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Genome-wide association analysis suggests novel loci for Hashimoto’s thyroiditis

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Abstract

Purpose

Hashimoto’s thyroiditis (HT) is the most common form of autoimmune thyroid diseases. Current knowledge of HT genetics is limited, and not a single genome-wide association study (GWAS) focusing exclusively on HT has been performed to date. In order to decipher genetic determinants of HT, we performed the first GWAS followed by replication in a total of 1443 individuals from Croatia.

Methods

We performed association analysis in a discovery cohort comprising 405 cases and 433 controls. We followed up 13 independent signals (P < 10−5) in 303 cases and 302 controls from two replication cohorts and then meta-analyzed results across discovery and replication datasets.

Results

We identified three variants suggestively associated with HT: rs12944194 located 206 kb from SDK2 (P = 1.8 × 10−6), rs75201096 inside GNA14 (P = 2.41 × 10−5) and rs791903 inside IP6K3 (P = 3.16 × 10−5). Genetic risk score (GRS), calculated using risk alleles of these loci, accounted for 4.82% of the total HT variance, and individuals from the top GRS quartile had 2.76 times higher odds for HT than individuals from the lowest GRS quartile.

Conclusions

Although discovered loci are implicated with susceptibility to HT for the first time, genomic regions harboring these loci exhibit good biological candidacy due to involvement in the regulation of the thyroid function and autoimmunity. Additionally, we observe genetic overlap between HT and several related traits, such as hypothyroidism, Graves’ disease and TPOAb. Our study adds a new knowledge of underlying HT genetics and sets a firm basis for further research.

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Funding

Formation of HT Biobank and genome-wide genotyping of patients with HT was supported by the Croatian Science Foundation (Grant no. 4950). The “10 001 Dalmatians” project was supported by the MRC Human Genetics Unit, The Croatian Ministry of Science, Education and Sports (Grant 216-1080315-0302), the European Union framework program 6 EUROSPAN project (Contract no. LSHG-CT-2006-018947), EU FP7 BBMRI-LPC (Biobanking and biomolecular resources research infrastructure—Large prospective cohort, Contract 313010) and the Croatian Science Foundation (Grant nos. 8875 and 1498).

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Authors and Affiliations

  1. Department of Medical Biology, School of Medicine, University of Split, Šoltanska 2, 21000, Split, Croatia

    L. Brčić, D. Kaličanin, I. Gunjača, T. Zemunik, M. Barbalić & V. Boraska Perica

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

    A. Barić, S. Gračan, M. Brekalo, V. Torlak Lovrić, M. Radman & A. Punda

  3. Department of Medical Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine, University of Osijek, Osijek, Croatia

    S. Tokić & L. Glavaš-Obrovac

  4. Department of Pediatrics, University Hospital Split, Split, Croatia

    V. Škrabić

  5. Department of Public Health, School of Medicine, University of Split, Split, Croatia

    A. Miljković, I. Kolčić & O. Polašek

  6. Department of Nuclear Medicine and Oncology, Faculty of Medicine, University of Osijek, Osijek, Croatia

    M. Štefanić

  7. Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    D. Lessel

Authors
  1. L. Brčić
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  2. A. Barić
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  8. S. Tokić
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  20. V. Boraska Perica
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Corresponding author

Correspondence to V. Boraska Perica.

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On behalf of all authors, the corresponding author states that there is no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Study was approved by two separate Ethics Committees: the University of Split, School of Medicine (Classification no. 003-08/14-03/0001; Registry no. 2181-198-03-04-14-0028) and University Hospital Split (Classification no. 530-02/13-01/11; Registry no. 2181-147-01/06/J.B.-14-2).

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Brčić, L., Barić, A., Gračan, S. et al. Genome-wide association analysis suggests novel loci for Hashimoto’s thyroiditis. J Endocrinol Invest 42, 567–576 (2019). https://doi.org/10.1007/s40618-018-0955-4

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  • DOI: https://doi.org/10.1007/s40618-018-0955-4

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