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Whole-genome sequence-based analysis of thyroid function

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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 Grundberg & 30 more Andrew 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, UK0K Consortium

Original languageEnglish
Article number5681
Number of pages10
JournalNature Communications
Accepted/In press27 Oct 2014
Published6 Mar 2015


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    ncomms6681.pdf, 1.15 MB, application/pdf

    Uploaded date:08 Jan 2016

    Version:Final published version

    Licence:CC BY

King's Authors


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.

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