Whole-genome sequence-based analysis of thyroid function
Authors: Taylor Peter N. , Porcu Eleonora , Chew Shelby , Campbell Purdey J. , Traglia Michela , Brown Suzanne J. , Mullin Benjamin H. , Shihab Hashem A. , Min Josine , Walter Klaudia , Memari Yasin , Huang Jie , Barnes Michael R. , Beilby John P. , Charoen Pimphen , Danecek Petr , Dudbridge Frank , Forgetta Vincenzo , Greenwood Celia , Grundberg Elin , Johnson Andrew D. , Hui Jennie , Lim Ee M. , McCarthy Shane , Muddyman Dawn , Panicker Vijay , Perry John R.B. , Bell Jordana T. , Yuan Wei , Relton Caroline , Gaunt Tom , Schlessinger David , Abecasis Goncalo , Cucca Francesco , Surdulescu Gabriela L. , Woltersdorf Wolfram , Zeggini Eleftheria , Zheng Hou-Feng , Toniolo Daniela , Dayan Colin M. , Naitza Silvia , Walsh John P. , Spector Tim , Davey Smith George , Durbin Richard , Brent Richards J. , Sanna Serena , Soranzo Nicole , Timpson Nicholas J. , Wilson Scott G. ,   The UK10K Consortium, Turki Saeed Al , Anderson Carl , Anney Richard , Antony Dinu , Artigas Maria Soler , Ayub Muhammad , Balasubramaniam Senduran , Barrett Jeffrey C. , Barroso Inês , Beales Phil , Bentham Jamie , Bhattacharya Shoumo , Birney Ewan , Blackwood Douglas , Bobrow Martin , Bochukova Elena , Bolton Patrick , Bounds Rebecca , Boustred Chris , Breen Gerome , Calissano Mattia , Carss Keren , Chatterjee Krishna , Chen Lu , Ciampi Antonio , Cirak Sebhattin , Clapham Peter , Clement Gail , Coates Guy , Collier David , Cosgrove Catherine , Cox Tony , Craddock Nick , Crooks Lucy , Curran Sarah , Curtis David , Daly Allan , Day-Williams Aaron , Day Ian N.M. , Down Thomas , Du Yuanping , Dunham Ian , Edkins Sarah , Ellis Peter , Evans David , Faroogi Sadaf , Fatemifar Ghazaleh , Fitzpatrick David R. , Flicek Paul , Flyod James , Foley A. Reghan , Franklin Christopher S. , Futema Marta , Gallagher Louise , Geihs Matthias , Geschwind Daniel , Griffin Heather , Grozeva Detelina , Guo Xueqin , Guo Xiaosen , Gurling Hugh , Hart Deborah , Hendricks Audrey , Holmans Peter , Howie Bryan , Huang Liren , Hubbard Tim , Humphries Steve E. , Hurles Matthew E. , Hysi Pirro , Jackson David K. , Jamshidi Yalda , Jing Tian , Joyce Chris , Kaye Jane , Keane Thomas , Keogh Julia , Kemp John , Kennedy Karen , Kolb-Kokocinski Anja , Lachance Genevieve , Langford Cordelia , Lawson Daniel , Lee Irene , Lek Monkol , Liang Jieqin , Lin Hong , Li Rui , Li Yingrui , Liu Ryan , Lönnqvist Jouko , Lopes Margarida , Iotchkova Valentina , MacArthur Daniel , Marchini Jonathan , Maslen John , Massimo Mangino , Mathieson Iain , Marenne Gaëlle , McGuffin Peter , McIntosh Andrew , McKechanie Andrew G. , McQuillin Andrew , Metrustry Sarah , Mitchison Hannah , Moayyeri Alireza , Morris James , Muntoni Francesco , Northstone Kate , O'Donnovan Michael , Onoufriadis Alexandros , O'Rahilly Stephen , Oualkacha Karim , Owen Michael J. , Palotie Aarno , Panoutsopoulou Kalliope , Parker Victoria , Parr Jeremy R. , Paternoster Lavinia , Paunio Tiina , Payne Felicity , Pietilainen Olli , Plagnol Vincent , Quaye Lydia , Quail Michael A. , Raymond Lucy , Rehnström Karola , Ring Susan , Ritchie Graham R.S. , Roberts Nicola , Savage David B. , Scambler Peter , Schiffels Stephen , Schmidts Miriam , Schoenmakers Nadia , Semple Robert K. , Serra Eva , Sharp Sally I. , Shin So-Youn , Skuse David , Small Kerrin , Southam Lorraine , Spasic-Boskovic Olivera , Clair David St , Stalker Jim , Stevens Elizabeth , Pourcian Beate St , Sun Jianping , Suvisaari Jaana , Tachmazidou Ionna , Tobin Martin D. , Valdes Ana , Kogelenberg Margriet Van , Vijayarangakannan Parthiban , Visscher Peter M. , Wain Louise V. , Walters James T.R. , Wang Guangbiao , Wang Jun , Wang Yu , Ward Kirsten , Wheeler Elanor , Whyte Tamieka , Williams Hywel , Williamson Kathleen A. , Wilson Crispian , Wong Kim , Xu ChangJiang , Yang Jian , Zhang Fend , Zhang Pingbo 
Published: March 2015

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.