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The effects of common genetic variation in 96 genes involved in thyroid hormone regulation on TSH and FT4 concentrations

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DOI

  • Rosalie B T M Sterenborg, Radboud University Medical Center
  • ,
  • Tessel E Galesloot, Radboud University Medical Center
  • ,
  • Alexander Teumer, Paediatric Haematology-Oncology Department, University Medicine Greifswald, Greifswald, Germany.
  • ,
  • Romana T Netea-Maier, Radboud University Medical Center
  • ,
  • Doug Speed
  • Marcel E Meima, Erasmus University Medical Center Cancer Institute, Department of Obstetrics and Gynaecology, Erasmus University Medical Center.
  • ,
  • W Edward Visser, Erasmus University Medical Center Cancer Institute, Department of Obstetrics and Gynaecology, Erasmus University Medical Center.
  • ,
  • Johannes W A Smit, Radboud University Medical Center
  • ,
  • Robin P Peeters, Erasmus University Medical Center Cancer Institute, Department of Obstetrics and Gynaecology, Erasmus University Medical Center.
  • ,
  • Marco Medici, Radboud University Medical Center

OBJECTIVE: While most of the variation in thyroid function is determined by genetic factors, single nucleotide polymorphisms (SNPs) identified via genome-wide association analyses have only explained ~5-9% of this variance so far. Most SNPs were in or nearby genes with no known role in thyroid hormone (TH) regulation. Therefore, we performed a large-scale candidate gene study investigating the effect of common genetic variation in established TH regulating genes on serum TSH and FT4 concentrations.

METHODS: SNPs in or within 10kb of 96 TH regulating genes were included (30,031 TSH SNPs, and 29,962 FT4 SNPs). Associations were studied in 54,288 individuals from the ThyroidOmics Consortium. Linkage disequilibrium-based clumping was used to identify independently associated SNPs. SNP-based explained variances were calculated using SumHer software.

RESULTS: We identified 23 novel TSH associated SNPs in predominantly hypothalamic-pituitary-thyroid axis genes and 25 novel FT4 associated SNPs in mainly peripheral metabolism and transport genes. Genome-wide SNP variation explained ~21% (SD 1.7) of the total variation in both TSH and FT4 concentrations, whereas SNPs in the 96 TH regulating genes explained 1.9-2.6% (SD 0.4).

CONCLUSION: Here we report the largest candidate gene analysis on thyroid function, resulting in a substantial increase in the number of genetic variants determining TSH and FT4 concentrations. Interestingly, these candidate gene SNPs explain only a minor part of the variation in TSH and FT4 concentrations, which substantiates the need for large genetic studies including common and rare variants to unravel novel, yet unknown, pathways in TH regulation.

OriginalsprogEngelsk
TidsskriftThe Journal of Clinical Endocrinology & Metabolism
Vol/bind107
Nummer6
Sider (fra-til)e2276-e2283
Antal sider8
ISSN0021-972X
DOI
StatusUdgivet - jun. 2022

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