Whole-genome sequence-based analysis of thyroid function

Nat Commun. 2015 Mar 6:6:5681. doi: 10.1038/ncomms6681.

Abstract

Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N=2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF≥1%) associated with TSH and FT4 (N=16,335). For TSH, we identify a novel variant in SYN2 (MAF=23.5%, P=6.15 × 10(-9)) and a new independent variant in PDE8B (MAF=10.4%, P=5.94 × 10(-14)). For FT4, we report a low-frequency variant near B4GALT6/SLC25A52 (MAF=3.2%, P=1.27 × 10(-9)) tagging a rare TTR variant (MAF=0.4%, P=2.14 × 10(-11)). All common variants explain ≥20% of the variance in TSH and FT4. Analysis of rare variants (MAF<1%) using sequence kernel association testing reveals a novel association with FT4 in NRG1. Our results demonstrate that increased coverage in whole-genome sequence association studies identifies novel variants associated with thyroid function.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / genetics
  • 3',5'-Cyclic-AMP Phosphodiesterases / metabolism
  • Cohort Studies
  • DNA Methylation / genetics
  • Genetic Association Studies
  • Genomics / methods
  • Humans
  • Synapsins / genetics
  • Synapsins / metabolism*
  • Thyroid Gland / metabolism
  • Thyroid Gland / physiology*
  • Thyrotropin / genetics
  • Thyrotropin / metabolism*
  • Thyroxine / genetics
  • Thyroxine / metabolism*
  • United Kingdom

Substances

  • SYN2 protein, human
  • Synapsins
  • Thyrotropin
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • PDE8B protein, human
  • Thyroxine