Whole-genome sequence-based analysis of thyroid function

Peter N Taylor, Eleonora Porcu, Shelby Chew, Purdey J Campbell, Michela Traglia, Suzanne J Brown, Benjamin H Mullin, Hashem A Shihab, Josine Min, Klaudia Walter, Yasin Memari, Jie Huang, Michael R Barnes, John P Beilby, Pimphen Charoen, Petr Danecek, Frank Dudbridge, Vincenzo Forgetta, Celia Greenwood, Elin GrundbergAndrew D Johnson, Jennie Hui, Ee M Lim, Shane McCarthy, Dawn Muddyman, Vijay Panicker, John R B Perry, Jordana T Bell, Wei Yuan, Caroline Relton, Tom Gaunt, David Schlessinger, Goncalo Abecasis, Francesco Cucca, Gabriela L Surdulescu, Wolfram Woltersdorf, Eleftheria Zeggini, Hou-Feng Zheng, Daniela Toniolo, Colin M Dayan, Silvia Naitza, John P Walsh, Tim Spector, George Davey Smith, Richard Durbin, J Brent Richards, Serena Sanna, Nicole Soranzo, Nicholas J Timpson, Scott G Wilson, UK0K Consortium

Research output: Contribution to journalArticle (Academic Journal)peer-review

47 Citations (Scopus)

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.

Original languageEnglish
Article number5681 (2015)
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 6 Mar 2015

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