Whole-genome sequence-based analysis of thyroid function.

Peter N Taylor,J Brent Richards,Dawn Muddyman,Michela Traglia,Yasin Memari,Daniela Toniolo,Klaudia Walter,Wolfram Woltersdorf,Jordana T Bell,Andrew D Johnson,Gabriela L Surdulescu,Michael R Barnes,Benjamin H Mullin,Scott G Wilson,Frank Dudbridge,Jennie Hui,Elin Grundberg,David Schlessinger,John P Walsh,Francesco Cucca,Shane Mccarthy,Serena Sanna,Vincenzo Forgetta,Silvia Naitza,Nicholas J Timpson,Eleonora Porcu,Vijay Panicker,Hashem A Shihab,Jie Huang,Richard Durbin,Eleftheria Zeggini,Shelby Chew,Hou-Feng Zheng,Wei Yuan,Petr Danecek,Suzanne J Brown,Nicole Soranzo,Pimphen Charoen,George Davey Smith,Goncalo R Abeçasis ,Caroline L Relton ,Tom R Gaunt ,Purdey J Campbell ,Tim D Spector ,Celia M.t Greenwood ,Josine L Min ,John Perry ,John Beilby ,Colin Dayan ,Ee Mun Lim

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.

Highlights

Normal thyroid function is essential for health, but its genetic architecture remains poorly understood
Genome-wide association studies (GWAS) identified common variants associated with TSH and FT47–9; in a recent HapMap-based meta-analysis[10], we identified 19 loci associated with TSH and 4 with FT4
A greater understanding of the relative proportion of thyroid function explained by common variants is possible with the availability of whole-genome sequencing (WGS) and this is essential to refine future research and analysis strategies when appraising the genetic architecture of thyroid function

Summary

Introduction

Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Rarer variants within the minor allele frequency (MAF) spectrum might account for a substantial proportion of the missing heritability as has been proposed for many polygenic traits[11] These variants, individually rare (MAFo1%), are collectively frequent, and while their effects may be insufficient to produce clear familial aggregation, effect sizes for individual variants are potentially much greater than those observed for common variants. In individuals with WGS data, we perform sequence kernel-based association testing (SKAT) analysis to identify regions of the genome where rare variants have the strongest association with thyroid function and identify a novel locus associated with FT4. Larger meta-analyses of studies with WGS data are required to identify additional common and rare variants, which may explain the missing heritability of thyroid function

Methods

Results

Conclusion