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Genome-wide meta-analysis identifies novel loci associated with free triiodothyronine and thyroid-stimulating hormone

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Abstract

Purpose

Thyroid hormones are essential for the normal function of almost all human tissues, and have critical roles in metabolism, differentiation and growth. Free triiodothyronine (fT3), free thyroxine (fT4) and thyroid-stimulating hormone (TSH) levels are under strong genetic influence; however, most of the heritability is yet unexplained.

Methods

In order to identify novel loci associated with fT3, fT4 and TSH serum levels we performed a genome-wide meta-analysis of 7 411 206 polymorphisms in up to 1731 euthyroid individuals from three Croatian cohorts from Dalmatia region: two genetically isolated island populations and one mainland population. Additionally, we also performed a bivariate analysis of fT3 and fT4 levels.

Results

The EPHB2 gene variant rs67142165 reached genome-wide significance for association with fT3 plasma levels (P = 9.27 × 10−9) and its significance was confirmed in bivariate analysis (P = 9.72 × 10−9). We also found a genome-wide significant association for variant rs13037502 upstream of the PTPN1 gene and TSH plasma levels (P = 1.67 × 10−8).

Conclusion

We identified a first genome-wide significant variant associated with fT3 plasma levels, as well as a novel locus associated with TSH plasma levels. These findings are biologically relevant and enrich our knowledge about the genetic basis of pituitary-thyroid axis function.

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Acknowledgements

The Croatian Science Foundation funded this work under the project “Identification of new genetic loci implicated in regulation of thyroid and parathyroid function” (Grant No. 1498). The “10 001 Dalmatians” project was funded by grants from the Medical Research Council (UK), European Commission Framework 6 project EUROSPAN (Contract No. LSHG-CT-2006-018947), the Republic of Croatia Ministry of Science, Education and Sports research Grant (216-1080315-0302), the Croatian Science Foundation (Grant 8875), CEKOM (Ministry of Economy, Entrepreneurship and Crafts) and the Research Centre of Excellence in Personalized Medicine (Ministry of Science and Education). We would like to thank all participants of this study and acknowledge invaluable support of the local teams in Zagreb and Split, especially that of the Institute for Anthropological Research, Zagreb, Croatia.

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  1. Marijana Popović and Antonela Matana equally contributed to the paper.

Authors and Affiliations

  1. Department of Medical Biology, University of Split, School of Medicine, Šoltanska 2, Split, Croatia

    M. Popović, A. Matana, I. Gunjača, D. Kaličanin, V. Boraska Perica, M. Barbalić & T. Zemunik

  2. Department of Nuclear Medicine, University Hospital Split, Spinčićeva 1, Split, Croatia

    V. Torlak, D. Brdar & A. Punda

  3. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, United Kingdom

    T. Boutin & C. Hayward

  4. Department of Public Health, University of Split, School of Medicine Split, Šoltanska 2, Split, Croatia

    I. Kolčić & O. Polašek

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Popović, M., Matana, A., Torlak, V. et al. Genome-wide meta-analysis identifies novel loci associated with free triiodothyronine and thyroid-stimulating hormone. J Endocrinol Invest 42, 1171–1180 (2019). https://doi.org/10.1007/s40618-019-01030-9

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