GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer

Nat Commun. 2020 Aug 7;11(1):3981. doi: 10.1038/s41467-020-17718-z.


Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. To better understand the genetic contribution to TSH levels, we conduct a GWAS meta-analysis at 22.4 million genetic markers in up to 119,715 individuals and identify 74 genome-wide significant loci for TSH, of which 28 are previously unreported. Functional experiments show that the thyroglobulin protein-altering variants P118L and G67S impact thyroglobulin secretion. Phenome-wide association analysis in the UK Biobank demonstrates the pleiotropic effects of TSH-associated variants and a polygenic score for higher TSH levels is associated with a reduced risk of thyroid cancer in the UK Biobank and three other independent studies. Two-sample Mendelian randomization using TSH index variants as instrumental variables suggests a protective effect of higher TSH levels (indicating lower thyroid function) on risk of thyroid cancer and goiter. Our findings highlight the pleiotropic effects of TSH-associated variants on thyroid function and growth of malignant and benign thyroid tumors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Genetic Loci
  • Genetic Pleiotropy*
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study*
  • Goiter / genetics
  • Humans
  • Mendelian Randomization Analysis
  • Multifactorial Inheritance / genetics
  • Mutation, Missense / genetics
  • Phenotype
  • Physical Chromosome Mapping
  • Prevalence
  • Risk Factors
  • Thyroglobulin / genetics
  • Thyroid Neoplasms / epidemiology
  • Thyroid Neoplasms / genetics*
  • Thyrotropin / genetics*


  • Thyrotropin
  • Thyroglobulin