A genetic risk score for thyroid peroxidase antibodies associates with clinical thyroid disease in community-based populations

J Clin Endocrinol Metab. 2015 May;100(5):E799-807. doi: 10.1210/jc.2014-4352. Epub 2015 Feb 26.


Context: Antibodies against thyroid peroxidase (TPOAbs) are detected in 90% of all patients with Hashimoto thyroiditis, the most common cause of hypothyroidism. Hypothyroidism is associated with a range of adverse outcomes. The current knowledge of its genetic underpinnings is limited.

Objective: The purpose of this study was to identify novel genetic variants associated with TPOAb concentrations and positivity using genome-wide association data and to characterize their association with thyroid function and disease.

Design, setting, and participants: We studied European ancestry participants of 3 independent prospective population-based studies: Atherosclerosis Risk In Communities study (n = 7524), Study of Health in Pomerania (n = 3803), and Study of Health in Pomerania-TREND (n = 887).

Exposure: Single nucleotide polymorphisms (SNPs), individually and combined into a genetic risk score (GRS), were examined.

Main outcomes: The main outcomes were TPOAb concentrations and positivity, thyroid hormone concentrations (TSH, free T4), and clinical thyroid diseases (subclinical and overt hypothyroidism and goiter).

Results: Significantly associated single nucleotide polymorphisms (P < 5 · 10(-8)) mapped into 4 genomic regions not previously implicated for TPOAbs (RERE, extended HLA region) and into 5 previously described loci. A higher Genetic Risk Score (GRS) based on these 9 SNPs showed strong and graded associations with higher TPOAb, TSH, and lower free T4 concentrations (P < .001). Compared with individuals in the lowest GRS quartile, those in the highest quartile had 1.80-fold higher odds of subclinical hypothyroidism (95% confidence interval, 1.27-2.55) and 1.89-fold higher odds of overt hypothyroidism (95% confidence interval, 1.24-2.87).

Conclusion: The identification of 4 novel genetic loci associated with TPOAb concentrations and positivity gives further insight into the genetic underpinnings of hypothyroidism. A GRS showed strong and graded associations with markers of thyroid function and disease in independent population-based studies.

Publication types

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

MeSH terms

  • Female
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Humans
  • Iodide Peroxidase / immunology*
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Prospective Studies
  • Risk Factors
  • Thyroid Diseases / blood
  • Thyroid Diseases / genetics*
  • Thyroid Diseases / immunology*
  • Thyrotropin / blood
  • Thyroxine / blood


  • Thyrotropin
  • Iodide Peroxidase
  • Thyroxine