMed  Google Scholar 

  34. van der Deure WM, Peeters RP, Visser TJ. Molecular aspects of thyroid hormone transporters, including MCT8, MCT10, and OATPs, and the effects of genetic variation in these transporters. J Mol Endocrinol. 2010;44:1–11.

    Article  PubMed  CAS  Google Scholar 

  35. Pizzagalli F, Varga Z, Huber RD, Folkers G, Meier PJ, St-Pierre MV. Identification of steroid sulfate transport processes in the human mammary gland. J Clin Endocrinol Metab. 2003;88:3902–12.

    Article  CAS  PubMed  Google Scholar 

  36. van der Deure WM, Hansen PS, Peeters RP, Kyvik KO, Friesema ECH, Hegedüs L, et al. Thyroid hormone transport and metabolism by organic anion transporter 1C1 and consequences of genetic variation. Endocrinology. 2008;149:5307–14.

    Article  PubMed  CAS  Google Scholar 

  37. van der Deure WM, Friesema ECH, de Jong FJ, de Rijke YB, de Jong FH, Uitterlinden AG, et al. Organic anion transporter 1B1: an important factor in hepatic thyroid hormone and estrogen transport and metabolism. Endocrinology. 2008;149:4695–701.

    Article  PubMed  CAS  Google Scholar 

  38. Roef GL, Rietzschel ER, De Meyer T, Bekaert S, De Buyzere ML, Van daele C, et al. Associations between single nucleotide polymorphisms in thyroid hormone transporter genes (MCT8, MCT10 and OATP1C1) and circulating thyroid hormones. Clin Chim Acta. 2013;425:227–32.

    Article  CAS  PubMed  Google Scholar 

  39. Lago-Leston R, Iglesias MJ, San-Jose E, Areal C, Eiras A, Araujo-Vilar D, et al. Prevalence and functional analysis of the S107P polymorphism (rs6647476) of the monocarboxylate transporter 8 (SLC16A2) gene in the male population of north-west Spain (Galicia). Clin Endocrinol. 2009;70:636–43.

    Article  CAS  Google Scholar 

  40. Jacobsson JA, Haitina T, Lindblom J, Fredriksson R. Identification of six putative human transporters with structural similarity to the drug transporter SLC22 family. Genomics. 2007;90:595–609.

    Article  CAS  PubMed  Google Scholar 

  41. Nigam SK, Bush KT, Martovetsky G, Ahn S-Y, Liu HC, Richard E, et al. The organic anion transporter (OAT) family: a systems biology perspective. Physiol Rev. 2015;95:83–123.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Sun W, Wu RR, van Poelje PD, Erion MD. Isolation of a family of organic anion transporters from human liver and kidney. Biochem Biophys Res Commun. 2001;283:417–22.

    Article  CAS  PubMed  Google Scholar 

  43. Volk C. OCTs, OATs, and OCTNs: structure and function of the polyspecific organic ion transporters of the SLC22 family. Wiley Interdiscip Rev: Membr Transp Signal. 2014;3:1–13.

    Article  CAS  Google Scholar 

  44. Ruth KS, Campbell PJ, Chew S, Lim EM, Hadlow N, Stuckey BG, et al. Genome-wide association study with 1000 genomes imputation identifies signals for nine sex hormone-related phenotypes. Eur J Hum Genet. 2016;24:284–90.

    Article  CAS  PubMed  Google Scholar 

  45. Zhang X, Li D, Li M, Ye M, Ding L, Cai H, et al. MicroRNA‐146a targets PRKCE to modulate papillary thyroid tumor development. Int J Cancer. 2014;134:257–67.

    Article  PubMed  CAS  Google Scholar 

  46. Li X, Thyssen G, Beliakoff J, Sun Z. The novel PIAS-like protein hZimp10 enhances Smad transcriptional activity. J Biol Chem. 2006;281:23748–56.

    Article  CAS  PubMed  Google Scholar 

  47. Tuccilli C, Baldini E, Sorrenti S, Di Gioia C, Bosco D, Ascoli V, et al. Papillary thyroid cancer is characterized by altered expression of genes involved in the sumoylation process. J Biol Regul Homeost Agents. 2015;29:655–62.

    CAS  PubMed  Google Scholar 

  48. Gerondopoulos A, Langemeyer L, Liang JR, Linford A, Barr FA. BLOC-3 mutated in Hermansky–Pudlak syndrome is a Rab32/38 guanine nucleotide exchange factor. Curr Biol. 2012;22:2135–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Seto S, Tsujimura K, Koide Y. Rab GTPases regulating phagosome maturation are differentially recruited to mycobacterial phagosomes. Traffic. 2011;12:407–20.

    Article  CAS  PubMed  Google Scholar 

  50. Takeda S, Fujiwara T, Shimizu F, Kawai A, Shinomiya K, Okuno S, et al. Isolation and mapping of karyopherin alpha 3 (KPNA3), a human gene that is highly homologous to genes encoding Xenopus importin, yeast SRP1 and human RCH1. Cytogenet Cell Genet. 1997;76:87–93.

    Article  CAS  PubMed  Google Scholar 

Download references


The Croatian Science Foundation funded this work under the project “Identification of new genetic loci implicated in the regulation of thyroid and parathyroid function” (Grant 1498). The “10 001 Dalmatians” project was funded by the Medical Research Council UK, The Croatian Ministry of Science, Education and Sports (Grant 216-1080315-0302), and the Croatian Science Foundation (Grant 8875).

Author information

Authors and Affiliations


Corresponding author

Correspondence to Ivana Gunjača.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Gunjača, I., Matana, A., Boutin, T. et al. Genome-wide association meta-analysis for total thyroid hormone levels in Croatian population. J Hum Genet 64, 473–480 (2019).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


Quick links