Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation

Nat Commun. 2018 Oct 26;9(1):4455. doi: 10.1038/s41467-018-06356-1.

Abstract

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

Publication types

  • Meta-Analysis

MeSH terms

  • 2-Aminoadipate Transaminase / genetics
  • 2-Aminoadipate Transaminase / metabolism*
  • Animals
  • Biological Transport
  • COS Cells
  • Chlorocebus aethiops
  • European Continental Ancestry Group
  • Gene Expression Regulation / genetics*
  • Genome-Wide Association Study
  • Humans
  • Hyperthyroidism / genetics
  • Hyperthyroidism / physiopathology
  • Hypothyroidism / genetics
  • Hypothyroidism / physiopathology
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Sodium-Phosphate Cotransporter Proteins, Type I / genetics
  • Sodium-Phosphate Cotransporter Proteins, Type I / metabolism*
  • Thyroid Gland / metabolism
  • Thyroid Gland / physiopathology
  • Thyroid Hormones / genetics*
  • Thyroid Hormones / metabolism
  • Thyrotropin / metabolism*

Substances

  • SLC17A4 protein, human
  • Sodium-Phosphate Cotransporter Proteins, Type I
  • Thyroid Hormones
  • Thyrotropin
  • 2-Aminoadipate Transaminase